Modulation of intercellular communication through cardiovascular connexin - 43 gap junction channels by anesthetic propofol

Abstract

Propofol is a widely used intravenous general anesthetic characterized by rapid induction and recovery. One of its major side effects is a reduction in systemic vascular resistance, leading to hypotension, and in some cases inhibition of cardiac conduction, resulting in bradycardia. Although these effects have been recognized for decades, the underlying molecular mechanisms remain incompletely understood. Propofol has been shown to modulate muscarinic receptors, sinoatrial node activity, and cardiac conduction in a concentration-dependent manner, while also exerting protective effects against ventricular arrhythmias during myocardial ischemia. Several studies suggest that propofol may modulate intercellular coupling via gap junction channels composed of connexin - 43 (Cx43), which play a critical role in vascular coordination and cardiac impulse propagation. The aim of this study was to investigate the effects of propofol on Cx43 gap junction channels. Gap junctional conductance was measured in HeLa cells expressing Cx43 using the dual whole-cell patch-clamp technique. Our results demonstrate that propofol significantly inhibits Cx43 gap junction channels, with complete inhibition observed at 45 µM. Previous studies have suggested that propofol modulates Cx43 gap junction channels via protein kinase C (PKC) activation, which phosphorylates Cx43 and reduces intercellular coupling. Consistent with these findings, we observed that a PKC-specific inhibitor significantly attenuated the inhibitory effect of propofol, confirming a PKC-dependent regulatory mechanism. To further investigate propofol’s mechanism of action, we performed experiments using a truncated Cx43 construct lacking the C-terminal domain, which is a primary site of phosphorylation involved in the regulation of channel opening and closing. Interestingly, our initial data show that 45 µM propofol still induced a complete blockade of these truncated channels. These findings suggest that propofol inhibits Cx43 gap junction channels through both indirect and direct mechanisms.