Angiotensin II type 1 receptor antagonism improves endothelial vasodilator function in L-NAME-induced hypertensive rats by a kinin-dependent mechanism.
OBJECTIVE
This study was designed to investigate the ability of a chronic blockade of angiotensin II type 1 receptors with losartan to reverse the endothelial dysfunction present in N-nitro-L-arginine methyl ester (L-NAME)-treated hypertensive rats and the possible dependence of this effect on bradykinin B2-receptor activation.


METHODS
Rats treated with L-NAME alone (60 mg/kg per day for 8 weeks) or with L-NAME + losartan, L-NAME + icatibant (a bradykinin B2-receptor antagonist) and L-NAME + losartan + icatibant were studied. Losartan, icatibant or losartan + icatibant were co-administered with L-NAME during the last 4 weeks of the experiment. Endothelial nitric oxide synthase gene expression in aortic tissues, plasma nitrite/nitrate concentrations, the relaxant effect of acetylcholine on norepinephrine-precontracted aortic rings and 6-keto-PGF1alpha release from aortic rings were used as markers of the endothelial function.


RESULTS
Rats treated with L-NAME alone and L-NAME + icatibant showed, as compared with untreated animals, a clear-cut increase in systolic blood pressure and a decrease of all the markers of endothelial function evaluated. In L-NAME-rats, administration of losartan reduced the systolic blood pressure and restored endothelial nitric oxide synthase gene expression, plasma nitrite/nitrate levels, the relaxant activity of acetylcholine on aortic rings and the generation of 6-keto-PGF1alpha from the aortic tissues. Co-administration of icatibant with losartan blunted the stimulatory effect of losartan on the markers of endothelial function evaluated.


CONCLUSIONS
These results demonstrated that losartan is capable of reversing the endothelial vasodilator dysfunction in L-NAME-induced hypertensive rats, and that the beneficial effect of losartan is mediated by bradykinin B2-receptor activation.
De Gennaro Colonna
Vito
V
Department of Pharmacology, Chemotherapy and Medical Toxicology, University of Milan, Milan, Italy. vita.colonna@unimi.it
Fioretti
Simona
S
Rigamonti
Antonello
A
Bonomo
Sara
S
Manfredi
Barbara
B
Muller
Eugenio E
EE
Berti
Ferruccio
F
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; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065094:Bradykinin B2 Receptor Antagonists; D004730:Endothelium, Vascular / Q000737:chemistry / Q000187:drug effects / Q000503:physiopathology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D007705:Kinins / Q000502:physiology*; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D009566:Nitrates / Q000097:blood; D052250:Nitric Oxide Synthase Type III / Q000032:analysis / Q000235:genetics; D009573:Nitrites / Q000097:blood; D009599:Nitroprusside / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000502:physiology; D043782:Receptor, Bradykinin B2 / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D065094:Bradykinin B2 Receptor Antagonists; D007705:Kinins; D009566:Nitrates; D009573:Nitrites; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D043782:Receptor, Bradykinin B2; D009599:Nitroprusside; D015121:6-Ketoprostaglandin F1 alpha; C065679:icatibant; D052250:Nitric Oxide Synthase Type III; D019808:Losartan; D000109:Acetylcholine; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester