Review ArticleReviews and Commentaries

Stimulators of Soluble Guanylyl Cyclase: Future Clinical Indications

Bobby D. Nossaman and Philip J. Kadowitz
Ochsner Journal March 2013, 13 (1) 147-156;

ABSTRACT

Background Soluble guanylyl cyclase (sGC) is expressed in mammalian cytoplasm and catalyzes the synthesis of the second messenger guanosine 3′,5′-monophosphate (cGMP) involved in important physiological functions such as relaxation of vascular smooth muscle, inhibition of platelet aggregation, modulation of inflammation, and control of vascular permeability. sGC is the intracellular receptor for nitric oxide (NO) and the active moiety in traditional organic nitrate therapy, recently as an inhalant in the intensive care unit and experimentally in improving microcirculatory flow in shock. However, dysfunction of the heme moiety on sGC occurs in a number of cardiovascular diseases, which reduces NO effectiveness.

Methods In this review, we examine animal studies and early clinical trials on agents that can directly stimulate sGC and may have future clinical application in cardiovascular disease and in perioperative care.

Conclusions Animal and early clinical studies have shown that sGC stimulator agents have great promise for treating cardiopulmonary disorders and may also have a role in modulating the inflammatory response observed in perioperative care.

Keywords

INTRODUCTION

The receptor for nitric oxide (NO) in vascular smooth muscle is the heterodimetric enzyme, soluble guanylyl cyclase (sGC).1,2 However, NO binding to sGC requires a reduced (ferrous) heme moiety for activation of the enzyme.3,4 Activated sGC catalyzes formation of guanosine 3′,5′-monophosphate (cGMP) from guanosine triphosphate, and cGMP plays a major role in regulating vascular tone as well as inhibiting platelet aggregation, modulating inflammation, and controlling vascular permeability (Figure 1).5-9 The NO-sGC-cGMP pathway serves in important physiologic roles, but pathway signaling can be impaired by scavenging of NO by free radicals, uncoupling of NO synthase (NOS), removal or oxidation of the heme moiety of sGC, downregulation of sGC, and increased phosphodiesterase (PDE) activity, which reduces NO bioavailability (Figure 1).10 Cardiovascular diseases such as systemic and pulmonary hypertension, coronary artery disease, congestive heart failure (CHF), peripheral vascular disease, diabetes, and atherosclerosis and non-cardiovascular diseases such as sepsis are associated with impaired NO-sGC-cGMP signaling.11-14

Figure 1.
Figure 1.

NO-sGC-cGMP pathway. Agonists such as acetylcholine, bradykinin, and serotonin encourage the production of nitric oxide (NO) though activation of nitric oxide synthase (NOS). Organic nitrate therapy and inhaled NO can stimulate soluble guanylyl cyclase (sGC) when the heme moiety on sGC is in a reduced (ferrous) state. Novel non-NO-dependent sGC stimulators can increase the activity of sGC. Activated sGC stimulates production of cyclic guanosine 3′,5′-monophosphate (cGMP) that through downstream mechanisms elicit relaxation of vascular smooth muscle, inhibition of platelet aggregation, modulation of inflammation, and control of vascular permeability. Phosphodiesterases (PDEs) break down cGMP. Oxidation of the heme moiety in sGC from stress, aging, injury, and the development of tolerance from organic nitrates reduces sGC activation. PDEs break down cGMP, whereas PDE5 inhibitors prevent the breakdown of cGMP. (Adapted with permission from Boerrigter G, Burnett JC Jr. Nitric oxide-independent stimulation of soluble guanylate cyclase with BAY 41-2272 in cardiovascular disease. Cardiovasc Drug Rev. 2007 Spring;25(1):30-45.)

Perioperative injury produces marked microcirculatory alterations as a result of early systemic inflammatory responses and tissue hypoperfusion.15-19 Although goal-directed hemodynamic therapy may decrease the incidence of perioperative complications and hospital length of stay, optimal management continues to be debated.20-23 Recent investigations demonstrated that low-dose NO therapy improves microvascular perfusion following injury.24-27 However, a major limitation in the current use of organic nitrates is the development of acute tolerance.28-30 Agents that could improve bioavailability of NO in vascular diseases by sensitizing sGC are the focus of this review.

CURRENT ORGANIC NITRATE THERAPY

Glyceryl trinitrate (nitroglycerin; GTN) and amyl nitrite have been used in the treatment of angina pectoris and heart failure for more than 140 years.31,32 Today, commonly used NO donor agents—isosorbide dinitrate, isosorbide-5-mononitrate, and GTN—are effective in reducing ventricular preload.33-36 These agents also decrease pulmonary and systemic vascular resistances but higher doses than those needed for reducing ventricular preload are required.37-42

Studies have shown GTN bioactivation requires the presence of thiols or sulfhydryl-containing compounds.1,43-45 Repeated administration of GTN depletes sulfhydryls and quickly produces tolerance to GTN, limiting its use to episodic care.45-48 Chronic administration of organic nitrates does not improve mortality following acute myocardial infarction, and continuous administration of GTN has induced endothelial dysfunction.46,49,50 However, in microcirculation abnormalities observed in acute heart failure and sepsis, administration of GTN improves tissue perfusion.24,26,51 The development of agents that could stimulate sGC to endogenous NO (bioavailable NO) or to low levels of exogenous NO donors may provide a novel therapeutic in the management of microcirculation abnormalities.

STIMULATION OF sGC BY NON-NO COMPOUNDS

In the 1990s, investigators observed that a benzylindazole, YC-1, originally designed as an inhibitor of platelet aggregation (Figure 2), also increased intracellular cGMP concentrations by 10-fold. This finding stimulated research in sGC regulation.52,53 Subsequent studies showed that stimulation of sGC by YC-1 was NO independent and independent of biotransformation.54,55 The combination of sodium nitroprusside (SNP), an NO donor, with YC-1 was found to be synergistic.56 These findings suggested that non-NO-donor compounds that stimulate sGC could have a therapeutic role in cardiovascular disease when NO formation and bioavailability are impaired or when tolerance to NO donors has developed.56-62 Because YC-1 could not be formulated as an oral preparation, limiting its potential for chronic therapy, a series of pyrazolopyridinylpyrimidine derivatives based on the YC-1 structure (Figure 2) led to the next generation of sGC stimulators for study in animals and then in early clinical trials.57-59

Figure 2.
Figure 2.

Chemical structures of soluble guanylyl cyclase stimulators.

Animal Studies

CHF and Systemic Hypertension

The prevalence of CHF is increasing and despite medical therapy continues to be associated with high morbidity and mortality.63 In a canine model of CHF, BAY 41-2272 (Figure 2) reduced mean arterial pressure and pulmonary arterial pressure with increased cardiac output. Renal blood flow increased and glomerular filtration rate was maintained. Importantly, plasma renin activity, angiotensin II, or aldosterone levels did not significantly change.63 In a chronic low-NO model of systemic hypertension and CHF induced with chronic administration of the nonspecific NOS inhibitor N-nitro-L-arginine methyl ester (L-NAME), BAY 41-2272 cotreatment abolished the development of systemic hypertension and attenuated cardiac hypertrophy induced by NOS inhibition in the control group. Moreover, the sGC stimulator was devoid of tolerance development.64 In a low-NO genetic model of hypertension, the oral sGC stimulator, BAY 41-2272, lowered mean arterial pressure, demonstrated antiplatelet activity, and enhanced survival. Moreover, the sGC stimulator was devoid of tolerance.65 In anesthetized dogs, intravenous administration of BAY 41-8543 (Figure 2) produced dose-dependent decreases in blood pressure and myocardial oxygen consumption with increases in coronary blood flow and heart rate.66 In conscious, spontaneously hypertensive rats, dose-dependent and long-lasting (for nearly 24 hours) decreases in blood pressure with the sGC stimulator were observed with a 3 mg/kg dose. Moreover, tachyphylaxis after multiple dosages did not develop.66 In a low-NO, high-renin rat model of hypertension, coadministration of the sGC stimulator prevented increases in blood pressure induced by L-NAME, and renal protective effects were observed. Finally, administration of BAY 41-8543 prolonged bleeding times, reduced thrombosis formation, and reduced mortality in this study.66

