Urotensin II-induced hypotensive responses in Wistar-Kyoto (Wky) and spontaneously hypertensive (Shr) rats.
Human urotensin II (hU-II) is a potent vasoactive peptide which modulates some of the functions of the cardiovascular and other systems. The in vivo mechanism of action by which hU-II may influence blood pressure in developmental and pathological conditions, is poorly understood. Herein, the blood pressure effects of hU-II (0.1-10 nmol/kg) injected intravenously (i.v.) were studied on ketamine/xylazine anesthetized male WKY and SHR rats aged 4 and 8 weeks. hU-II elicited dose-dependent decreases in mean arterial pressure in both strains of animals. The hypotensive responses to hU-II were, however, significantly higher in SHR rats, independently of age. Four-week-old SHR rats (which are normotensive) were, however, less responsive than their hypertensive 8-week-old counterparts. A series of pharmacological inhibitors were used to identify putative endogenous (endothelial) factors that might account for the hU-II-mediated hypotension in 8-week-old SHR. These include the non-selective nitric oxide synthase inhibitor L-NAME (5 micromol/kg), the non-selective cyclooxygenase inhibitor meclofenamate (16 micromol/kg), the voltage-sensitive and ATP-sensitive K+-channel inhibitors, 4-aminopyridine (5 micromol/kg) and glybenclamide (10 micromol/kg), the cytochrome P450 CYP2C9 inhibitor sulfaphenazole (15 micromol/kg), the cytoskeletal fixation agent phalloidin (15 micromol/kg), the endothelin ETB receptor antagonist BQ-788(35 micromol/kg), the bradykinin B2 receptor antagonist HOE 140 (0.5 micromol/kg), the angiotensin AT2 antagonist PD 123319(10 micromol/kg) and the UT receptor antagonist urantide (10 micromol/kg). These agents were administered i.v. either at 2.5, 10 or 40 min prior hU-II injection (10 nmol/kg). Among these inhibitors, sulfaphenazole and phalloidin were able to reduce hU-II-induced hypotension. This suggests that the vasodepressor effect of hU-II is mediated by UT receptors and relies in part on the release of epoxide related products; increased microvascular permeability may also contribute to the blood pressure lowering effect of hU-II. Since urantide blocks the constrictor effects of hU-II on isolated aorta, but is inactive against the hypotensive action of hU-II in vivo, the results presented in this paper provide, for the first time, evidence for the existence of two different functional sites for hU-II.
Gendron
Gabrielle
G
Department of Pharmacology, Faculty of medicine, Université de Sherbrooke, Sherbrooke, Canada J1H 5N4.
Gobeil
Fernand
F
Bélanger
Simon
S
Gagnon
Sandra
S
Regoli
Domenico
D
D'Orléans-Juste
Pedro
P
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007022:Hypotension / Q000139:chemically induced / Q000503:physiopathology*; D007275:Injections, Intravenous; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D036361:Peptide Hormones / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology*; D010590:Phalloidine / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017208:Rats, Wistar; D013045:Species Specificity; D013426:Sulfaphenazole / Q000494:pharmacology; D013997:Time Factors
D047908:Intracellular Signaling Peptides and Proteins; D036361:Peptide Hormones; C479080:UTS2B protein, human; D013426:Sulfaphenazole; D010590:Phalloidine; D001920:Bradykinin