Protective effect of pretreatment with the calcium antagonist anipamil on the ischemic-reperfused rat myocardium: A phosphorus-31 nuclear magnetic resonance study

Abstract

To assess whether the prophylactic administration of anipamil, a new calcium antagonist, protects the heart against the effects of ischemia and reperfusion, rats were injected intraperitoneally twice daily for 5 days with 5 mg/kg body weight of this drug. The heart was then isolated and perfused by the Langendorff technique. Phosphorus-31 nuclear magnetic resonance spectroscopy was used to monitor myocardial energy metabolism and intracellular pH during control perfusion and 30 min of total ischemia (37 degrees C), followed by 30 min of reperfusion. Pretreatment with anipamil altered neither left ventricular developed pressure under normoxic conditions nor the rate and extent of depletion of adenosine triphosphate (ATP) and creatine phosphate during ischemia. Intracellular acidification, however, was attenuated. On reperfusion, hearts from anipamil-pretreated animals recovered significantly better than untreated hearts with respect to replenishment of ATP and creatine phosphate stores, restitution of low levels of intracellular inorganic phosphate and recovery of left ventricular function and coronary flow. Intracellular pH recovered rapidly to preischemic levels, whereas in untreated hearts a complex intracellular inorganic phosphate peak indicated the existence of areas of different pH within the myocardium. It is concluded that anipamil pretreatment protects the heart against some of the deleterious effects of ischemia and reperfusion. Because this protection occurred in the absence of a negative inotropic effect during normoxia, it cannot be attributed to an energy-sparing effect during ischemia. Therefore, alternative mechanisms of action are to be considered.

Prolonged protective effect of the calcium antagonist anipamil on the ischemic reperfused rabbit myocardium: Comparison with verapamil

“…Our findings, however, are apparently in contrast with the results of Kirkels et al [41], who have recently shown a cardioprotective action of anipamil in the rat in the absence of a negative inotropic effect during normoxia and of an energy-sparing effect during ischemia. They proposed that the mechanism of action of anipamil is related to direct preservation of the cell membrane during ischemia.…”

Effect of D-600 on ischemic and reperfused rabbit myocardium: relation with timing and modality of administration

“…From other studies conducted with various different calcium antagonists, it is evident that for optimal direct myocardial protection they should be present before, or at the latest, during the ischemic episode (13,18,25,34). The accepted mechanism involved in the protective effect of calcium antagonists is indirect, depending on their ability to spare ATP during ischemia, due to their negative inotropic properties (2,13,20,43).…”

“…However, Henry and Wahl (21) recently showed that diltiazem and nifedipine are protective on the quiescent hypoxic myocardium, thereby excluding a mechanism related to energy conservation. Kirkels et al (25) reported that anipamil, a derivative of verapamil, protects against ischemia and reperfusion in the absence of a negative inotropic effect during normoxia. Others (23,30) showed protection with different calcium antagonists at concentrations which do not exert a negative inotropic effect.…”

“…Since the animals received the last injection of D-600 2 h before they were killed, we must assume that the protective effect results from the ability of D-600 to bind to cardiac tissue. Phenylalkylamines like verapamil and D-600 are supposed to act by initially dissolving into the phospholipid bilayer and subsequently migrating towards the slow channels (22,25). Furthermore, it has been demonstrated that D-600 migrates within the sarcolemma and acts on the internal portion of the myocardial membrane (22).…”

“…They include: unloading of the heart by peripheral arterial vasodilatation, negative inotropic and chronotropic effects reducing myocardial oxygen consumption and enhancement of collateral flow improving blood supply (4,8,27,34,40). More recently, additional direct effects of calcium antagonists have been suggested on myocardial metabolism (9,25,30), cell membrane (10), release of neuroendocrine substances (6,7,23) or cellular viability (5,23).…”