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 prolongat ion of isometric contractions, 2) the maximal response was similar to 60% of that to isoproterenol (Iso(max)), 3) the PIE was associated wit h 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 ha d 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 Iso(max) at 1 0(-12) M (first phase); the curve became steeper at 10(-9) M and highe r (second phase), achieving the maximal response at 10(-7) M to 3 x 10 (-7) M. An ET(A)-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 d id not affect the second phase. BQ-123 at 10(-8) M to 10(-6) M antagon ized the PIE of ET-3, [Thr(2)]sarafotoxin S6b, and [Glu(9)]sarafotoxin S6b in a concentration-dependent manner. The PIE of ET-3 was abolishe d by 10(-6) M BQ-123. An ET(B)-selective partial agonist IRL-1620 neit her elicited a PIE nor affected the PIE of ET-3. These findings indica te that the PIE of ET receptor agonists on rabbit ventricular myocardi um cannot be totally explained by occupancy of the ET(A) or ET(B) rece ptor.