The effect of BAY 41-2272 on cardiac remodeling and fibrosis was examined in a rat model of hypertension induced by suprarenal aortic constriction.67 Daily administration of the sGC stimulator for 14 days decreased collagen accumulation in the left ventricle and reduced angiotensin-converting enzyme messenger RNA (mRNA) and enzymatic activity.67 The sGC stimulator BAY 63-2521 (Riociguat) (Figure 2) was investigated in high- and low-renin rat models of hypertension.68 In hypertensive-transgenic rats treated with the NOS inhibitor L-NAME (high-renin model) and in rats with five-sixths nephrectomy (low-renin model), Riociguat treatment improved survival, as well as normalized blood pressure in both models of hypertension. In the high-renin model, Riociguat also reduced cardiac damage as suggested by lower atrial natriuretic peptide plasma levels, reduced relative left ventricular weights, and lower cardiac interstitial fibrosis. Riociguat also reduced renal damage as observed by lower plasma creatinine and urea levels, with less evidence of glomerulosclerosis and renal interstitial fibrosis. In the low-renin study, Riociguat reduced cardiac damage as indicated by lower atrial natriuretic peptide plasma levels, an observed decrease in relative left ventricular weights, smaller myocyte diameters and arterial media/lumen ratios, and reduced renal damage as suggested by improved creatinine clearance rates and decreased renal interstitial fibrosis.68 In a Dahl salt-sensitive rat model maintained on a high-salt diet for 14 weeks, hemodynamics, biomarkers of tissue remodeling and degeneration, and mortality were assessed with Riociguat (BAY 63-2521) in two dose regimens, 3 or 10 mg/kg/d.69 Daily administration of the sGC stimulator markedly attenuated development of systemic hypertension, improved systolic heart function, and increased survival rates from 33% to 85%. Histological examination of the heart and kidneys revealed that the sGC stimulator significantly reduced fibrotic tissue remodeling and degeneration. In the myocardium and renal cortex, mRNA expressions of the profibrotic biomarkers—tissue inhibitor of matrix metalloproteinase-1, osteopontin, and plasminogen activator inhibitor-1—were attenuated by administration of BAY 63-2521.69 These observations suggest that sGC stimulators would be beneficial in the treatment of cardiovascular disease such as CHF and systemic hypertension.

Pulmonary Hypertension

Pulmonary arterial hypertension is a rare progressive disorder and is often fatal within 3 years without treatment.70,71 Pulmonary hypertension is also often associated with other diseases (eg, portal hypertension, collagen vascular diseases, drug abuse, toxins, chronic thromboembolism, cancer, and right heart failure following cardiac and lung transplantation).72-76

In a chronic hypoxia-induced model of pulmonary hypertension, BAY 41-2272 (Figure 2) reduced right ventricular hypertrophy and pulmonary vascular remodeling.77 In an ovine fetal model of pulmonary hypertension, chronic infusion of BAY 41-2272 produced potent sustained decreases in pulmonary arterial pressure; however, with infusion at higher rates, systemic arterial pressure also decreased.78 In an acute model of pulmonary hypertension, inhalation of either BAY 41-2272 or BAY 41-8543 (Figure 2) in awake lambs produced selective pulmonary vasodilation. Moreover, BAY 41-8543 also enhanced the magnitude and prolonged the duration of the vasodilator response to inhaled NO.79,80 However, in contrast to the above findings, in an intact-chest rat model, intravenous administration of BAY 41-8543 during baseline or under controlled conditions produced small decreases in pulmonary arterial pressure, increases in cardiac output, and large dose-dependent decreases in systemic arterial pressure.81 When pulmonary and systemic arterial tone was elevated with the thromboxane receptor agonist U46619, BAY 41-8543 produced larger dose-dependent decreases in pulmonary and systemic arterial pressure.81 Analyses of the percent decreases in pulmonary and systemic arterial pressures in response to BAY 41-8543 were not different. These data suggested that the sGC stimulator had similar vasodilator activities in the pulmonary and systemic vascular beds in the intact-chest rat.81

In a second investigation of responses to BAY 41-8543 conducted in elevated tone conditions induced by the NOS inhibitor L-NAME, again pulmonary and systemic arterial pressures decreased following administration of the sGC stimulator. However, the vasodilator responses in L-NAME–treated animals caused by BAY 41-8543 were lower than the vasodilator responses caused by BAY 41-8543 in U46619-infused animals.81 A comparison of vasodilator responses to BAY 41-8543 at the same level of pulmonary arterial pressure indicated that the decreases in pulmonary arterial pressure in response to the sGC stimulator were reduced by more than 50% in L-NAME–treated animals.81 These findings suggest that responses to the sGC stimulator were NO independent and occurred in the absence of endogenous NO formation and that vasodilator responses to the sGC stimulator were present but markedly attenuated.81

Finally, the synergistic role of BAY 41-8543 with exogenous NO was examined in the intact-chest model with the NO donor SNP.81 Separate administrations of BAY 41-8543 and SNP produced significant decreases in pulmonary and systemic arterial pressures, but the administration of a small dose of the NO donor in the presence of BAY 41-8543 produced a significantly greater decrease in pulmonary and systemic arterial pressures than the sum of responses to either agent when administered alone.81 These results demonstrate that BAY 41-8543 can synergize with exogenous NO in mediating vasodilator responses. Overall, these findings suggest that these compounds have dual actions in that they can directly stimulate the native form of the enzyme and also render it more sensitive to endogenously produced NO or augment the action of NO donors.80,82 Hence, the use of an sGC stimulator alone or in combination with an NO donor could expand the usefulness of NO therapy in the intensive care unit.80-82

In an animal model of acute pulmonary hypertension induced by pulmonary embolism from the infusion of plastic microspheres, treatment with BAY 41-8543 produced a 2.2-fold increase in cardiac output and a significant reduction in right ventricular peak systolic pressure.83 Moreover, treatment with the sGC stimulator normalized oxygen saturation and serum lactate levels. Treatment with BAY 41-8543 also significantly reduced plasma free-hemoglobin content by 80%. These findings suggest that pharmacologic dilation of the nonobstructed pulmonary vasculature with the use of an sGC stimulator could be effective in the treatment of acute pulmonary hypertension from pulmonary embolism.83

Antiplatelet and Antiinflammatory Actions

The NO-sGC-cGMP pathway inhibits platelet aggregation and leukocyte adhesion, and the use of sGC stimulators could be clinically beneficial in thrombogenic and inflammatory disorders.7-9 The sGC stimulator BAY 41-2272 blocked collagen-induced aggregation in washed human platelets, but GTN—which requires metabolism to an NO donor in platelets—did not block aggregation. BAY 41-2272 also significantly increased tail-bleeding times.65 However in another study, the inhibition of platelet aggregation by BAY 41-2272 required the reduced form of sGC and the presence of NO.84 In an endothelial NOS knockout mice model, administration of BAY 41-2272 reduced the incidence of increased leukocyte rolling and adhesion observed in this model of inflammation.85 Adiposity has been shown to greatly increase the risk of atherothrombotic events due to a chronic state of oxidative stress.86 In a high-fat rat model, BAY 41-2272 inhibited platelet aggregation but was less effective in rats fed standard chow. This finding suggests that decreased NO bioavailability is present in obesity because of defects in the prosthetic heme group of sGC.86

Inhaled NO has decreased pulmonary vascular permeability in some, but not in all studies.87-95 One observed complication with inhaled NO is an increase in vascular permeability due to formation of reactive oxygen species from high oxygen concentrations during ventilation and subsequent hyperoxia-induced invasion of leukocytes.90,93,96 In an isolated ischemic-reperfusion rabbit lung model, administration of BAY 41-2272 significantly attenuated vascular leakage and suppressed reactive oxygen species generation.97 These studies suggest that during low NO bioavailability states, BAY 42-2272 could modulate platelet aggregation, leukocyte activation, and vascular leakage—key components of the inflammatory response to injury.

