THE PROTECTIVE EFFECT OF D-SOTALOL AGAINST HYPOXIA-INDUCED MYOCARDIALUNCOUPLING

The effects of D-sotalol on intercellular electrical coupling and ultr astructure under hypoxic conditions were investigated in myocardial sa mples from eight young (1-2 months) and four older (10-12 months) guin ea pigs. A right ventricular muscle strip was kept simultaneously in t wo divided chambers and superfused with normoxic and/or hypoxic (97% N -2+ 3% C-o2) Krebs solution. Hypoxia caused shortening of action poten tial duration (APD) and electrical cell-to-cell uncoupling. If the unc oupling appeared after short-term hypoxia (less than 30 min), administ ration of 3.10(-7)M of D-sotalol to the hypoxic perfusate led to a rec overy of electrical coupling. Transmission electron microscopy reveale d moderate reversible ultrastructural alterations of the cardiomyocyte s. No apparent changes in intercellular junctions were observed. The r ecoupling effect of sotalol decreased with the time of hypoxia as the ultrastructural damage progressed. After prolonged hypoxia (more than 30 min), cardiomyocytes were markedly injured, intercellular junctions were severely affected, and gap junctions occurred less frequently. I n these cases, administration of D-sotalol caused only transient recou pling. After 1h of hypoxia, no recoupling was observed. Pretreatment w ith D-sotalol prevented hypoxia-induced electrical uncoupling and mark edly attenuated ultrastructural damage, although shortening of APD sti ll persisted. Our results indicate that the cardioprotective effect of D-sotalol on electrical intercellular coupling is closely associated with sotalol-induced prevention of the ultrastructural damage. Conside ring previous results, we suggest that this protective effect of D-sot alol may be related to its ability to increase intracellular cyclic ad enosine monophosphate and, thereby, to decrease cytosolic free Ca. The se effects can explain the antiarrhythmic and defibrillating propertie s of D-sotalol.