title: Cardiovascular effects of endothelin 1 in pithed spontaneously hypertensive rats: evaluation of its mechanism(s) of action.
abstract: The present experiments were carried out to investigate the cardiovascular effects of endothelin 1 (ET) in pithed spontaneously hypertensive (SH) rats and to evaluate its mechanism of action. The results show that ET (0.1-3 nmol/kg i.v.) is a powerful vasoconstrictor agent in the pithed rat. However, at a dose of 3 nmol/kg i.v. all the pithed animals "died" following a gradual decrease in mean arterial blood pressure and pulse pressure and changes in the form of the electrocardiogram (ECG). The predominant feature of the change in the ECG was a progressive decrease in the amplitude of the T wave resulting in a depression of the curve representing repolarization. Investigations in isolated perfused SH rat hearts showed that ET powerfully reduces coronary flow concentration-dependently (IC50 2.1 +/- 0.3 nM) an effect associated with sinus bradycardia and a decrease in coronary pressure amplitude. No overt ECG changes were seen. Control experiments with mechanical flow restriction suggest that bradycardia is a consequence of reduced coronary flow and that the ECG changes observed in vivo can be explained on the basis of coronary insufficiency and resulting myocardial hypoxia. Vasoconstrictor responses to angiotensin II (0.4 microgram/kg i.v.), phenylephrine (8 micrograms/kg i.v.) and ET (0.5 nmol/kg i.v.) were antagonised by around 70% by isradipine (0.03 mg/kg i.a.). The results suggest that endothelin-induced vasoconstriction may involve receptor operated channel activation and opening of voltage sensitive Ca2+ channels.
authors.affiliation: Preclinical Research, Sandoz Ltd., Basel, Switzerland.
authors.forename: A K
authors.initials: AK
authors.lastname: Mir
authors.forename: H
authors.initials: H
authors.lastname: Berthold
authors.forename: G E
authors.initials: GE
authors.lastname: Scholtysik
authors.forename: J R
authors.initials: JR
authors.lastname: Fozard
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D003655:Decerebrate State; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D016232:Endothelins; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D066298:In Vitro Techniques; D017275:Isradipine; D008297:Male; D010455:Peptides / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR
chemical_list: D016232:Endothelins; D010455:Peptides; D011725:Pyridines; D000804:Angiotensin II; D010656:Phenylephrine; D017275:Isradipine