Effect of an Endothelin Receptor Antagonist and an Angiotensin Converting Enzyme Inhibitor on Metabolism and Contraction in the Ischemic and Reperfused Rabbit Heart

Abstract

ince the first report on endothelin (ET), 1 there have been many studies regarding its effects of cardiovascular system in various in vitro and in vivo models. Recently, ET has been reported to contribute to the extension of myocardial infarct size 2 and, moreover, ET-1 interacts with several neuroendocrine systems such as the renin-angiotensin system. 3 The effect of ET-1 in conjunction with the renin-angiotensin system on myocardial ischemia and reperfusion injury has not been clearly identified.The purpose of the present study was to examine the effect of the ETA/ETB receptor antagonist, TAK-044, and/or an angiotensin converting enzyme (ACE) inhibitor, temocaprilat, on the myocardial metabolism, contraction and relaxation of the ischemic and reperfused rabbit heart. Myocardial energy metabolism was measured by phosphorus 31-nuclear magnetic resonance ( 31 P-NMR) spectrometer. The administration of these agents was found to improve abnormal myocardial energy metabolism. Methods Isolated Heart PreparationMale Japanese white rabbits weighing 1.6-1.7 kg were anesthetized by intravenous injection of sodium pentobarbital (30 mg/kg). The chest was opened and heparin sodium (1,000 IU/kg) was injected through the right atrial appendage. The heart was quickly removed and after aortic cannulation the retrograde Langendorff perfusion was initiated without delay.The hearts were perfused at a constant perfusion pressure of 80 mmHg with modified Tyroide's solution at 37°C of the following composition (in mmol/L); NaCl 108, KCl 5, MgCl2 1, HEPES 5, CaCl2 2, glucose 10, sodium acetate 20. The perfusate was oxygenated with 100% O2 using a bubble-type artificial lung (Japan Medical Supply Co, Ltd, Hiroshima, Japan) adjusted to pH 7.40. The perfusate was recycled to an artificial lung after passing through the heart. A 40-m Swank filter (Nipro Co, Ltd, Tokyo, Japan) was placed within this route to remove any contaminants.To measure left ventricular (LV) pressure, a latex balloon was inserted into the left ventricle via a left atrial incision. The balloon was large enough so that no pressure was generated by itself over the range of left ventricular volumes used in the experiment. The balloon was filled with bubblefree saline and attached to a pressure transducer (Millar Instruments Inc, Houston, TX, USA) connected to a polygraph system RM-6000 (Nihon Kohden Co, Tokyo, Japan). The effect of an endothelin (ET) A/ETB receptor antagonist, TAK-044, and/or an angiotensin converting enzyme (ACE) inhibitor, temocaprilat, on myocardial metabolism and contraction during ischemia and reperfusion was examined by phosphorus 31-nuclear magnetic resonance ( 31 P-NMR) in Langendorff rabbit hearts. After normothermic 15 min global ischemia, 60 min of postischemic reperfusion was carried out. TAK-044 and/or temocaprilat was administered from 40 min prior to the global ischemia. Adenosine triphosphate (ATP), creatine phosphate, inorganic phosphate, pH, left ventricular systolic developed pressure (LVDev.P), left ventricular end-diastolic pressure ...

Role of endothelin in cardiovascular disease

“…150 Pre-treatment of rabbit hearts with TAK-044 and the ACE inhibitor, temocaprilat, demonstrated a significant potentiation of the positive effects on myocardial energy metabolism of each agent alone during ischaemia and reperfusion. 151 TAK-044 significantly reduced ischaemic cellular injury in ischaemia/reperfused rat hearts. 152 Both selective ET A antagonism, by BQ-123, and selective ET B antagonism, by BQ-788, improved myocardial contractility and endothelium-dependent vasodilatation in a heterotopically-transplanted rat heart reperfused after ischaemia.…”

Vasopeptidase Inhibition In A Canine Model Of Exercise‐Induced Left Ventricular Dysfunction

“…While chronic ACE inhibition reduces afterload and may increase coronary blood flow due to accumulation of bradykinin and production of nitric oxide, 15 there is currently no clear evidence for ACE inhibition‐mediated anti‐ischaemic activity during low‐flow ischaemia. To our knowledge, unequivocal ACE inhibition‐ mediated anti‐ischaemic activity has only been demonstrated in preclinical animal and cell‐based models that have used variations of global ischaemia and reperfusion 3–8 . These preclinical models do not address the possible effects of ACE inhibition during the transient low‐flow myocardial ischaemia that accompanies exertional angina.…”

“…of global ischaemia and reperfusion. [3][4][5][6][7][8] These preclinical models do not address the possible effects of ACE inhibition during the transient low-flow myocardial ischaemia that accompanies exertional angina. The effects of chronic ACE inhibition on exercise capacity in patients with stable angina have been evaluated in several clinical studies, with either a clearly negative [35][36][37][38][39] or marginally positive result.…”

“…There is an evolving body of evidence that suggests that chronic ACE inhibition may confer cardioprotection under certain circumstances. 1,2 While ACE inhibition has been shown to be cardioprotective in various models of global ischaemia and reperfusion, [3][4][5][6][7][8] improvements in ventricular function during low-flow myocardial ischaemia have not been demonstrated. Limited preclinical studies have reported bradykinin-related antiischaemic activity with the selective inhibition of NEP.…”