The protective effect of D-sotalol against hypoxia-induced myocardial uncoupling.
The effects of D-sotalol on intercellular electrical coupling and ultrastructure under hypoxic conditions were investigated in myocardial samples from eight young (1-2 months) and four older (10-12 months) guinea pigs. A right ventricular muscle strip was kept simultaneously in two divided chambers and superfused with normoxic and/or hypoxic (97% N2+ 3% Co2) Krebs solution. Hypoxia caused shortening of action potential duration (APD) and electrical cell-to-cell uncoupling. If the uncoupling appeared after short-term hypoxia (less than 30 min), administration of 3.10(-7)M of D-sotalol to the hypoxic perfusate led to a recovery of electrical coupling. Transmission electron microscopy revealed moderate reversible ultrastructural alterations of the cardiomyocytes. No apparent changes in intercellular junctions were observed. The recoupling 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. In these cases, administration of D-sotalol caused only transient recoupling. After 1 h of hypoxia, no recoupling was observed. Pretreatment with D-sotalol prevented hypoxia-induced electrical uncoupling and markedly attenuated ultrastructural damage, although shortening of APD still 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. Considering previous results, we suggest that this protective effect of D-sotalol may be related to its ability to increase intracellular cyclic adenosine monophosphate and, thereby, to decrease cytosolic free Ca. These effects can explain the antiarrhythmic and defibrillating properties of D-sotalol.
Manoach
M
M
Department of Physiology, Tel-Aviv University, Medical School, Israel.
Tribulova
N
N
Imanaga
I
I
D000200:Action Potentials; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D002450:Cell Communication / Q000187:drug effects; D015687:Cell Hypoxia; D000242:Cyclic AMP / Q000378:metabolism; D004553:Electric Conductivity; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D008854:Microscopy, Electron; D009206:Myocardium / Q000648:ultrastructure; D013015:Sotalol / Q000494:pharmacology*; D013997:Time Factors
D000889:Anti-Arrhythmia Agents; D013015:Sotalol; D000242:Cyclic AMP