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.