Clinical Trials

The first sGC stimulator to undergo clinical study was BAY 41-8543 (Figure 2).57 As expected in a Phase I study, systemic arterial pressure decreased in healthy volunteers following oral administration, suggesting efficacy of the drug in humans. However, the pharmacokinetic finding of prolonged clearance rates and the pharmacodynamic presence of active metabolites supported the development of additional sGC stimulator compounds.57,98 Subsequently, BAY 63-2521 (Riociguat) was developed (Figure 2). When administered in 58 healthy male volunteers as a single oral dose (0.25-5 mg), researchers observed no serious adverse events.99 Although systolic blood pressure (SBP) was not significantly affected, both mean arterial and diastolic pressures were decreased. Moreover, dose-related increases in heart rate up to ∼11 beats per minute were observed with the higher mg dose. The higher dose was not well tolerated; volunteers complained of headache, nasal congestion, flushing, feeling hot, orthostatic hypotension, and palpitations. Plasma levels of norepinephrine and renin were elevated, but levels of aldosterone and angiotensin II were not.99

A Phase I study evaluated the short-term safety profile of BAY 63-2561 (Riociguat) to determine tolerability and efficacy in patients with moderate to severe pulmonary hypertension caused by primary pulmonary arterial hypertension, distal chronic thromboembolic pulmonary hypertension, or pulmonary hypertension from mild to moderate interstitial lung disease.100 Safety and tolerability studies involved 19 patients receiving single doses of Riociquat up to 2.5 mg. The administration of the sGC stimulator significantly improved pulmonary hemodynamic parameters and cardiac index to a greater extent than what was observed following administration of inhaled NO. Although Riociguat demonstrated no selectivity for the pulmonary circulation, mean SBP remained >110 mmHg.100 The drug was well tolerated and found to be superior to inhaled NO in the pulmonary circulation.100

In a Phase II study, 75 patients with a diagnosis of chronic thromboembolic pulmonary hypertension or pulmonary arterial hypertension received oral Riociguat in 0.5-mg increments in 2-week intervals from 1 mg to a maximum of 2.5 mg 3 times a day titrated to systemic SBP for 12 weeks.101 The dose of the sGC stimulator was titrated upward to a stable arterial pressure range of 90-100 mmHg or until observation of syncope or dizziness. Riociguat was well tolerated, but asymptomatic hypotension (SBP ≤ 90 mmHg) was observed in 11/75 (15%) patients, blood pressure normalized in 9 patients, and dose alteration was required in 2 patients.101 Pulmonary vascular resistance significantly decreased, and the median 6-minute walking distance test scores significantly improved. Although adverse events of dyspepsia, headache, and hypotension occurred, these events were considered mild to moderate in 96% of patients, with medication discontinued in 4% of patients.101 As a result of these initial studies, 3 additional studies have been introduced worldwide in patients with pulmonary hypertension (NCT00454558, NCT00910429, NCT00855465).

Because anticoagulants are used in patients with pulmonary hypertension, a Phase I study investigated the potential interactions between Riociguat and warfarin.102 Steady-state plasma levels of Riociguat did not affect the pharmacokinetics of warfarin, prothrombin times, or factor VII clotting activity.102 Although these findings are promising, repeat clinically relevant studies are needed to confirm the observed nonpharmacokinetic interaction between sGC stimulator agents and warfarin.

FUTURE CLINICAL APPLICATIONS

These sGC agents are undergoing clinical trials in patients with pulmonary hypertension and could be released in the near future. This class of agents could have additional roles in patients with endothelial dysfunction. Prior administration of sGC stimulators in a yet-to-be-defined preoperative period may allow stressed vascular beds to be more responsive to low levels of endogenous NO with associated relaxation of vascular smooth muscle, less platelet aggregation, modulation of inflammation, and control of vascular permeability. Although inhaled NO has not been shown to improve outcomes in patients with acute respiratory distress syndrome103-106—largely due to the development of tolerance and increased superoxide, endothelin-1, and peroxynitrite formation107-110—inhaled NO has been shown to reduce pulmonary vascular permeability in the lungs.111 The coadministration of a low-dose sGC stimulator in the intensive care unit could make inhaled NO therapy more effective in the treatment of acute pulmonary hypertension, improve right ventricular output, and reduce pulmonary vascular permeability following cardiac transplantation or in patients who develop acute lung injury.112-115

Finally, an initial goal in the intensive care unit is to restore microcirculation to provide effective oxygen delivery and tissue perfusion to maintain aerobic metabolism.116-118 Although current therapy is to optimize systemic hemodynamics, the relationship between systemic hemodynamics and microcirculatory perfusion during resuscitation is unclear.116,119 However, studies in cardiogenic and septic shock showed that topical application of acetylcholine reversed sublingual microcirculatory disturbances, suggesting that the vascular endothelium was still responsive to vasodilators.120,121 Because low-dose GTN has been shown to improve microcirculation abnormalities in patients with severe heart failure24 and in patients with septic shock,25,27 the use of sGC stimulators may allow the enzyme to also respond to low levels of bioavailable NO or to a low-dose NO donor and have benefit in the intensive care unit.

CONCLUSIONS

The NO-sGC-cGMP pathway plays an important role in the regulation of vascular tone and in the modulation of platelet aggregation, inflammation, and vascular permeability. However, endothelial dysfunction observed in cardiovascular disease inhibits this pathway. Current organic nitrate therapy is limited to episodic care and has no current role in preventive medicine. Animal and early clinical studies have shown that sGC stimulator agents offer great promise in the medical management of cardiopulmonary disorders, such as systemic and pulmonary hypertension and CHF. These agents may also have a role in modulation of the inflammatory response observed in perioperative care. These agents may allow the vascular endothelium to respond to bioavailable NO or, in selected cases, to low-dose NO donors. As these agents continue to undergo extensive animal and early Phase III trials, we look forward to their release for clinical use in cardiovascular diseases as well as in perioperative medicine.

This article meets the Accreditation Council for Graduate Medical Education and the American Board of Medical Specialtes Maintenance of Certification competencies for Patient Care and Medical Knowledge.

Footnotes

  • Funding: This research was supported by NIH grants HL 62000 and HL 77421.

