title: Contractile and arrhythmic effects of endothelin receptor agonists in human heart in vitro: blockade with SB 209670.
abstract: It is known that binding sites with endothelin(A) (ET)(A) and ET(B) receptor characteristics coexist in human heart but little is known about the receptors that mediate cardiostimulant effects of ET receptor agonists or their consequences. Functional studies were performed on isolated human cardiac tissues. The maximal positive inotropic effects of ET-1 were right atrium > left atrium = right ventricle. The rank order of potencies of agonists in right atrium was sarafotoxin S6c > ET-1 = ET-2 > or = ET-3. The ET(A) receptor-selective compounds BQ123 (10 microM) and A-127722 (1 microM) only slightly blocked (<0.5 log-unit shift) the effects of lower concentrations of ET-1, and the ET(B) receptor antagonist Ro46-8443 (10 microM) did not cause blockade. SB 209670 caused concentration-dependent rightward shifts of ET-1 and sarafotoxin S6c concentration-effect curves with Schild slopes not different from one and affinities (-logM K(B)) of 7.0 and 7.9, respectively. ET-1 caused arrhythmic contractions in right atrial trabeculae that were prevented by 10 microM SB 209670 but not 10 microM BQ123 or 1 microM A-127722, precluding ET(A) receptors. ET-1 caused a higher incidence of arrhythmic contractions in tissues taken from patients treated with beta-blockers before surgery than in tissues from non-beta blocker-treated patients. Sarafotoxin S6c produced arrhythmias that were prevented by SB 209670. The positive inotropic effects of ET-1 in human right atrial myocardium are mediated mostly by a non-ET(A), non-ET(B) receptor. Ventricular inotropic ET receptors differ from atrial inotropic ET receptors. ET-1 induced arrhythmic contractions in human atria do not appear to be mediated by an ET(A) receptor.
authors.affiliation: Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: K M
authors.initials: KM
authors.lastname: Burrell
authors.forename: P
authors.initials: P
authors.lastname: Molenaar
authors.forename: P J
authors.initials: PJ
authors.lastname: Dawson
authors.forename: A J
authors.initials: AJ
authors.lastname: Kaumann
mesh_terms: D000328:Adult; D000368:Aged; D001145:Arrhythmias, Cardiac / Q000209:etiology*; D020517:Atrial Appendage; D003331:Coronary Vessels / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000494:pharmacology*; D005260:Female; D006352:Heart Ventricles; D006801:Humans; D066298:In Vitro Techniques; D007189:Indans / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009119:Muscle Contraction; D009200:Myocardial Contraction / Q000187:drug effects*; D017466:Receptors, Endothelin / Q000819:agonists*; D014757:Viper Venoms / Q000494:pharmacology
chemical_list: D016232:Endothelins; D007189:Indans; D017466:Receptors, Endothelin; D014757:Viper Venoms; C057354:sarafotoxins s6; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-