The Effect of the Anesthetic Propofol on Connexins of Cardiovascular System

Abstract

Propofol is a widely used general anesthetic, which causes a rapid induction of anesthesia. The most prominent side effect of propofol is the decrease of systemic vascular resistance that leads to hypotension. Moreover, in some cases, propofol has been shown to inhibit cardiac conduction and cause bradycardia, but its pathophysiological mechanism is still not fully understood. On the other hand, propofol was shown to have a protective effect against ventricular arrhythmias during myocardial ischemia. Several studies have shown that propofol may regulate cell coupling through gap junction (GJ) channels formed of Cx43. However, it is unclear how propofol affects all cardiac connexins. It is known that Cx37, Cx40, Cx43 and Cx45 form gap junction channels in cardiovascular system. These connexins are required for coordination of vascular responses and play a key role in ensuring propagation of action potential in cardiac tissue. The aim of this study was to get a better understanding of the capacity of propofol to affect cardiovascular connexins. First, we compared the effect of various propofol concentrations on GJs formed by cardiovascular connexins which were expressed exogenously in human cervix epithelial adenocarcinoma cells (HeLa). The junctional conductance was measured using double whole-cell patch clamp method. Our data show that Cx40 and Cx43 channels exhibit similar sensitivity to propofol (IC50 Cx40 - 17µM; Cx43 – 15µM), while Cx45 channels are sensitive to much higher propofol concentrations (IC50 60µM). Interestingly, the vascular Cx37, which is an important player in dilation of vascular beds, was the most susceptible to propofol (IC50 5µM). Propofol may affect Cx43 GJ channels through activation of protein kinase C (PKC), which in turn phosphorylates Cx43 and reduces coupling through GJs. In our study, the kinase inhibitor GF109203X was used to assess this putative pathway of propofol action on GJs. It is established that low concentrations (40nM) of GF109203X specifically inhibit PKC while higher concentrations (2 µM) inhibit both PKC and protein kinase A (PKA). Our data showed that low concentration of GF109203X significantly reduced inhibition of Cx43 channels by propofol. In contrast, both concentrations of GF109203X had no effect on inhibition of Cx40 and Cx45 channels by propofol. The findings indicate that both low and high kinase inhibitor concentrations considerably lessened propofol’s blocking effect on Cx37.