ENDOTHELIN-1-INDUCED RELEASE OF THROMBOXANE A(2) INCREASES THE VASOCONSTRICTOR EFFECT OF ENDOTHELIN-1 IN POSTISCHEMIC REPERFUSED RAT HEARTS

Background The release and vasoconstrictor effect of endothelin-l (ET- l) are increased after myocardial ischemia, suggesting a role for ET-1 in ischemia/reperfusion injury. However, the mechanisms of the increa sed vasoconstriction by ET-1 are unknown. The aim of this study was to test whether ET-l-induced release of thromboxane A(2) (TXA(2)) contri butes to the vasoconstrictor effect of ET-1 in nonischemic hearts and whether such release can increase the vasoconstrictor effect of ET-1 i n postischemic reperfused hearts. Methods and Results ET-l-induced rel ease of TXA(2) was assessed by measurement of the concentrations of it s stable metabolite thromboxane B-2 (TXB(2)) in the coronary effluent of nonischemic and reperfused isolated rat hearts before and after adm inistration of 0.01 nmol ET-1 using an enzyme immunoassay. The contrib ution of ET-l-induced release of TXA, to the vasoconstrictor effect of ET-1 was assessed by measurement of the effects of ET-I with and with out the cyclooxygenase inhibitor indomethacin or the TXA(2)/endoperoxi de receptor antagonist SQ 30,741 using P-31 magnetic resonance spectro scopy. In nonischemic hearts, ET-1 led to a small increase in TXB(2) t he coronary effluent (3.9+/-1.5 pg/mL; n=3), but neither indomethacin nor SQ 30;741 significantly diminished the vasoconstrictor effects of ET-I (reduction of coronary how, 4.0+/-0.4 and 4.5+/-0.3 mL/min, respe ctively, versus 4.9+/-0.5 mL/min for ET-1 alone; n=8, 6, acid 9, re sp ectively). In postischemic reperfused hearts, however, ET-1 led to a g reater increase in TXB(2) (13.7+/-1.5 pg/mL; P<.05 versus nonischemic hearts; n=3), and both indomethacin and SQ 30,741 diminished the vasoc onstrictor effects of ET-I (reduction of coronary flow, 2.6+/-0.3 and 2.2+/-0.3 mL/min, respectively, versus 4.0+/-0.1 mL/min for ET-1 alone ; n=8, 8, and 6, respectively; P<.05). Furthermore, indomethacin and S Q 30;741 prevented the detrimental effects of ET-1 on left ventricular developed pressure, intracellular pH, and phosphocreatine during repe rfusion. Conclusions ET-l-induced release of TXA(2) does not significa ntly contribute to the vasoconstrictor effect of ET-1 in nonischemic h earts but can increase the vasoconstrictor effect of ET-1 in postische mic reperfused hearts.