Angiotensin-converting enzyme inhibition and angiotensin AT1-receptor antagonism equally improve endothelial vasodilator function in L-NAME-induced hypertensive rats.
Male Sprague-Dawley rats given N(omega)-nitro-L-arginine methyl ester (L-NAME) in drinking water for 8 weeks showed: (1) a clear-cut increase in systolic blood pressure; (2) a consistent decrease of endothelial-cell nitric oxide synthase (eNOS) gene expression in aortic tissue; (3) a marked reduction of plasma nitrite/nitrate concentrations; (4) a reduction of the relaxant activity of acetylcholine (ACh, from 10(-10) to 10(-4) M) on norepinephrine-precontracted aortic rings (reduction by 48+/-5%); (5) a marked decrease (-58%) of the basal release of 6-keto-prostaglandin F1alpha (6-keto-PGF1alpha) from aortic rings. In L-NAME-treated rats, administration in the last 4 weeks of either the angiotensin-converting enzyme (ACE) inhibitor enalapril (10 mg/kg/day in tap water) or the angiotensin AT(1)-receptor antagonist losartan (10 mg/kg/day in tap water) decreased systolic blood pressure levels, completely restored eNOS mRNA levels in aortic tissue and plasma nitrite/nitrate levels, and allowed a consistent recovery of both the relaxant activity of acetylcholine and the generation of 6-keto-PGF1alpha. Coadministration of icatibant, a bradykinin B(2)-receptor antagonist (200 microg/kg/day), with enalapril blunted the stimulatory effect of the ACE inhibitor on eNOS mRNA expression, circulating levels of nitrite/nitrate, the relaxant activity of ACh and the release of 6-keto-PGF1alpha in L-NAME-treated rats. The generation of 6-keto-PGF1alpha from aortic rings was also decreased in rats coadministered icatibant with losartan. These findings indicate that (1) the ACE inhibitor enalapril and the angiotensin AT(1)-receptor blocker losartan are equally effective to reverse NAME-induced endothelial dysfunction; (2) the beneficial effect of enalapril on the endothelial vasodilator function in L-NAME-treated rats is mediated by bradykinin B(2)-receptor activation; and (3) the enhanced endothelial generation of prostacyclin induced by losartan in L-NAME rats is also mediated by bradykinin B(2)-receptor activation.
De Gennaro Colonna
Vito
V
Department of Pharmacology, Chemoterapy and Medical Toxicology, University of Milan, Via Vanvitelli 32, 20129 Milan, Italy. vito.colonna@unimi.it
Rigamonti
Antonello
A
Fioretti
Simona
S
Bonomo
Sara
S
Manfredi
Barbara
B
Ferrario
Paolo
P
Bianchi
Mauro
M
Berti
Ferruccio
F
Muller
Eugenio E
EE
Rossoni
Giuseppe
G
D015121:6-Ketoprostaglandin F1 alpha / Q000378:metabolism; D000109:Acetylcholine / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065168:Bradykinin Receptor Antagonists; D004656:Enalapril / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006973:Hypertension / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology*; D066298:In Vitro Techniques; D019808:Losartan / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000494:pharmacology*; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D009573:Nitrites / Q000097:blood; D009638:Norepinephrine / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013599:Systole; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D065168:Bradykinin Receptor Antagonists; D004791:Enzyme Inhibitors; D009566:Nitrates; D009573:Nitrites; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D014665:Vasodilator Agents; D015121:6-Ketoprostaglandin F1 alpha; D004656:Enalapril; C065679:icatibant; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D007703:Peptidyl-Dipeptidase A; D019808:Losartan; D000109:Acetylcholine; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester; D009638:Norepinephrine