Combined blockade of endothelin-1 and thromboxane A(2) receptors against postischaemic contractile dysfunction in rat hearts.

1. Endothelin-1 (ET-1) may play a role in myocardial ischaemia/reperfusion injury because both the release and vasoconstrictor effect of ET-1 are increased after ischaemia. Since the increased vasoconstrictor effect of ET-1 can be mediated by ET-1-induced release of thromboxane A(2) (TXA(2)), the aim of this study was to test whether combined blockade of ET and TXA(2) receptors protects the coronary flow, contractile performance, and cardiac energy metabolism during ischaemia and reperfusion. 2. Bosentan (antagonist for ET(A) and ET(B) receptors, 1 microM based on concentration-response curves of ET-1), SQ 30,741 (antagonist of TXA(2) receptors, 0.1 microM), or the combination thereof was administered to isolated perfused rat hearts undergoing 15 min of global ischaemia and 60 min of reperfusion. 3. Neither bosentan or SQ 30,741 alone, nor the combination thereof, improved the incomplete postischaemic recovery of coronary flow, left ventricular developed pressure, phosphocreatine, or ATP. However, they attenuated ischaemia-induced acidosis but this did not translate into a measurable effect on haemodynamic or metabolic variables. 4. Thus, combined blockade of ET and TXA(2) receptors does not protect the coronary flow, contractile performance, and cardiac energy metabolism during ischaemia and reperfusion in isolated perfused rat hearts. This finding suggests that neither ET-1 nor ET-1-induced release of TXA(2) play a major role in the postischaemic recovery of the cardiac contractile function and energy metabolism.

Bradykinin-dependent cardioprotective effects of losartan against ischemia and reperfusion in rat hearts.

It is unclear whether losartan, an angiotensin II type 1 (AT1) receptor antagonist, protects the heart against acute ischemia-reperfusion injury. Therefore we evaluated cardiac protection conferred by pre- and postischemic treatment as well as by exclusive postischemic treatment with losartan. Furthermore, we sought to determine both the extent of this protection and its dependence on bradykinin in comparison with quinaprilat, a cardioprotective angiotensin-converting enzyme inhibitor. Cardiac protection was assessed as recovery of coronary flow, left ventricular developed pressure, phosphocreatine, and adenosine triphosphate (ATP) in isolated perfused rat hearts after 15 min of global ischemia and 30 min of postischemic reperfusion. We found that, in hearts pre- and postischemically treated with losartan (1 microM) or quinaprilat (0.1 microM), these variables all recovered significantly better than those in untreated control hearts. In hearts that were only postischemically treated with losartan, these variables also recovered significantly better than those in control hearts. In contrast, in hearts treated with the combination of the bradykinin B2 receptor antagonist Hoe 140 with quinaprilat or losartan, the recovery of the variables no longer differed from that in control hearts. In conclusion, losartan protects the heart against acute ischemia-reperfusion injury. This protection can be achieved by pre- and postischemic treatment as well as by exclusive postischemic treatment with losartan. Furthermore, the extent of this protection is equivalent to that conferred by quinaprilat and, unexpectedly, dependent on bradykinin.

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

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.