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Absence of nitrate tolerance after long-term treatment with ramipril: an endothelium-dependent mechanism.

Abstract：

:To determine whether nitrate tolerance is attenuated on aortas isolated from rats treated in the long term with an angiotensin-converting enzyme (ACE) inhibitor, five groups of rats were studied in parallel. Group 1 received ramipril, 1 mg/ kg/day, p.o., for 6 weeks; group 2 received ramipril at the same dose for 4 weeks, and the last 2 weeks, a cotreatment with ramipril plus HOE 140 (a bradykinin B2 antagonist, 500 microg/ kg/day, s.c. injections); group 3 received losartan, 2 mg/kg/day, p.o., for 6 weeks; group 4 received losartan at the same dose, and the last 2 weeks, a cotreatment with losartan plus HOE 140; and group 5 served as control. Rings of thoracic aorta from these groups were studied in organ baths. After nitroglycerin preincubation (10 microM for 30 min) in vitro, the dose-response curves to nitroglycerin were significantly shifted to the right in the control group but not in group 1. This protective effect was partially present in group 3; it was completely abolished in groups 2 and 4. In groups 1 and 3, it also was abolished after nitric oxide synthase (cNOS) inhibition (L-NMMA incubation) or removal of the endothelium. Superoxide anion accumulation (assessed by lucigenin chemiluminescence) was increased by nitroglycerin incubation in the control group but not in groups 1 and 3. After in vivo exposure to nitroglycerin (50 mg/kg subcutaneously twice daily for 4 days), this protection against nitrate tolerance also was observed in groups 1 and 3. Thus long-term ACE inhibition prevents nitrate tolerance by an endothelium-dependent mechanism involving mainly an enhanced NO availability via B2-kinin receptor. This effect on the cNOS pathway seems to attenuate the superoxide anion accumulation induced by nitroglycerin exposure (probably via a downregulation of oxidative enzyme).

journal_name

J Cardiovasc Pharmacol

journal_title

Journal of cardiovascular pharmacology

authors

Berkenboom G,Fontaine D,Unger P,Baldassarre S,Preumont N,Fontaine J

doi

10.1097/00005344-199910000-00011

subject

Has Abstract

pub_date

1999-10-01 00:00:00

pages

547-53

issue

eissn

0160-2446

issn

1533-4023

journal_volume

pub_type

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Absence of nitrate tolerance after long-term treatment with ramipril: an endothelium-dependent mechanism.