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(Circulation. 1996;94:742-747.)
© 1996 American Heart Association, Inc.

Articles

Endothelin-1–Induced Release of Thromboxane A₂ Increases the Vasoconstrictor Effect of Endothelin-1 in Postischemic Reperfused Rat Hearts

Christian E. Zaugg, PhD; Pius S. Hornstein, PhD; Peili Zhu, MD; David Simper, MD; Thomas F. Luscher, MD; Peter R. Allegrini, PhD; Peter T. Buser, MD

the Division of Cardiology (C.E.Z., P.S.H., P.Z., D.S., P.T.B.), University Hospital Basel; Division of Cardiology (T.F.L.), University Hospital Bern; and Biology Research Laboratory, CIBA Ltd (P.R.A.), Basel, Switzerland.

Correspondence to Christian E. Zaugg, PhD, Division of Cardiology, DIM, University Hospital, Petersgraben 4, 4031 Basel, Switzerland.

Background The release and vasoconstrictor effect of endothelin-1 (ET-1) are increased after myocardial ischemia, suggesting a role for ET-1 in ischemia/reperfusion injury. However, the mechanisms of the increased vasoconstriction by ET-1 are unknown. The aim of this study was to test whether ET-1–induced release of thromboxane A₂ (TXA₂) contributes to the vasoconstrictor effect of ET-1 in nonischemic hearts and whether such release can increase the vasoconstrictor effect of ET-1 in postischemic reperfused hearts.

Methods and Results ET-1–induced release of TXA₂ was assessed by measurement of the concentrations of its stable metabolite thromboxane B₂ (TXB₂) in the coronary effluent of nonischemic and reperfused isolated rat hearts before and after administration of 0.01 nmol ET-1 using an enzyme immunoassay. The contribution of ET-1–induced release of TXA₂ to the vasoconstrictor effect of ET-1 was assessed by measurement of the effects of ET-1 with and without the cyclooxygenase inhibitor indomethacin or the TXA₂/endoperoxide receptor antagonist SQ 30,741 using ³¹P magnetic resonance spectroscopy. In nonischemic hearts, ET-1 led to a small increase in TXB₂ in the coronary effluent (3.9±1.5 pg/mL; n=3), but neither indomethacin nor SQ 30,741 significantly diminished the vasoconstrictor effects of ET-1 (reduction of coronary flow, 4.0±0.4 and 4.5±0.3 mL/min, respectively, versus 4.9±0.5 mL/min for ET-1 alone; n=8, 6, and 9, respectively). In postischemic reperfused hearts, however, ET-1 led to a greater increase in TXB₂ (13.7±1.5 pg/mL; P<.05 versus nonischemic hearts; n=3), and both indomethacin and SQ 30,741 diminished the vasoconstrictor effects of ET-1 (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 SQ 30,741 prevented the detrimental effects of ET-1 on left ventricular developed pressure, intracellular pH, and phosphocreatine during reperfusion.

Conclusions ET-1–induced release of TXA₂ does not significantly contribute to the vasoconstrictor effect of ET-1 in nonischemic hearts but can increase the vasoconstrictor effect of ET-1 in postischemic reperfused hearts.

Key Words: endothelin • thromboxane • ischemia • reperfusion • vasoconstriction

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