Attenuation of cyclosporine A-induced vascular toxicity by ramipril.
We wished to determine whether chronic inhibition of angiotensin-converting enzyme (ACE) prevents the vascular toxicity of cyclosporine A (Cx). In aortas isolated from rats treated with ramipril [10 mg/kg/day orally (p.o.) for 4 weeks], the endothelium-dependent relaxations to acetylcholine (ACh) were potentiated (the area under the curve (AUC) decreased from 154 +/- 35 to 63 +/- 12, p < 0.05), but contractions induced by phenylephrine (PE) and angiotensin II (AII) were not affected. Therefore, we studied three groups of rats in parallel. Group 1 received ramipril 10 mg/kg/day p.o. for 4 weeks and ramipril 10 mg/kg/day p.o. plus Cx 20 mg/kg/day intramuscularly, in fifth week; group 2 received Cx only (20 mg/kg/day i.m. for 1 week), and group 3 served as control. In group 2, ACh-induced relaxations were reduced as compared with those of the control group (AUC increased from 141 +/- 34 to 240 +/- 32, p < 0.05), whereas in group 1, AUC was not significantly different from that of group 3 (195 +/- 28 vs. 141 +/- 34). In group 2, PE- and AII-induced contractions were enhanced; AUC values for PE and AII were 495 +/- 45 versus 348 +/-38 in group 3 and 424 +/- 28 versus 314 +/- 17 in group 3, respectively (p < 0.05). In group 1, AUCs for PE and AII were not significantly different from those of group 3. After mechanical removal of the endothelium, the increased responsiveness to PE and AII persisted in group 2 whereas AUC values in group 1 were not different from those of group 3.(ABSTRACT TRUNCATED AT 250 WORDS)
Berkenboom
G
G
Department of Cardiology, Erasme Hospital, Brussels, Belgium.
Brékine
D
D
Unger
P
P
Gulbis
B
B
Fontaine
J
J
D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D016572:Cyclosporine / Q000037:antagonists & inhibitors* / Q000633:toxicity; D004730:Endothelium, Vascular / Q000187:drug effects; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010656:Phenylephrine / Q000494:pharmacology; D017257:Ramipril / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D000804:Angiotensin II; D010656:Phenylephrine; D016572:Cyclosporine; D017257:Ramipril; D000109:Acetylcholine