Protective Effect of the Specific Endothelin-1 Antagonist BQ610 on Mechanical Function and Energy Metabolism During Ischemia/Reperfusion Injury in Isolated Perfused Rat Hearts

Abstract

Endothelin-1 (ET-1) has been suggested to be involved in the pathophysiology of ischemia/reperfusion injury, but direct proof for this is still sparse. We tested whether protection of high-energy phosphate metabolism contributes to the beneficial effects of ETA receptor antagonists during ischemia/reperfusion. In isolated, buffer-perfused rat hearts, isovolumic function was measured by a left ventricular (LV) balloon, and 31P nuclear magnetic resonance spectra were continuously recorded. Two protocols were performed: (a) 15-min control, 30-min total, global ischemia, and 15-min reperfusion; and (b) 15-min control, 15-min total, global ischemia, and 30-min reperfusion. Treatment with BQ610 (1.75 micrograms/min) or saline was started during control and continued throughout the protocol. BQ610 did not affect function or energy metabolism under control conditions. In BQ610-treated hearts subjected to 30-min ischemia, time to ischemic contracture was significantly delayed (treated 10.6 +/- 0.4 min; untreated 8.1 +/- 0.7 min), and end-diastolic pressure (EDP) remained lower (after 30-min ischemia 26 +/- 2 vs. 35 +/- 2 mm Hg). In addition, recovery of mechanical function in BQ610-treated hearts was accelerated during reperfusion. BQ610 did not affect ATP but significantly accelerated and increased creatine phosphate (51 +/- 7 vs. 37 +/- 3%) recovery on reperfusion after 30-min ischemia. BQ610-treated hearts subjected to 15-min ischemia also showed lower EDP during ischemia and accelerated recovery of mechanical function during reperfusion. However, in this case, there were no differences in high-energy phosphate concentrations between treated and untreated hearts. We conclude that the protective action of BQ610 on mechanical function during ischemia/reperfusion injury can be but is not consistently associated with beneficial effects on cardiac high-energy phosphate metabolism.

Different Contributions of Endothelin-A and Endothelin-B Receptors in Postischemic Cardiac Dysfunction and Norepinephrine Overflow in Rat Hearts

“…[12][13][14][37][38][39] In the present study, we also observed that ABT-627 alone and the combination of ABT-627/A-192621 had similar protective effects against postischemic cardiac dysfunction in rat hearts. Previous studies have demonstrated that ET-1 mRNA expression and its peptide production are increased in cardiomyocytes subjected to ischemia 40 and that plasma ET-1 levels are elevated in both humans 5 and experimental animals 11,41 with myocardial infarction.…”

“…Actually, a monoclonal antibody against ET-1 can reduce infarct size in rats after coronary artery ligation and reperfusion. 11 Moreover, both selective ET A receptor antagonists and nonselective ET A /ET B receptor antagonists exhibited protective effects against postischemic cardiac dysfunction, [12][13][14] although others failed to observe such beneficial effects. 15 Norepinephrine (NE) release from cardiac sympathetic nerve endings occurs mainly by 2 pathways: Ca 2ϩ -dependent exocytotic release and Ca 2ϩ -independent carrier-mediated release via activation of the NE transporter (NET) in the outward direction.…”

Effects of exogenous big endothelin-1 on postischemic cardiac dysfunction and norepinephrine overflow in rat hearts

“…It has been mentioned that ET-1 plays a critical role in heart injury mostly through the activation of ET A receptors. 7,9,10,14 However, our present data showed that ET-1 generated from exogenously applied big ET-1 preferentially acts on ET B receptors rather than ET A receptors in the postischemic heart. In the present study, we have chosen the doses of exogenous big ET-1 in the ranges from 0.1 to 1 nM.…”

“…[7][8][9][10]14 In addition, we obtained evidence that exogenously applied ET-1 to the ischemic heart further enhanced the NE overflow and exacerbates the postischemic cardiac dusfunction. 10 In the present study, we expected that exogenously applied big ET-1 would cause deterioration of cardiac function following the global ischemia and reperfusion, because exogenously applied big ET-1 exerts qualitatively similar effects to ET-1, in the cardiovascular system in vivo and in vitro.…”

“…Indeed, both selective ET A receptor antagonists and non-selective ET A /ET B receptor antagonists exhibited protective effects against the postischemic cardiac dysfunction. [7][8][9][10] Enhancement of cardiac sympathetic nerve activity and its consequent effect on norepinephrine (NE) overflow from the nerve endings has also been considered as a factor that aggravates cell damage in ischemic myocardium. 11 In fact, it has been demonstrated that the negative modulation of NE release significantly suppresses postischemic cardiac dysfunction.…”