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1. We compared the effects of the angiotensin converting enzyme (ACE) inhibitor enalapril and the angiotensin AT(1) receptor antagonist valsartan in cyclosporine A (CsA)-induced hypertension and nephrotoxicity in spontaneously hypertensive rats (SHR). 2. SHR (8 - 9 weeks old) on high-sodium diet were given CsA (5 mg kg(-1)d (-1) s.c. ) for 6 weeks. The rats were treated concomitantly either with enalapril (30 mg kg(-1)d (-1) p.o.) or valsartan (3 or 30 mg kg(-1) d (-1) p.o.). To evaluate the role of bradykinin in the action of enalapril, some rats received a bradykinin B(2) receptor antagonist icatibant (HOE 140, 500 microg kg(-1) d (-1) s.c.) during the last 2 weeks of enalapril treatment. 3. Blood pressure was recorded every second week by tail cuff method. Renal function was measured by serum creatinine, creatinine clearance and urinary excretion of proteins at the end of the experiment. The activity of the renal kallikrein-kinin system was estimated by urinary kallikrein excretion. 4. CsA caused hypertension, impaired renal function and induced morphological nephrotoxicity with glomerular damage and interstitial fibrosis. Enalapril and the lower dose of valsartan attenuated the CsA-induced hypertension to the same extent, while the higher dose of valsartan totally abolished it. Icatibant did not reduce the antihypertensive effect of enalapril. Urinary kallikrein excretion was similar in all groups. 5. Enalapril and valsartan equally prevented the CsA-induced deterioration of kidney function and morphology. 6. The renin-angiotensin but not the kallikrein-kinin system plays a crucial role in CsA-toxicity during high intake of sodium in SHR.

1. The effects of nitric oxide (NO) releasing substances, sodium nitroprusside, 3-morpholino sydnonimine (SIN-1) and a novel oxatriazole derivative, GEA 3162, on blood pressure and heart rate were studied after peripheral or central administration in anaesthetized normotensive Wistar rats. 2. Given as cumulative intravenous injections, both nitroprusside and GEA 3162 (24-188 nmol kg-1) induced short-lasting and dose-dependent decreases in mean arterial pressure, while SIN-1 decreased blood pressure only slightly even after larger doses (94-3000 nmol kg-1). Heart rate increased concomitantly with the hypotensive effect of the NO-releasing substances. 3. Cumulative intracerebroventricular administration of GEA 3162 (24-188 nmol kg-1) induced a dose-dependent hypotension with slight but insignificant increases in heart rate. In contrast, intracerebroventricular nitroprusside induced little change in blood pressure, while a large dose of SIN-1 (3000 nmol kg-1, i.c.v.) slightly increased mean arterial pressure. However, intracerebroventricular nitroprusside and SIN-1 increased heart rate at doses that did not significantly affect blood pressure. 4. To determine whether the cardiovascular effects of GEA 3162 were attributable to an elevation of cyclic GMP levels, pretreatments with methylene blue, a putative guanylate cyclase inhibitor, were performed. This substance failed to attenuate the cardiovascular effects of peripherally or centrally administered GEA 3162, suggesting that the effects were independent of guanylate cyclase. 5. In conclusion, the centrally administered NO-donor, GEA 3162, induced a dose-dependent. hypotensive response without significant changes in heart rate. Furthermore, intracerebroventricular injections of nitroprusside and SIN-1 increased heart rate without affecting blood pressure. These results suggest that NO released by these drugs may affect central mechanisms involved in cardiovascular regulation independently of cyclic GMP.