trandolapril and Cerebrovascular-Disorders

Previous studies have demonstrated differences in the progression to glomerulosclerosis with the use of calcium channel blockers (CCB). The results with angiotensin-converting enzyme (ACE) inhibitors are more consistent. Moreover, only two studies have examined the combined effects of these drug classes on the development of glomerulosclerosis. The aim of the study presented here was to test the hypothesis that nonhypotensive doses of the combination (VT) of a nondihydropyridine CCB, verapamil (V), and an ACE-inhibitor, trandolapril (T), will slow the development of glomerulosclerosis better than either agent alone in stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP were randomized to treatment in one of three groups with nonhypotensive doses of these agents; a fourth group served as control (C). The control rats developed significant increases in proteinuria compared with the other groups (C, 190 +/- 35 mg.kg-1.d-1 versus VT, 19 +/- 12 mg.kg-1.d-1; P < 0.05). This finding correlated with the degree of glomerulosclerosis (mean severity grading for C, 3.31 +/- 0.21 versus VT, 1.6 +/- 0.51; P < 0.05). Moreover, there was no significant reduction in arterial pressure between these groups (C, 282 +/- 5 versus VT, 259 +/- 13 mm Hg; P = 0.12). Despite persisting hypertension, the rise in proteinuria was also attenuated in both the V group (57 +/- 21 mg.kg-1.d-1) and the T group (43 +/- 24 mg.kg-1.d-1). However, compared with the control rats, kidney morphology was unchanged. Lastly, creatinine clearance was better preserved in the VT group compared with the control group (C, 0.57 +/- 0.01 versus VT, 0.74 +/- 0.06 mL.min-1.100 g-1; P < 0.05). It was concluded that the combination of nonhypotensive doses of VT attenuates the rise in proteinuria and progression to glomerulosclerosis. This study supports the concept that VT may have effects on the glomerulus that are independent of blood pressure reduction.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Blood Pressure; Calcium Channel Blockers; Cerebrovascular Disorders; Creatinine; Disease Progression; Disease Susceptibility; Drug Synergism; Drug Therapy, Combination; Glomerulosclerosis, Focal Segmental; Hypertension; Indoles; Kidney; Male; Metabolic Clearance Rate; Proteinuria; Rats; Rats, Inbred SHR; Verapamil

The effects of chronic therapy with the angiotensin-converting enzyme (ACE) inhibitor trandolapril and/or Ca2+ antagonist verapamil on endothelial and vascular smooth muscle (VSM) function were studied in spontaneously hypertensive, stroke-prone rats (SHRSP). Dosages decreasing systolic blood pressure (SBP) by 20% were administered orally (p.o.) by gavage as monotherapy or combination therapy for 8 weeks, beginning at age 6 weeks. Combination therapy dosages were the same as those used in monotherapy (trandolapril 0.7 mg/kg/day verapamil 20 mg/kg/day) in one group; the second group received only half the monotherapy dosage. The study was placebo-controlled and performed in parallel groups. Isometric tension was measured in aortic rings suspended in organ chambers (95% C2/5% CO2; 37 degrees C). SBP decreased in all groups, as compared with placebo [30-47 mm Hg, analysis of variance (ANOVA), p < 0.05], but decrease was more pronounced in rats receiving high-dose combination (76 mm Hg, ANOVA, p < 0.05). In norepinephrine (NE)-contracted rings, endothelium-dependent relaxation to acetylcholine (ACh) was augmented similarly with all forms of therapy (maximal relaxations 89-94%) as compared with placebo (64 +/- 6%, p < 0.05). In contrast, the response to sodium nitroprusside (SNP) was similar in all groups (NS). In quiescent rings, ACh elicited endothelium-dependent contractions (in the presence of N omega-monomethyl-L-arginine, L-NAME) that were not affected by therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Administration, Oral; Angiotensin-Converting Enzyme Inhibitors; Animals; Body Weight; Cerebrovascular Disorders; Drug Administration Schedule; Drug Therapy, Combination; Endothelium, Vascular; Hypertension; Indoles; Male; Muscle Contraction; Nitric Oxide; Norepinephrine; Rats; Rats, Inbred SHR; Verapamil

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.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Cerebrovascular Disorders; Heart Diseases; Hypertension; Indoles; Kidney Diseases; Male; Rats; Rats, Inbred SHR; Time Factors