Ramipril prevents endothelial dysfunction induced by oxidized low-density lipoproteins: a bradykinin-dependent mechanism.
We wished to determine whether the acute toxic effects of oxidized LDL are attenuated in aortas isolated from rats chronically treated with an angiotensin-converting enzyme (ACE) inhibitor. In aortic rings incubated with human oxidized LDL (300 microg/mL), the endothelium-dependent relaxations to acetylcholine were attenuated, but not those to A23187 and to nitroprusside. This toxic effect of oxidized LDL was completely prevented in preparations coincubated with oxidized LDL and the nitric oxide (NO) precursor L-arginine (0.3 mmol/L). In aortas isolated from rats orally treated for 6 weeks with 10 mg/kg ramipril (group 1) or 1 mg/kg ramipril (group 2), this toxic effect of oxidized LDL was also markedly attenuated. In contrast, in aortas isolated from rats cotreated with ramipril (10 mg/kg) for 6 weeks and subcutaneous injections of Hoe 140 (a B2 kinin antagonist), 500 microg/kg per day for the last 2 weeks (group 3) or from rats orally treated for 6 weeks with losartan (an AT1-type angiotensin II receptor antagonist), 20 mg/kg (group 4), the inhibitory effect of oxidized LDL on acetylcholine-induced relaxations was similar to that observed in the control group (group 5). Moreover, long-term treatment with ramipril increased relaxations to acetylcholine in groups 1 and 2 and also relaxations to A23187 and aortic cGMP content in group 1, suggesting an enhanced NO availability. Thus, the protective effect of long-term ACE inhibition against the acute vascular toxicity of oxidized LDL is bradykinin dependent and seems to involve a facilitation of NO release via endothelial B2 kinin receptors.
Berkenboom
G
G
Department of Cardiology, Erasme Hospital, Brussels, Belgium.
Langer
I
I
Carpentier
Y
Y
Grosfils
K
K
Fontaine
J
J
D000109:Acetylcholine / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001011:Aorta / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D065168:Bradykinin Receptor Antagonists; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D006162:Guanylate Cyclase / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D017257:Ramipril / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D065168:Bradykinin Receptor Antagonists; D008077:Lipoproteins, LDL; C099252:oxidized low density lipoprotein; D009569:Nitric Oxide; C065679:icatibant; D006162:Guanylate Cyclase; D019808:Losartan; D017257:Ramipril; D000109:Acetylcholine; D001920:Bradykinin