REFERENCES

  1. ↵
    1. Arnold WP,
    2. Mittal CK,
    3. Katsuki S,
    4. Murad F
    (8, 1977) Nitric oxide activates guanylate cyclase and increases guanosine 3′:5′-cyclic monophosphate levels in various tissue preparations. Proc Natl Acad Sci U S A 74(8):3203–3207, pmid:20623.
    OpenUrlAbstract/FREE Full Text
  2. ↵
    1. McNamara DB,
    2. Kadowitz PJ,
    3. Hyman AL,
    4. Ignarro LJ
    (12, 1980) Adenosine 3′,5′-monophosphate formation by preparations of rat liver soluble guanylate cyclase activated with nitric oxide, nitrosyl ferroheme, S-nitrosothiols, and other nitroso compounds. Can J Physiol Pharmacol 58(12):1446–1456, pmid:6113040.
    OpenUrlCrossRefPubMed
  3. ↵
    1. DeRubertis FR,
    2. Craven PA,
    3. Pratt DW
    (7 14, 1978) Electron spin resonance study of the role of nitrosyl-heme in the activation of guanylate cyclase by nitrosoguanidine and related agonists. Biochem Biophys Res Commun 83(1):158–167, pmid:29621.
    OpenUrlPubMed
  4. ↵
    1. Craven PA,
    2. DeRubertis FR
    (12 10, 1978) Restoration of the responsiveness of purified guanylate cyclase to nitrosoguanidine, nitric oxide, and related activators by heme and hemeproteins. Evidence for involvement of the paramagnetic nitrosyl-heme complex in enzyme activation. J Biol Chem 253(23):8433–8443, pmid:30778.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Hardman JG,
    2. Sutherland EW
    (12 10, 1969) Guanyl cyclase, an enzyme catalyzing the formation of guanosine 3′,5′-monophosphate from guanosine trihosphate. J Biol Chem 244(23):6363–6370, pmid:4982201.
    OpenUrlAbstract/FREE Full Text
    1. Hardman JG,
    2. Davis JW,
    3. Sutherland EW
    (12 10, 1969) Effects of some hormonal and other factors on the excretion of guanosine 3′,5′-monophosphate and adenosine 3′,5′-monophosphate in rat urine. J Biol Chem 244(23):6354–6362, pmid:4311196.
    OpenUrlAbstract/FREE Full Text
  7. ↵
    1. Moncada S,
    2. Palmer RM,
    3. Higgs EA
    (10, 1988) The discovery of nitric oxide as the endogenous nitrovasodilator. Hypertension 12(4):365–372, pmid:3049340.
    OpenUrlAbstract/FREE Full Text
    1. Moncada S,
    2. Higgs EA
    (2006) Nitric oxide and the vascular endothelium. Handb Exp Pharmacol (176 Pt 1):213–254, pmid:16999221.
    OpenUrlCrossRefPubMed
  9. ↵
    1. Oliver JA
    (6, 1992) Endothelium-derived relaxing factor contributes to the regulation of endothelial permeability. J Cell Physiol 151(3):506–511, pmid:1363553.
    OpenUrlCrossRefPubMed
  10. ↵
    1. Münzel T,
    2. Daiber A,
    3. Ullrich V,
    4. Mülsch A
    (8, 2005) Vascular consequences of endothelial nitric oxide synthase uncoupling for the activity and expression of the soluble guanylyl cyclase and the cGMP-dependent protein kinase. Arterioscler Thromb Vasc Biol 25(8):1551–1557, pmid:15879305, Epub 2005 May 5.
    OpenUrlAbstract/FREE Full Text
  11. ↵
    1. Ott IM,
    2. Alter ML,
    3. von Websky K,
    4. et al.
    (2012) Effects of stimulation of soluble guanylate cyclase on diabetic nephropathy in diabetic eNOS knockout mice on top of angiotensin II receptor blockade. PLoS One 7(8), e42623, doi: 10.1371/journal.pone.0042623. Epub 2012 Aug 10.
    1. Bundhoo SS,
    2. Anderson RA,
    3. Sagan E,
    4. et al.
    (11, 2011) Direct vasoactive properties of thienopyridine-derived nitrosothiols. J Cardiovasc Pharmacol 58(5):550–558, pmid:21822146.
    OpenUrlPubMed
    1. Girgis RE
    (3, 2010) Emerging drugs for pulmonary hypertension. Expert Opin Emerg Drugs 15(1):71–85, pmid:20095920.
    OpenUrlCrossRefPubMed
  14. ↵
    1. Nava E,
    2. Noll G,
    3. Lüscher TF
    (6, 1995) Nitric oxide in cardiovascular diseases. Ann Med 27(3):343–351, pmid:7546624.
    OpenUrlPubMed
  15. ↵
    1. Ni Choileain N, Redmond HP
    (11, 2006) Cell response to surgery. Arch Surg 141(11):1132–1140, pmid:17116807.
    OpenUrlCrossRefPubMed
    1. Wang P,
    2. Hauptman JG,
    3. Chaudry IH
    (12, 1990) Hemorrhage produces depression in microvascular blood flow which persists despite fluid resuscitation. Circ Shock 32(4):307–318, pmid:2289304.
    OpenUrlPubMed
    1. Watkins JM,
    2. Spain DA,
    3. Krysztopik RJ,
    4. Downard PJ,
    5. Wilson MA,
    6. Garrison RN
    (12, 1996) Heparan preserves intestinal perfusion after hemorrhage and resuscitation. J Surg Res 66(2):154–158, pmid:9024828.
    OpenUrlCrossRefPubMed
    1. Vollmar B,
    2. Menger MD
    (11, 2004) Volume replacement and microhemodynamic changes in polytrauma. Langenbecks Arch Surg 389(6):485–491, pmid:15118861, Epub 2004 Apr 28.
    OpenUrlCrossRefPubMed
  19. ↵
    1. Szopinski J,
    2. Kusza K,
    3. Semionow M
    (12, 2011) Microcirculatory responses to hypovolemic shock. J Trauma 71(6):1779–1788, pmid:22182889.
    OpenUrlCrossRefPubMed
  20. ↵
    1. Senagore AJ,
    2. Emery T,
    3. Luchtefeld M,
    4. Kim D,
    5. Dujovny N,
    6. Hoedema R
    (12, 2009) Fluid management for laparoscopic colectomy: a prospective, randomized assessment of goal-directed administration of balanced salt solution or hetastarch coupled with an enhanced recovery program. Dis Colon Rectum 52(12):1935–1940, pmid:19934912.
    OpenUrlCrossRefPubMed
    1. Puskarich MA,
    2. Marchick MR,
    3. Kline JA,
    4. Steuerwald MT,
    5. Jones AE
    (2009) One year mortality of patients treated with an emergency department based early goal directed therapy protocol for severe sepsis and septic shock: a before and after study. Crit Care 13(5):R167, pmid:19845956, Epub 2009 Oct 21.
    OpenUrlCrossRefPubMed
    1. McIntyre LA,
    2. Fergusson D,
    3. Cook DJ,
    4. et al.
    (12, 2008) Canadian Critical Care Trials Group. Fluid resuscitation in the management of early septic shock (FINESS): a randomized controlled feasibility trial. Can J Anaesth 55(12):819–826, pmid:19050085.
    OpenUrlCrossRefPubMed
  23. ↵
    1. Harten J,
    2. Crozier JE,
    3. McCreath B,
    4. et al.
    (6, 2008) Effect of intraoperative fluid optimisation on renal function in patients undergoing emergency abdominal surgery: a randomised controlled pilot study (ISRCTN 11799696). Int J Surg 6(3):197–204, pmid:18424200, Epub 2008 Mar 12.
    OpenUrlCrossRefPubMed
  24. ↵
    1. den Uil CA,
    2. Caliskan K,
    3. Lagrand WK,
    4. et al.
    (11, 2009) Dose-dependent benefit of nitroglycerin on microcirculation of patients with severe heart failure. Intensive Care Med 35(11):1893–1899, pmid:19639300, Epub 2009 Jul 29.
