Pharmacological properties of endothelin receptor subtypes mediating positive inotropic effects in rabbit heart.
The positive inotropic effect (PIE) of endothelin (ET) isoforms, ET-1 and ET-3, was similar in that 1) the PIE was associated with prolongation of isometric contractions, 2) the maximal response was approximately 60% of that to isoproterenol (Isomax), 3) the PIE was associated with acceleration of PI hydrolysis, and 4) it was selectively antagonized by phorbol 12,13-dibutyrate. Because the concentration-response curve for ET-1 was biphasic (whereas that for ET-3 was monophasic), ET-1 had a PIE greater than ET-3 up to 10(-8) M. ET-1 induced a PIE at 3 x 10(-14) M and higher, which reached a plateau of 10-20% of Isomax at 10(-12) M (first phase); the curve became steeper at 10(-9) M and higher (second phase), achieving the maximal response at 10(-7) M to 3 x 10(-7) M. An ETA-selective antagonist, BQ-123, did not affect the PIE of ET-1 up to 10(-7) M; it abolished the first phase at 10(-6) M but did not affect the second phase. BQ-123 at 10(-8) to 10(-6) M antagonized the PIE of ET-3, [Thr2]sarafotoxin S6b, and [Glu9]sarafotoxin S6b in a concentration-dependent manner. The PIE of ET-3 was abolished by 10(-6) M BQ-123. An ETB-selective partial agonist IRL-1620 neither elicited a PIE nor affected the PIE of ET-3. These findings indicate that the PIE of ET receptor agonists on rabbit ventricular myocardium cannot be totally explained by occupancy of the ETA or ETB receptor.
Kasai
H
H
Department of Pharmacology, Yamagata University School of Medicine, Japan.
Takanashi
M
M
Takasaki
C
C
Endoh
M
M
D000818:Animals; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007295:Inositol Phosphates / Q000378:metabolism; D007536:Isomerism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011817:Rabbits; D017466:Receptors, Endothelin / Q000378:metabolism*
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007295:Inositol Phosphates; D010456:Peptides, Cyclic; D017466:Receptors, Endothelin; C045537:inositol 4-phosphate; D015240:Phorbol 12,13-Dibutyrate; C072247:cyclo(Trp-Asp-Pro-Val-Leu)