Differential effects of the sodium calcium exchange inhibitor, KB-R7943, on ischemia and reperfusion injury in isolated guinea pig ventricular myocytes.
Effects of the Na(+)-Ca(2+) exchange (NCX) inhibitor KB-R7943 on electrical and contractile function were examined in guinea pig ventricular myocytes exposed to ischemia and reperfusion. Action potentials and transmembrane currents were recorded with microelectrodes; contractions were measured with an edge detector. Cells were exposed to simulated ischemia (hypoxia, hypercapnia, hyperkalemia, acidosis, lactate accumulation, no glucose) for 20 min and reperfused with Tyrode's solution. Experiments were conducted at 37 degrees C in the absence or presence of KB-R7943. Low concentrations of KB-R7943 (0.1 microM) had little impact on changes in contractions, membrane potential, or Ca(2+) current induced by ischemia and reperfusion. However, higher concentrations of KB-R7943 (0.5 and 1.0 microM) reduced the magnitude of Ca(2+) current and promoted action potential abbreviation in both ischemia and reperfusion. High concentrations of KB-R7943 also promoted post-ischemic contractile dysfunction (stunning) in reperfusion. In the absence of KB-R7943, the arrhythmogenic transient inward current (I(TI)) plus aftercontractions occurred upon reperfusion, and some cells exhibited irreversible cell injury (hypercontracture). Higher concentrations of KB-R7943 (0.5 and 1.0 micoM) did not affect the occurrence or magnitude of I(TI) and aftercontractions and did not affect the occurrence of hypercontracture. In contrast, 0.1 microM KB-R7943 virtually abolished I(TI), aftercontractions and hypercontracture. Thus, low concentrations of KB-R7943 protected against ischemia and reperfusion injury, but higher concentrations of drug actually exacerbated detrimental effects of ischemia and reperfusion. These results suggest that inhibition of I(TI) may contribute to the antiarrhythmic effects of KB-R7943 on reperfusion-induced arrhythmias.
Department of Pharmacology, 5850 College Street, Dalhousie University, Halifax, Nova Scotia, Canada B3H 1X5.
Ashley C
AC
MacDonald
Susan E
SE
Howlett
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D008839:Microelectrodes; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000473:pathology; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors*; D013890:Thiourea / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology
C101670:2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate; D000889:Anti-Arrhythmia Agents; D019831:Sodium-Calcium Exchanger; D013890:Thiourea