    OpenUrlCrossRefPubMed
  25. ↵
    1. Spronk PE,
    2. Rommes JH,
    3. Schaar C,
    4. Ince C
    (3, 2006) Thrombolysis in fulminant purpura: observations on changes in microcirculatory perfusion during successful treatment. Thromb Haemost 95(3):576–578, pmid:16525591.
    OpenUrlPubMed
  26. ↵
    1. Spronk PE,
    2. Ince C,
    3. Gardien MJ,
    4. Mathura KR,
    5. Oudemans-van Straaten HM,
    6. Zandstra DF
    (11 2, 2002) Nitroglycerin in septic shock after intravascular volume resuscitation. Lancet 360(9343):1395–1396, pmid:12423989.
    OpenUrlCrossRefPubMed
  27. ↵
    1. Boerma EC,
    2. Koopmans M,
    3. Konijn A,
    4. et al.
    (1, 2010) Effects of nitroglycerin on sublingual microcirculatory blood flow in patients with severe sepsis/septic shock after a strict resuscitation protocol: a double-blind randomized placebo controlled trial. Crit Care Med 38(1):93–100, pmid:19730258.
    OpenUrlCrossRefPubMed
  28. ↵
    1. Nossaman VE,
    2. Nossaman BD,
    3. Kadowitz PJ
    (Jul-Aug 2010) Nitrates and nitrites in the treatment of ischemic cardiac disease. Cardiol Rev 18(4):190–197, pmid:20539102.
    OpenUrlCrossRefPubMed
    1. Mayer B,
    2. Beretta M
    (9, 2008) The enigma of nitroglycerin bioactivation and nitrate tolerance: news, views and troubles. Br J Pharmacol 155(2):170–184, pmid:18574453, Epub 2008 Jun 23.
    OpenUrlCrossRefPubMed
  30. ↵
    1. Münzel T,
    2. Daiber A,
    3. Mülsch A
    (9 30, 2005) Explaining the phenomenon of nitrate tolerance. Circ Res 97(7):618–628, pmid:16195486.
    OpenUrlAbstract/FREE Full Text
  31. ↵
    1. Murrell W
    (1879) Nitro-glycerine as a remedy for angina pectoris. Lancet, 80–81, Jan 18:113(2890):.
  32. ↵
    1. Brunton TL
    (1867) On the use of nitrite of amyl in angina pectoris. Lancet, 97–98, Jul 27:90(2291):.
  33. ↵
    1. Bogaert MG
    (4, 1972) Organic nitrates in angina pectoris. Arch Int Pharmacodyn Ther, 196:Suppl 196:25-.
    1. Battock DJ,
    2. Levitt PW,
    3. Steele PP
    (10, 1976) Effects of isosorbide dinitrate and nitroglycerin on central circulatory dynamics in coronary artery disease. Am Heart J 92(4):455–458, pmid:822703.
    OpenUrlCrossRefPubMed
    1. Silber S
    (1990) Nitrates: why and how should they be used today? Current status of the clinical usefulness of nitroglycerin, isosorbide dinitrate and isosorbide-5-mononitrate. Eur J Clin Pharmacol 38(Suppl 1):S35–S51, pmid:2113003.
    OpenUrlCrossRefPubMed
  36. ↵
    1. Parker JA
    (5 30, 1996) Organic nitrates: new formulations and their clinical advantages. Am J Cardiol 77(13):38C–40C.
    OpenUrlPubMed
  37. ↵
    1. Johnson JB,
    2. Fairley A,
    3. Carter C
    (1, 1959) Effects of sublingual nitroglycerin on pulmonary arterial pressure in patients with left ventricular failure. Ann Intern Med 50(1):34–42, pmid:13617828.
    OpenUrlPubMed
    1. Fremont RE
    (9, 1961) The actions of organic nitrates on the cardiopulmonary and peripheral circulations. Angiology 12:391–400, pmid:13701721.
    OpenUrlCrossRefPubMed
    1. Mikulic E,
    2. Franciosa JA,
    3. Cohn JN
    (9, 1975) Comparative hemodynamic effects of chewable isosorbide dinitrate and nitroglycerin in patients with congestive heart failure. Circulation 52(3):477–482, pmid:808359.
    OpenUrlAbstract/FREE Full Text
    1. Charuzi Y
    (12, 1982) Use of nitroglycerin ointment in acute pulmonary edema and hypertension. Chest 82(6):800, pmid:6814840.
    OpenUrlPubMed
    1. Palevsky HI,
    2. Fishman AP
    (1985) Vasodilator therapy for primary pulmonary hypertension. Annu Rev Med 36:563–578, pmid:2859832.
    OpenUrlPubMed
  42. ↵
    1. Bundgaard H,
    2. Boesgaard S,
    3. Mortensen SA,
    4. Arendrup H,
    5. Aldershvile J
    (1997) Effect of nitroglycerin in patients with increased pulmonary vascular resistance undergoing cardiac transplantation. Scand Cardiovasc J 31(6):339–342, pmid:9455782.
    OpenUrlPubMed
  43. ↵
    1. Murad F,
    2. Mittal CK,
    3. Arnold WP,
    4. Katsuki S,
    5. Kimura H
    (1978) Guanylate cyclase: activation by azide, nitro compounds, nitric oxide, and hydroxyl radical and inhibition by hemoglobin and myoglobin. Adv Cyclic Nucleotide Res 9:145–158, pmid:27076.
    OpenUrlPubMed
    1. Ignarro LJ,
    2. Lippton H,
    3. Edwards JC,
    4. et al.
    (9, 1981) Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: evidence for the involvement of S-nitrosothiols as active intermediates. J Pharmacol Exp Ther 218(3):739–749, pmid:6115052.
    OpenUrlFREE Full Text
  45. ↵
    1. Needleman P,
    2. Jakschik B,
    3. Johnson EM Jr.
    (11, 1973) Sulfhydryl requirement for relaxation of vascular smooth muscle. J Pharmacol Exp Ther 187(2):324–331, pmid:4201275.
    OpenUrlAbstract/FREE Full Text
  46. ↵
    1. Jugdutt BI
    (1994) Use of nitroglycerin for the treatment of acute myocardial infarction. Heart Vessels 9(1):3–13, pmid:8113155.
    OpenUrlCrossRefPubMed
    1. Needleman P
    (1976) Organic nitrate metabolism. Annu Rev Pharmacol Toxicol 16:81–93, pmid:820240.
    OpenUrlCrossRefPubMed
  48. ↵
    1. Needleman P,
    2. Johnson EM Jr.
    (3, 1973) Mechanism of tolerance development to organic nitrates. J Pharmacol Exp Ther 184(3):709–715, pmid:4631470.
    OpenUrlAbstract/FREE Full Text
  49. ↵
    1. Daiber A,
    2. Wenzel P,
    3. Oelze M,
    4. Schuhmacher S,
    5. Jansen T,
    6. Münzel T
    (3 16, 2009) Mitochondrial aldehyde dehydrogenase (ALDH-2)--maker of and marker for nitrate tolerance in response to nitroglycerin treatment. Chem Biol Interact 178(1-3):40–47, pmid:18834868, Epub 2008 Sep 10.
    OpenUrlCrossRefPubMed
  50. ↵
    1. Schulz E,
    2. Tsilimingas N,
    3. Rinze R,
    4. et al.
    (3 12, 2002) Functional and biochemical analysis of endothelial (dys)function and NO/cGMP signaling in human blood vessels with and without nitroglycerin pretreatment. Circulation 105(10):1170–1175, pmid:11889009.
    OpenUrlAbstract/FREE Full Text
  51. ↵
    1. den Uil CA,
    2. Lagrand WK,
    3. Spronk PE,
    4. et al.
    (4, 2009) Low-dose nitroglycerin improves microcirculation in hospitalized patients with acute heart failure. Eur J Heart Fail 11(4):386–390, pmid:19211570, Epub 2009 Feb 10.
    OpenUrlCrossRefPubMed
  52. ↵
    1. Ko FN,
    2. Wu CC,
    3. Kuo SC,
    4. Lee FY,
    5. Teng CM
    (12 15, 1994) YC-1, a novel activator of platelet guanylate cyclase. Blood 84(12):4226–4233, pmid:7527671.
