Endothelin-1-induced release of thromboxane A2 increases the vasoconstrictor effect of endothelin-1 in postischemic reperfused rat hearts

• Published in: Circulation (New York, N.Y.) Vol. 94; no. 4; pp. 742 - 747
• Main Authors: ZAUGG, C. E, HORNSTEIN, P. S, ZHU, P, SIMPER, D, LÜSCHER, T. F, ALLEGRINI, P. R, BUSER, P. T
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 15.08.1996; American Heart Association, Inc
• Subjects: Adenosine Triphosphate - metabolism; Animals; Biological and medical sciences; Cardiology. Vascular system; Coronary Circulation - drug effects; Coronary heart disease; Cyclooxygenase Inhibitors - pharmacology; Endothelins - pharmacology; Heart; Heart - drug effects; Heart - physiology; Immunoenzyme Techniques; In Vitro Techniques; Indomethacin - pharmacology; Magnetic Resonance Spectroscopy; Medical sciences; Models, Cardiovascular; Myocardial Contraction - drug effects; Myocardial Reperfusion; Myocardium - metabolism; Phosphates - metabolism; Phosphocreatine - metabolism; Rats; Rats, Sprague-Dawley; Receptors, Thromboxane - antagonists & inhibitors; Thromboxane A2 - analogs & derivatives; Thromboxane A2 - metabolism; Thromboxane A2 - pharmacology; Time Factors; Vasoconstriction - drug effects; Vasoconstrictor Agents; Ventricular Function, Left - drug effects; Animal model; Infarct; Rat; Pathogenesis; Thromboxane A2; Rodentia; Cardiovascular disease; Endothelin 1; Experimental study; Coronary heart disease; Myocardial disease; Vasodilation; Vertebrata; Mammalia; Animal; Myocardium; Biological effect
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.94.4.742

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. 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. 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.