title: Role of intracellular Na+ in Ca2+ overload and depressed recovery of ventricular function of reperfused ischemic rat hearts. Possible involvement of H+-Na+ and Na+-Ca2+ exchange.
abstract: The roles of H+-Na+ and Na+-Ca2+ exchange in the depression of ventricular function were studied in the reperfused isolated ischemic rat heart. Zero-flow global ischemia was induced for either 15 or 30 minutes and was followed by 30 minutes of aerobic reperfusion. Intracellular Na+ (Na+i) and 45Ca2+ uptake were measured during ischemia and reperfusion. Accumulation of Na+i was modified by prior glycogen depletion and by treatment with amiloride, a H+-Na+ exchange inhibitor, or monensin, a Na+ ionophore. Na+i rose continuously during ischemia and rapidly during the first two minutes of reperfusion. The larger inhibitory effect of amiloride and preischemic glycogen depletion was on Na+i accumulation during reperfusion; this finding suggests that the uptake occurs by H+-Na+ exchange. Reduction of Na+i accumulation by glycogen depletion was associated with less lactate and, presumably, H+ production and accumulation during ischemia. The rapid increase in Na+i during early reperfusion may reflect the readjustment of the low intracellular pH resulting from ischemia. The level of Na+i at the end of ischemia and especially after two minutes of reperfusion were linearly correlated with 45Ca2+ uptake and depression of ventricular function during subsequent reperfusion. This highly significant correlation between Na+i and 45Ca2+ uptake when Na+i was varied by several independent procedures, including monensin, strongly suggests that reperfusion 45Ca2+ uptake occurs at least in part by Na+-Ca2+ exchange. The rate of 45Ca2+ uptake during reperfusion was linearly and highly significantly correlated with elevation of diastolic pressure, reduced developed pressure, and decreased recovery of ventricular function. The data strongly support a mechanism of ischemic cell damage that involves excessive production and accumulation of H+ during ischemia that exchanges for extracellular Na+ during ischemia and rapidly during the first few minutes of reperfusion. Increased Na+i then causes excessive 45Ca2+ uptake and depressed recovery of cellular functions with continued reperfusion. Increased levels of Na+i may be a major event that couples a decreased intracellular pH during ischemia to excessive 45Ca2+ uptake and depressed recovery of cellular function with reperfusion.
authors.affiliation: Sigfried and Janet Weis Center for Research, Geisinger Clinic, Danville, Pennsylvania.
authors.forename: M
authors.initials: M
authors.lastname: Tani
authors.forename: J R
authors.initials: JR
authors.lastname: Neely
mesh_terms: D000818:Animals; D002118:Calcium / Q000502:physiology*; D002352:Carrier Proteins / Q000502:physiology; D003327:Coronary Disease / Q000503:physiopathology*; D006321:Heart / Q000503:physiopathology*; D006352:Heart Ventricles; D007425:Intracellular Membranes / Q000378:metabolism*; D008297:Male; D015425:Myocardial Reperfusion; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000502:physiology*; D019831:Sodium-Calcium Exchanger; D017923:Sodium-Hydrogen Exchangers
chemical_list: D002352:Carrier Proteins; D019831:Sodium-Calcium Exchanger; D017923:Sodium-Hydrogen Exchangers; D012964:Sodium; D002118:Calcium