    OpenUrlAbstract/FREE Full Text
  53. ↵
    1. Wu CC,
    2. Ko FN,
    3. Kuo SC,
    4. Lee FY,
    5. Teng CM
    (10, 1995) YC-1 inhibited human platelet aggregation through NO-independent activation of soluble guanylate cyclase. Br J Pharmacol 116(3):1973–1978, pmid:8640334.
    OpenUrlCrossRefPubMed
  54. ↵
    1. Friebe A,
    2. Schultz G,
    3. Koesling D
    (12 16, 1996) Sensitizing soluble guanylyl cyclase to become a highly CO-sensitive enzyme. EMBO J 15(24):6863–6868, pmid:9003762.
    OpenUrlPubMed
  55. ↵
    1. Feelisch M,
    2. Kotsonis P,
    3. Siebe J,
    4. Clement B,
    5. Schmidt HH
    (8, 1999) The soluble guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-a] quinoxalin-1-one is a nonselective heme protein inhibitor of nitric oxide synthase and other cytochrome P-450 enzymes involved in nitric oxide donor bioactivation. Mol Pharmacol 56(2):243–253, pmid:10419542.
    OpenUrlAbstract/FREE Full Text
  56. ↵
    1. Mülsch A,
    2. Bauersachs J,
    3. Schäfer A,
    4. Stasch JP,
    5. Kast R,
    6. Busse R
    (2, 1997) Effect of YC-1, an NO-independent, superoxide-sensitive stimulator of soluble guanylyl cyclase, on smooth muscle responsiveness to nitrovasodilators. Br J Pharmacol 120(4):681–689, pmid:9051308.
    OpenUrlCrossRefPubMed
  57. ↵
    1. Stasch JP,
    2. Hobbs AJ
    (2009) NO-independent, haem-dependent soluble guanylate cyclase stimulators. Handb Exp Pharmacol (191):277–308, pmid:19089334.
    OpenUrlCrossRefPubMed
    1. Straub A,
    2. Stasch JP,
    3. Alonso-Alija C,
    4. et al.
    (3 26, 2001) NO-independent stimulators of soluble guanylate cyclase. Bioorg Med Chem Lett 11(6):781–784, pmid:11277519.
    OpenUrlCrossRefPubMed
  59. ↵
    1. Evgenov OV,
    2. Pacher P,
    3. Schmidt PM,
    4. et al.
    (9, 2006) NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential. Nat Rev Drug Discov 5(9):755–768, pmid:16955067.
    OpenUrlCrossRefPubMed
    1. Teng CM,
    2. Wu CC,
    3. Ko FN,
    4. Lee FY,
    5. Kuo SC
    (2 12, 1997) YC-1, a nitric oxide-independent activator of soluble guanylate cyclase, inhibits platelet-rich thrombosis in mice. Eur J Pharmacol 320(2-3):161–166, pmid:9059849.
    OpenUrlCrossRefPubMed
    1. Wegener JW,
    2. Gath I,
    3. Förstermann U,
    4. Nawrath H
    (12, 1997) Activation of soluble guanylyl cyclase by YC-1 in aortic smooth muscle but not in ventricular myocardium from rat. Br J Pharmacol 122(7):1523–1529, pmid:9421305.
    OpenUrlCrossRefPubMed
  62. ↵
    1. Wu CC,
    2. Ko FN,
    3. Teng CM
    (2 13, 1997) Inhibition of platelet adhesion to collagen by cGMP-elevating agents. Biochem Biophys Res Commun 231(2):412–416, pmid:9070290.
    OpenUrlCrossRefPubMed
  63. ↵
    1. Boerrigter G,
    2. Costello-Boerrigter LC,
    3. Cataliotti A,
    4. et al.
    (2 11, 2003) Cardiorenal and humoral properties of a novel direct soluble guanylate cyclase stimulator BAY 41-2272 in experimental congestive heart failure. Circulation 107(5):686–689, pmid:12578869.
    OpenUrlAbstract/FREE Full Text
  64. ↵
    1. Zanfolin M,
    2. Faro R,
    3. Araujo EG,
    4. Guaraldo AM,
    5. Antunes E,
    6. De Nucci G
    (3, 2006) Protective effects of BAY 41-2272 (sGC stimulator) on hypertension, heart, and cardiomyocyte hypertrophy induced by chronic L-NAME treatment in rats. J Cardiovasc Pharmacol 47(3):391–395, pmid:16633081.
    OpenUrlPubMed
  65. ↵
    1. Stasch JP,
    2. Becker EM,
    3. Alonso-Alija C,
    4. et al.
    (3 8, 2001) NO-independent regulatory site on soluble guanylate cyclase. Nature 410(6825):212–215, pmid:11242081.
    OpenUrlCrossRefPubMed
  66. ↵
    1. Stasch JP,
    2. Dembowsky K,
    3. Perzborn E,
    4. Stahl E,
    5. Schramm M
    (1, 2002) Cardiovascular actions of a novel NO-independent guanylyl cyclase stimulator, BAY 41-8543: in vivo studies. Br J Pharmacol 135(2):344–355, pmid:11815369.
    OpenUrlCrossRefPubMed
  67. ↵
    1. Masuyama H,
    2. Tsuruda T,
    3. Sekita Y,
    4. et al.
    (7, 2009) Pressure-independent effects of pharmacological stimulation of soluble guanylate cyclase on fibrosis in pressure-overloaded rat heart. Hypertens Res 32(7):597–603, pmid:19424280, Epub 2009 May 8.
    OpenUrlCrossRefPubMed
  68. ↵
    1. Sharkovska Y,
    2. Kalk P,
    3. Lawrenz B,
    4. et al.
    (8, 2010) Nitric oxide-independent stimulation of soluble guanylate cyclase reduces organ damage in experimental low-renin and high-renin models. J Hypertens 28(8):1666–1675, pmid:20613628.
    OpenUrlCrossRefPubMed
  69. ↵
    1. Geschka S,
    2. Kretschmer A,
    3. Sharkovska Y,
    4. et al.
    (2011) Soluble guanylate cyclase stimulation prevents fibrotic tissue remodeling and improves survival in salt-sensitive Dahl rats. PLoS One 6(7), :e21853. Epub 2011 Jul 18.
  70. ↵
    1. Lasker GF,
    2. Maley JH,
    3. Pankey EA,
    4. Kadowitz PJ
    (4, 2011) Targeting soluble guanylate cyclase for the treatment of pulmonary hypertension. Expert Rev Respir Med 5(2):153–161, pmid:21510726.
    OpenUrlCrossRefPubMed
  71. ↵
    1. Murthy SN,
    2. Nossaman BD,
    3. Kadowitz PJ
    (Mar-Apr 2010) New approaches to the treatment of pulmonary hypertension: from bench to bedside. Cardiol Rev 18(2):76–84, pmid:20160533.
    OpenUrlCrossRefPubMed
  72. ↵
    1. McGoon MD,
    2. Kane GC
    (2, 2009) Pulmonary hypertension: diagnosis and management. Mayo Clin Proc 84(2):191–207, pmid:19181654, Erratum in: Mayo Clin Proc. 2009 Apr;84(4):386.
    OpenUrlCrossRefPubMed
    1. Steinhorn RH
    (12, 2008) Nitric oxide and beyond: new insights and therapies for pulmonary hypertension. J Perinatol 28(Suppl 3):S67–S71, pmid:19057613.
    OpenUrlCrossRefPubMed
    1. Nossaman BD,
    2. Nossaman VE,
    3. Murthy SN,
    4. Kadowitz PJ
    (1, 2010) Role of the RhoA/Rho-kinase pathway in the regulation of pulmonary vasoconstrictor function. Can J Physiol Pharmacol 88(1):1–8, pmid:20130732.
    OpenUrlCrossRefPubMed
    1. Pasero D,
    2. Martin EL,
    3. Davi A,
    4. et al.
    (5, 2010) The effects of inhaled nitric oxide after lung transplantation. Minerva Anestesiol 76(5):353–361, pmid:20395898.
    OpenUrlPubMed
  76. ↵
    1. Palmero V,
    2. Sulica R
    (8, 2010) Sarcoidosis-associated pulmonary hypertension: assessment and management. Semin Respir Crit Care Med 31(4):494–500, pmid:20665399, Epub 2010 Jul 27.
    OpenUrlCrossRefPubMed
