A novel role of propofol and its analogues in arterial vasorelaxation and blood pressure reduction via inhibition of calcium activated chloride channel ANO1.

BACKGROUND AND PURPOSE: Propofol, a widely used intravenous anaesthetic, is commonly associated with side effect of hypotension, a significant concern in clinical practice. However, the underlying mechanism of propofol-induced hypotension is not fully defined.

EXPERIMENTAL APPROACH: Electrophysiological recordings of macroscopic and single-channel currents of Ca2+ activated Cl- channel (CaCC) ANO1 channels are employed. Ex vivo myography recordings of isolated mesenteric arterioles are utilized to quantify propofol-induced relaxation in pre-constricted blood vessels. The effects of propofol were tested in vivo by measuring changes in systolic and diastolic blood pressure following an infusion of the anaesthetic.

KEY

RESULTS

Propofol inhibits macroscopic ANO1 currents expressed in HEK293T cells in a concentration-dependent manner with an IC50 of 39.2 μM and also reduces the channel open probability without altering its single channel conductance. Four propofol analogues, 2-tert-butyl-6-methylphenol, 2,6-di-sec-butylphenol, 2,6-dimethylphenol and 2,6-di-tert-butylphenol, inhibit ANO1 currents with different potencies with IC50 values variable from 59 to 3629 μM. Ex vivo myography recordings demonstrate that propofol dose-dependently relaxes noradrenaline-preconstricted mesenteric arterioles. In vivo, intravenous infusion of propofol significantly reduces both systolic and diastolic blood pressure. Conversely, propofol-induced hypotension is reversed by co-administration of ANO1 channel opener Eact.

CONCLUSIONS AND IMPLICATIONS: Propofol causes arterial vasorelaxation and ANO1 inhibition by propofol contributes to its blood pressure-lowering effect. This mechanism may explain the hypotension frequently encountered during clinical use of propofol, providing an insight into strategies to mitigate this side effect.