Enalapril and quinapril improve endothelial vasodilator function and aortic eNOS gene expression in L-NAME-treated rats.
Endothelial dysfunction ensuing inhibition of nitric oxide synthase (NOS) was investigated in male Sprague-Dawley rats given N(omega)-nitro-L-arginine methyl ester (L-NAME) in drinking water for 8 weeks. Age-matched rats served as controls. L-NAME-treated rats, as compared to control animals, showed: (1) a clear-cut increase in systolic blood pressure; (2) a consistent decrease of endothelial-cell NOS (eNOS) gene expression in aortic tissue; (3) a reduction of the relaxant activity of acetylcholine (ACh, from 10(-10) to 10(-4) M) on norepinephrine-precontracted aortic rings (reduction by 52+/-5%); (4) a marked decrease (-50%) of the basal release of 6-keto-prostaglandin F(1 alpha) (6-keto-PGF(1 alpha)) from aortic rings. In L-NAME-treated rats, administration in the last 2 weeks of either the angiotensin-converting enzyme inhibitor enalapril (1 mg/kg/day) or the cognate drug quinapril (1 mg/kg/day) decreased systolic blood pressure levels, completely restored eNOS mRNA levels in aortic tissue, and allowed a consistent recovery of both the relaxant activity of ACh and the generation of 6-keto-PGF(1 alpha). No difference was present in the ability of the two angiotensin-converting enzyme inhibitors to reverse NAME-induced endothelial dysfunction. These findings indicate that L-NAME-induced hypertension in the rat relies on the marked impairment of the endothelial vasodilator function, with an ensuing contribution by a decreased production of prostacyclin by the endothelial cells. Angiotensin-converting enzyme inhibition by enalapril or quinapril was equally effective in improving endothelial vasodilator function, prostacyclin endothelial production and restoring aortic eNOS mRNA.
De Gennaro Colonna
Vito
V
Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Via Vanvitelli 32, 20129 Milan, Italy. vito.colonna@unimi.it
Rossoni
Giuseppe
G
Rigamonti
Antonello
A
Bonomo
Sara
S
Manfredi
Barbara
B
Berti
Ferruccio
F
Muller
Eugenio
E
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004656:Enalapril / Q000494:pharmacology* / Q000627:therapeutic use; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy / Q000201:enzymology; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D000077583:Quinapril; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044005:Tetrahydroisoquinolines; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000627:therapeutic use
D000806:Angiotensin-Converting Enzyme Inhibitors; D007546:Isoquinolines; D012333:RNA, Messenger; D044005:Tetrahydroisoquinolines; D014665:Vasodilator Agents; D015121:6-Ketoprostaglandin F1 alpha; D004656:Enalapril; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D000077583:Quinapril; D019331:NG-Nitroarginine Methyl Ester