  77. ↵
    1. Deruelle P,
    2. Balasubramaniam V,
    3. Kunig AM,
    4. et al.
    (2006) BAY 41-2272, a direct activator of soluble guanylate cyclase, reduces right ventricular hypertrophy and prevents pulmonary vascular remodeling during chronic hypoxia in neonatal rats. Biol Neonate 90(2):135–144, pmid:16582538, Epub 2006 Mar 19.
    OpenUrlCrossRefPubMed
  78. ↵
    1. Deruelle P,
    2. Grover TR,
    3. Storme L,
    4. Abman SH
    (4, 2005) Effects of BAY 41-2272, a soluble guanylate cyclase activator, on pulmonary vascular reactivity in the ovine fetus. Am J Physiol Lung Cell Mol Physiol 288(4):L727–L733, pmid:15608146, Epub 2004 Dec 17.
    OpenUrlCrossRefPubMed
  79. ↵
    1. Evgenov OV,
    2. Kohane DS,
    3. Bloch KD,
    4. et al.
    (12 1, 2007) Inhaled agonists of soluble guanylate cyclase induce selective pulmonary vasodilation. Am J Respir Crit Care Med 176(11):1138–1145, pmid:17872487, Epub 2007 Sep 13.
    OpenUrlCrossRefPubMed
  80. ↵
    1. Deruelle P,
    2. Grover TR,
    3. Abman SH
    (11, 2005) Pulmonary vascular effects of nitric oxide-cGMP augmentation in a model of chronic pulmonary hypertension in fetal and neonatal sheep. Am J Physiol Lung Cell Mol Physiol 289(5):L798–806, pmid:15964898, Epub 2005 Jun 17.
    OpenUrlCrossRefPubMed
  81. ↵
    1. Badejo AM Jr.,
    2. Nossaman VE,
    3. Pankey EA,
    4. et al.
    (10, 2010) Pulmonary and systemic vasodilator responses to the soluble guanylyl cyclase stimulator, BAY 41-8543, are modulated by nitric oxide. Am J Physiol Heart Circ Physiol 299(4):H1153–H1159, pmid:20639220, Epub 2010 Jul 16.
    OpenUrlCrossRefPubMed
  82. ↵
    1. Evgenov OV,
    2. Ichinose F,
    3. Evgenov NV,
    4. et al.
    (10 12, 2004) Soluble guanylate cyclase activator reverses acute pulmonary hypertension and augments the pulmonary vasodilator response to inhaled nitric oxide in awake lambs. Circulation 110(15):2253–2259, pmid:15466650, Epub 2004 Oct 4.
    OpenUrlAbstract/FREE Full Text
  83. ↵
    1. Watts JA,
    2. Gellar MA,
    3. Fulkerson MB,
    4. Kline JA
    (12, 2011) Pulmonary vascular reserve during experimental pulmonary embolism: effects of a soluble guanylate cyclase stimulator, BAY 41-8543. Crit Care Med 39(12):2700–2704, pmid:21705882.
    OpenUrlPubMed
  84. ↵
    1. Roger S,
    2. Badier-Commander C,
    3. Paysant J,
    4. Cordi A,
    5. Verbeuren TJ,
    6. Félétou M
    (11, 2010) The anti-aggregating effect of BAY 41-2272, a stimulator of soluble guanylyl cyclase, requires the presence of nitric oxide. Br J Pharmacol 161(5):1044–1058, pmid:20977455.
    OpenUrlPubMed
  85. ↵
    1. Ahluwalia A,
    2. Foster P,
    3. Scotland RS,
    4. et al.
    (2 3, 2004) Antiinflammatory activity of soluble guanylate cyclase: cGMP-dependent down-regulation of P-selectin expression and leukocyte recruitment. Proc Natl Acad Sci U S A 101(5):1386–1391, pmid:14742866, Epub 2004 Jan 23.
    OpenUrlAbstract/FREE Full Text
  86. ↵
    1. Monteiro PF,
    2. Morganti RP,
    3. Delbin MA,
    4. et al.
    (1 16, 2012) Platelet hyperaggregability in high-fat fed rats: a role for intraplatelet reactive-oxygen species production. Cardiovasc Diabetol 11:5, pmid:22248260.
    OpenUrlCrossRefPubMed
  87. ↵
    1. Bjertnaes LJ,
    2. Koizumi T,
    3. Newman JH
    (11, 1998) Inhaled nitric oxide reduces lung fluid filtration after endotoxin in awake sheep. Am J Respir Crit Care Med 158(5 Pt 1):1416–1423, pmid:9817688.
    OpenUrlPubMed
    1. Hermle G,
    2. Schütte H,
    3. Walmrath D,
    4. et al.
    (10, 1999) Ventilation-perfusion mismatch after lung ischemia-reperfusion. Protective effect of nitric oxide. Am J Respir Crit Care Med 160(4):1179–1187, pmid:10508805.
    OpenUrlCrossRefPubMed
    1. Ishibe Y,
    2. Liu R,
    3. Ueda M,
    4. Mori K,
    5. Miura N
    (9, 1999) Role of inhaled nitric oxide in ischaemia-reperfusion injury in the perfused rabbit lung. Br J Anaesth 83(3):430–435, pmid:10655914.
    OpenUrlCrossRefPubMed
  90. ↵
    1. Bhabra MS,
    2. Hopkinson DN,
    3. Shaw TE,
    4. Hooper TL
    (11 15, 1999) Modulation of lung reperfusion injury by nitric oxide: impact of inspired oxygen fraction. Transplantation 68(9):1238–1243, pmid:10573058.
    OpenUrlCrossRefPubMed
    1. McElroy MC,
    2. Wiener-Kronish JP,
    3. Miyazaki H,
    4. et al.
    (4, 1997) Nitric oxide attenuates lung endothelial injury caused by sublethal hyperoxia in rats. Am J Physiol 272(4 Pt 1):L631–L638, pmid:9142935.
    OpenUrlPubMed
    1. Ader F,
    2. Le Berre R,
    3. Lancel S,
    4. et al.
    (3, 2007) Inhaled nitric oxide increases endothelial permeability in Pseudomonas aeruginosa pneumonia. Intensive Care Med 33(3):503–510, pmid:17219196, Epub 2007 Jan 12.
    OpenUrlPubMed
  93. ↵
    1. Filaire M,
    2. Fadel E,
    3. Decante B,
    4. et al.
    (3, 2007) Inhaled nitric oxide does not prevent postpneumonectomy pulmonary edema in pigs. J Thorac Cardiovasc Surg 133(3):770–774, pmid:17320582.
    OpenUrlCrossRefPubMed
    1. Broccard AF,
    2. Feihl F,
    3. Vannay C,
    4. et al.
    (9, 2004) Effects of L-NAME and inhaled nitric oxide on ventilator-induced lung injury in isolated, perfused rabbit lungs. Crit Care Med 32(9):1872–1878, pmid:15343015.
    OpenUrlCrossRefPubMed
  95. ↵
    1. Nader ND,
    2. Knight PR,
    3. Bobela I,
    4. et al.
    (9, 1999) High-dose nitric oxide inhalation increases lung injury after gastric aspiration. Anesthesiology 91(3):741–749, pmid:10485786.
    OpenUrlCrossRefPubMed
  96. ↵
    1. Waldow T,
    2. Witt W,
    3. Ulmer A,
    4. et al.
    (2008) Preconditioning by inhaled nitric oxide prevents hyperoxic and ischemia/reperfusion injury in rat lungs. Pulm Pharmacol Ther 21(2):418–429, pmid:18453045.
    OpenUrlCrossRefPubMed
  97. ↵
    1. Egemnazarov B,
    2. Sydykov A,
    3. Schermuly RT,
    4. et al.
    (3, 2009) Novel soluble guanylyl cyclase stimulator BAY 41-2272 attenuates ischemia-reperfusion-induced lung injury. Am J Physiol Lung Cell Mol Physiol 296(3):L462–L469, pmid:19074557, Epub 2008 Dec 12.
    OpenUrlCrossRefPubMed
  98. ↵
    1. Straub A,
    2. Benet-Buckholz J,
    3. Fröde R,
    4. et al.
    (6, 2002) Metabolites of orally active NO-independent pyrazolopyridine stimulators of soluble guanylate cyclase. Bioorg Med Chem 10(6):1711–1717, pmid:11937330, Erratum in: Bioorg Med Chem. 2002 Sep;10(9):3075.
    OpenUrlCrossRefPubMed
  99. ↵
    1. Frey R,
