HALOTHANE MODIFIES ISCHEMIA-ASSOCIATED INJURY TO THE VOLTAGE-SENSITIVE CALCIUM CHANNELS IN CANINE HEART SARCOLEMMA

Background: Recent experimental data suggest that functional and metab olic changes in the myocardium caused during ischemia and subsequent r eperfusion may be attenuated by the volatile anesthetics through the p revention of intracellular calcium accumulation. The main purpose of t he current research is to identify a mechanism responsible for the alt erations of ischemia-associated injury to the voltage-sensitive Ca2+ c hannels (VSCC) in the sarcolemma during halothane anesthesia. Methods: The effect of 10 min myocardial ischemia in canine heart and 20 min r eperfusion on the function of the VSCC in the sarcolemma was examined in the presence or absence of 1.6 vol% halothane administered in vivo. The membranes were isolated through differential centrifugation/filtr ation from the ischemic (left anterior descending territory) and norma lly perfused myocardium. Comparison of binding characteristics in the ischemic and nonischemic zones was made using equilibrium-binding stud ies of a dihydropyridine calcium channel blocker, [H-3]isradipine (0.0 5-1.0 nM), to the VSCC in the sarcolemma. Control studies were perform ed on membranes prepared from the same perfusion zones, but from heart s who were not exposed to ischemia. Results: The control studies (n = 5) showed no difference in binding kinetics between the different zone s in the heart. After 10 min of ischemia, a 50 to 95% increase in spec ific [3H]isradipine binding to the sarcolemmal membranes was observed as compared to control membranes (P < 0.001). The maximal binding capa city (B-max) increased by 85%, whereas the dissociation constant (Kd) remained unchanged. In the reperfusion experiments, a moderately incre ased binding (of 32%) was observed with a 40% increase in B-max (P = N S). In the presence of 1.6% inhaled halothane, the effect of ischemia was attenuated. A decrease of 32.1% to 41.8% in equilibrium binding wa s observed (31% decrease in B-max; P < 0.03 and 0.02, respectively). C onclusions: Even a brief period of myocardial ischemia produces a mark ed increase in the available high-affinity binding sites in the VSCC, a finding that is well correlated with previous experimental observati on of increased calcium ion influx to the myocardial cell. On reperfus ion, some recovery of the ischemic changes in the VSCC was evident. Th e binding kinetics which characterize this early phase of cell injury were reversed by halothane anesthesia, indicating a possible reduction in calcium entry, which may represent one of the beneficial effects o f the anesthetic in the ischemic heart.