Absence of nitrate tolerance after long-term treatment with ramipril: an endothelium-dependent mechanism.
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).
Berkenboom
G
G
Department of Cardiology, Erasme Hospital, Brussels, Belgium.
Fontaine
D
D
Unger
P
P
Baldassarre
S
S
Preumont
N
N
Fontaine
J
J
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001013:Aorta, Thoracic / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004361:Drug Tolerance / Q000502:physiology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009566:Nitrates / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D005996:Nitroglycerin / Q000494:pharmacology; D017257:Ramipril / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013481:Superoxides / Q000378:metabolism; D013997:Time Factors; D014665:Vasodilator Agents / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D009566:Nitrates; D014665:Vasodilator Agents; D013481:Superoxides; D019323:omega-N-Methylarginine; C065679:icatibant; D019001:Nitric Oxide Synthase; D005996:Nitroglycerin; D019808:Losartan; D017257:Ramipril; D001920:Bradykinin