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Vol. 292, Issue 1, 449-459, January 2000
Department of Pharmacology, University of Melbourne, Parkville,
Victoria, Australia (K.M.B., P.M., P.J.D.); Cardiovascular Research
Unit, Department of Medicine, University of Queensland, The Prince
Charles Hospital, Chermside, Queensland, Australia (P.M.); and
Physiological Laboratory, University of Cambridge, Cambridge, United
Kingdom (A.J.K.)
It is known that binding sites with endothelinA
(ET)A and ETB 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 
ET-3. The ETA receptor-selective compounds
BQ123 (10 µM) and A-127722 (1 µM) only slightly blocked (<0.5
log-unit shift) the effects of lower concentrations of ET-1, and the
ETB receptor antagonist Ro46-8443 (10 µM) 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 KB) of 7.0 and 7.9, respectively. ET-1 caused arrhythmic contractions in right
atrial trabeculae that were prevented by 10 µM SB 209670 but not 10 µM BQ123 or 1 µM A-127722, precluding ETA receptors.
ET-1 caused a higher incidence of arrhythmic contractions in tissues
taken from patients treated with 
-blockers before surgery than in
tissues from non- 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-ETA, non-ETB 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 ETA receptor.
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