The renal and glomerular dynamic effects of combining thiazide and angiotensin antagonists have not been reported. The present study was designed to examine the effects of hydrochlorothiazide (HCTZ) alone or in combination with an angiotensin-converting enzyme inhibitor or ANG II type 1-receptor blocker on renal hemodynamics, glomerular dynamics, renal function, and renal histopathology in the N(omega)-nitro-l-arginine methyl ester-treated spontaneously hypertensive rat (l-NAME/SHR) model. HCTZ (80 mg x kg(-1) x day(-1)) alone or in combination with enalapril (30 mg x kg(-1) x day(-1)) or losartan (30 mg x kg(-1) x day(-1)) or enalapril (15 mg.kg(-1).day(-1)) plus losartan (15 mg x kg(-1) x day(-1)) was administered to l-NAME/SHR (5.0 +/- 0.10 mg x kg(-1) x day(-1)) for 3 wk. Mean arterial pressure, total peripheral resistance, renal plasma flow, glomerular filtration rate, glomerular hydrostatic pressure, afferent and efferent glomerular arteriolar resistances, single nephron plasma flow, single nephron glomerular filtration rate, serum creatinine concentration, 24-h urinary protein excretion, and glomerular and arteriolar injury scores were determined. HCTZ reduced mean arterial pressure, total peripheral resistance, glomerular hydrostatic pressure, and afferent and efferent glomerular arteriolar resistances (P < 0.05, at least) but slightly increased renal plasma flow and single nephron plasma flow associated with reduced serum creatinine concentration, urinary protein excretion, and arteriolar injury score compared with l-NAME/SHR control. However, the combination of enalapril and/or losartan with HCTZ markedly improved each of these functions. These results demonstrated minor benefits of HCTZ monotherapy and a marked superiority of its combination with enalapril and/or losartan over HCTZ monotherapy on renoprotection in l-NAME/SHR, thereby providing strong evidence of their clinical benefits for hypertensive patients with renal functional impairment.