Trandolapril's protective effects in stroke-prone spontaneously hypertensive rats persist long after treatment withdrawal.
The effects of long-term oral administration of the angiotensin-converting enzyme (ACE) inhibitor trandolapril (0.01 mg/kg [T0.01] and 1 mg/kg [T1]) on the occurrence of stroke and on mortality were investigated in young salt-loaded stroke-prone spontaneously hypertensive rats during the treatment period (5-20 weeks of age) and up to 8 weeks thereafter. During the treatment period T1, but not T0.01, limited the increase in blood pressure. However, both doses of trandolapril prevented stroke and mortality and strongly opposed (T0.01) or abolished (T1) the increases in saline intake, diuresis, and proteinuria observed in control animals. Simultaneously, trandolapril markedly prevented (T0.01) or abolished (T1) vascular fibrinoid necrosis formation in the brain, kidney, and heart. Finally, trandolapril dose-dependently reduced arterial thickening and glomerular and tubulointerstitial lesions in the kidney, as well as arterial thickening, infarction, and fibrosis in the myocardium. At 8 weeks after treatment withdrawal, the antihypertensive effect of T1 had disappeared, but stroke-related mortality and fibrinoid necrosis remained completely suppressed. Further, no additional cerebral, renal, or cardiac lesions developed, and no increase in proteinuria occurred. In the T0.01 group, 17% of the animals died, fibrinoid necrosis tended to develop, organ lesions worsened, and proteinuria strongly increased. We conclude that (1) early ACE inhibition with trandolapril affords a long-lasting protection versus stroke and mortality both during and after the treatment period; and (2) that this beneficial effect is due to the suppression of fibrinoid necrosis formation and not to the drug's antihypertensive action. In contrast, both properties appear to contribute to trandolapril's renal and cardiac protective effects.
Richer
C
C
Departement de Pharmacologie, Faculté de Médecine, Paris-Sud, Le Kremlin-Bicêtre, France.
Fornes
P
P
Vacher
E
E
Bruneval
P
P
Giudicelli
J F
JF
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D002561:Cerebrovascular Disorders / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D006331:Heart Diseases / Q000517:prevention & control; D006973:Hypertension / Q000188:drug therapy / Q000503:physiopathology*; D007211:Indoles / Q000008:administration & dosage / Q000494:pharmacology*; D007674:Kidney Diseases / Q000517:prevention & control; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D013997:Time Factors
D000806:Angiotensin-Converting Enzyme Inhibitors; D007211:Indoles; C052035:trandolapril