    2. Mück W,
    3. Unger S,
    4. et al.
    (8, 2008) Single-dose pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase stimulator BAY 63-2521: an ascending-dose study in healthy male volunteers. J Clin Pharmacol 48(8):926–934, pmid:18519919, Epub 2008 Jun 2.
    OpenUrlCrossRefPubMed
  100. ↵
    1. Grimminger F,
    2. Weimann G,
    3. Frey R,
    4. et al.
    (4, 2009) First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J 33(4):785–792, pmid:19129292, Epub 2009 Jan 7.
    OpenUrlAbstract/FREE Full Text
  101. ↵
    1. Ghofrani HA,
    2. Hoeper MM,
    3. Halank M,
    4. et al.
    (10, 2010) Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study. Eur Respir J 36(4):792–799, pmid:20530034, Epub 2010 Jun 7.
    OpenUrlAbstract/FREE Full Text
  102. ↵
    1. Frey R,
    2. Mück W,
    3. Kirschbaum N,
    4. et al.
    (7, 2011) Riociguat (BAY 63-2521) and warfarin: a pharmacodynamic and pharmacokinetic interaction study. J Clin Pharmacol 51(7):1051–1060, pmid:20801938, Epub 2010 Aug 27.
    OpenUrlCrossRefPubMed
    1. Taylor RW,
    2. Zimmerman JL,
    3. Dellinger RP,
    4. et al.
    (4 7, 2004) Inhaled Nitric Oxide in ARDS Study Group. Low-dose inhaled nitric oxide in patients with acute lung injury: a randomized controlled trial. JAMA 291(13):1603–1609, pmid:15069048.
    OpenUrlCrossRefPubMed
    1. Dellinger RP,
    2. Zimmerman JL,
    3. Taylor RW,
    4. et al.
    (1, 1998) Effects of inhaled nitric oxide in patients with acute respiratory distress syndrome: results of a randomized phase II trial. Inhaled Nitric Oxide in ARDS Study Group. Crit Care Med 26(1):15–23, pmid:9428538.
    OpenUrlCrossRefPubMed
    1. Dellinger RP,
    2. Zimmerman JL,
    3. Taylor RW,
    4. Straube RC
    (3, 1998) Placebo and inhaled nitric oxide mortality the same in ARDS clinical trial. Crit Care Med 26(3):619, pmid:9504596.
    OpenUrlPubMed
    1. Angus DC,
    2. Clermont G,
    3. Linde-Zwirble WT,
    4. et al.
    (12, 2006) NO-06 Investigators. Healthcare costs and long-term outcomes after acute respiratory distress syndrome: A phase III trial of inhaled nitric oxide. Crit Care Med 34(12):2883–2890, pmid:17075373.
    OpenUrlCrossRefPubMed
    1. Weinberger B,
    2. Laskin DL,
    3. Heck DE,
    4. Laskin JD
    (1, 2001) The toxicology of inhaled nitric oxide. Toxicol Sci 59(1):5–16, pmid:11134540.
    OpenUrlCrossRefPubMed
    1. Casey DB,
    2. Pankey EA,
    3. Badejo AM,
    4. et al.
    (4, 2012) Peroxynitrite has potent pulmonary vasodilator activity in the rat. Can J Physiol Pharmacol 90(4):485–500, pmid:22452357, Epub 2012 Mar 27.
    OpenUrlCrossRefPubMed
    1. Oishi P,
    2. Grobe A,
    3. Benavidez E,
    4. et al.
    (2, 2006) Inhaled nitric oxide induced NOS inhibition and rebound pulmonary hypertension: a role for superoxide and peroxynitrite in the intact lamb. Am J Physiol Lung Cell Mol Physiol 290(2):L359–366, pmid:16258003, Epub 2005 Oct 28.
    OpenUrlCrossRefPubMed
    1. Nossaman BD,
    2. Dabisch PA,
    3. Liles JT,
    4. et al.
    (2, 2004) Peroxynitrite does not impair pulmonary and systemic vascular responses. J Appl Physiol 96(2):455–462, pmid:14715677.
    OpenUrlCrossRefPubMed
  111. ↵
    1. Poss WB,
    2. Timmons OD,
    3. Farrukh IS,
    4. Hoidal JR,
    5. Michael JR
    (9, 1995) Inhaled nitric oxide prevents the increase in pulmonary vascular permeability caused by hydrogen peroxide. J Appl Physiol 79(3):886–891, pmid:8567532.
    OpenUrlPubMed
  112. ↵
    1. Dellinger RP
    (9, 1999) Inhaled nitric oxide in acute lung injury and acute respiratory distress syndrome. Inability to translate physiologic benefit to clinical outcome benefit in adult clinical trials. Intensive Care Med 25(9):881–883, pmid:10501736.
    OpenUrlCrossRefPubMed
    1. Lundin S,
    2. Mang H,
    3. Smithies M,
    4. Stenqvist O,
    5. Frostell C
    (9, 1999) Inhalation of nitric oxide in acute lung injury: results of a European multicentre study. The European Study Group of Inhaled Nitric Oxide. Intensive Care Med 25(9):911–919, pmid:10501745.
    OpenUrlCrossRefPubMed
    1. Kavanagh BP,
    2. Mouchawar A,
    3. Goldsmith J,
    4. Pearl RG
    (3, 1994) Effects of inhaled NO and inhibition of endogenous NO synthesis in oxidant-induced acute lung injury. J Appl Physiol 76(3):1324–1329, pmid:8005878.
    OpenUrlPubMed
  115. ↵
    1. Takashima S,
    2. Date H,
    3. Aoe M,
    4. Yamashita M,
    5. Andou A,
    6. Shimizu N
    (8, 1998) Effects of inhaled nitric oxide in canine lung transplantation from non-heart-beating donor. Jpn J Thorac Cardiovasc Surg 46(8):657–663, pmid:9785859.
    OpenUrlPubMed
  116. ↵
    1. Bozza FA,
    2. Carnevale R,
    3. Japiassú AM,
    4. et al.
    (9, 2010) Early fluid resuscitation in sepsis: evidence and perspectives. Shock 34(Suppl 1):40–43, pmid:20714265.
    OpenUrlPubMed
    1. Trzeciak S,
    2. McCoy JV,
    3. Phillip Dellinger R,
    4. et al.
    (12, 2008) Microcirculatory Alterations in Resuscitation and Shock (MARS) investigators. Early increases in microcirculatory perfusion during protocol-directed resuscitation are associated with reduced multi-organ failure at 24 h in patients with sepsis. Intensive Care Med 34(12):2210–2217, pmid:18594793, Epub 2008 Jul 2.
    OpenUrlCrossRefPubMed
  118. ↵
    1. Trzeciak S,
    2. Cinel I,
    3. Phillip Dellinger R,
    4. et al.
    (5, 2008) Microcirculatory Alterations in Resuscitation and Shock (MARS) Investigators. Resuscitating the microcirculation in sepsis: the central role of nitric oxide, emerging concepts for novel therapies, and challenges for clinical trials. Acad Emerg Med 15(5):399–413, pmid:18439194.
    OpenUrlCrossRefPubMed
  119. ↵
    1. De Backer D,
    2. Ortiz JA,
    3. Salgado D
    (6, 2010) Coupling microcirculation to systemic hemodynamics. Curr Opin Crit Care 16(3):250–254, pmid:20179590.
    OpenUrlCrossRefPubMed
  120. ↵
    1. De Backer D,
    2. Creteur J,
    3. Preiser JC,
    4. Dubois MJ,
    5. Vincent JL
    (7 1, 2002) Microvascular blood flow is altered in patients with sepsis. Am J Respir Crit Care Med 166(1):98–104, pmid:12091178.
    OpenUrlCrossRefPubMed
  121. ↵
    1. Buwalda M,
    2. Ince C
    (9, 2002) Opening the microcirculation: can vasodilators be useful in sepsis? Intensive Care Med 28(9):1208–1217, pmid:12209267, Epub 2002 Jul 27.
    OpenUrlCrossRefPubMed
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