Contractile and arrhythmic effects of endothelin receptor agonists in human heart in vitro: Blockade with SB 209670

It is known that binding sites with endothelin(A) (ET)(A) and ETB receptor characteristics coexist in human heart but little is known about the recept ors that mediate cardiostimulant effects of ET receptor agonists or their c onsequences. Functional studies were performed on isolated human cardiac ti ssues. The maximal positive inotropic effects of ET-1 were right atrium. le ft atrium = right ventricle. The rank order of potencies of agonists in rig ht atrium was sarafotoxin S6c > ET-1 = ET-2 greater than or equal to ET-3. The ETA receptor-selective compounds BQ123 (10 mu M) and A-127722 (1 mu M) only slightly blocked (<0.5 log-unit shift) the effects of lower concentrat ions of ET-1, and the ETB receptor antagonist Ro46-8443 (10 mu M) did not c ause blockade. SB 209670 caused concentration-dependent rightward shifts of ET-1 and sarafotoxin S6c concentration-effect curves with Schild slopes no t different from one and affinities (-logM K-B) of 7.0 and 7.9, respectivel y. ET-1 caused arrhythmic contractions in right atrial trabeculae that were prevented by 10 mu M SB 209670 but not 10 mu M BQ123 or 1 mu M A-127722, p recluding ETA receptors. ET-1 caused a higher incidence of arrhythmic contr actions in tissues taken from patients treated with beta-blockers before su rgery than in tissues from non-beta blocker-treated patients. Sarafotoxin S 6c produced arrhythmias that were prevented by SB 209670. The positive inot ropic effects of ET-1 in human right atrial myocardium are mediated mostly by a non-ETA, non-ETB receptor. Ventricular inotropic ET receptors differ f rom atrial inotropic ET receptors. ET-1 induced arrhythmic contractions in human atria do not appear to be mediated by an ETA receptor.