The Protective effect ofd-sotalol against hypoxia-induced myocardial uncoupling

Abstract

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.

Myocardial Ca2+handling and cell-to-cell coupling, key factors in prevention of sudden cardiac deathThis article is one of a selection of papers published in a special issue on Advances in Cardiovascular Research.

“…This suggestion fits with a previous study demonstrating recovery of electrical coupling in papillary muscle subjected to hypoxia that was associated with the preservation of the integrity of the gap junctions, most likely due to attenuation of Ca 2+ overload by sotalol (Manoach et al 1996). Prevention and (or) attenuation of Ca 2+ overload were also thought to be implicated in the defibrillating ability of several antiarrhythmic compounds, like amiodarone (Kojima et al 1995), sotalol, tedisamil, and procainamide (Manoach et al 2003), most likely because of increased intercellular coupling (Manoach et al 1996) that in turn decreased dispersion of spatial conduction velocity (Ujhelyi et al 1999). Further evidence supporting a crucial role (and close relationship) of cell-to-cell coupling and Ca 2+ handling comes from experiments demonstrating distinct patterns of VF in guinea pig hearts, that is, sVF in old animals but transient spontaneously terminating VF in young animals.…”

Oxygen demand of perfused heart preparations: how electromechanical function and inadequate oxygenation affect physiology and optical measurements

“…; Manoach et al . ) concomitantly with changes in Δ G ATP , the pattern of ADP shortening is expected to be the same as with ischaemia.…”

“…Like ischaemia, hypoxia has been shown to impair cell‐to‐cell coupling and compromise gap junction conductance (Manoach et al . ; Matsumura et al . ; Danon et al .…”

“…In isolated ventricular muscle strips, hypoxia shortens APD and results in cell‐to‐cell uncoupling (Manoach et al . ), and the duration of hypoxia (0–80 min) is correlated with the degree of cell‐to‐cell uncoupling and reduced Cx43 phosphorylation, thereby slowing conduction velocity (Matsumura et al . ).…”

Sotalol: The Mechanism of Its Antiarrhythmic‐Defibrillating Effect

“…It failed, however, to recover functional myocardial coupling after hypoxia lasting more than 30 min. Electrical uncoupling, induced by hypoxia for up to 30 min duration, was accompanied by reversible subcellular alterations of the cardiomyocytes (40). Focal dehiscence of adhesive junctions and changes in gap junctions (disordered transverse densities) were found by transmission electron microscopy examination.…”