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Previously, we reported that propofol hyperpolarizes vascular smooth muscle (VSM) cells of small arteries and veins. The current study was designed to determine whether propofol-mediated hyperpolarization is the result of specific effects on potassium channels known to exist in VSM and on steps in the intracellular nitric oxide (NO), cyclic guanosine monophosphate (cGMP), and cyclic adenosine monophosphate (cAMP) second messenger pathways. VSM transmembrane potentials (Em) were measured in situ in sympathetically denervated, small mesenteric arteries and veins of Sprague-Dawley rats. Effects of propofol on VSM Em were determined before and during superfusion with specific inhibitors of VSM calcium-activated (KCa), adenosine triphosphate-sensitive (KATP), voltage-dependent (Kv), and inward rectifying (KIR) potassium channels and with endogenous mediators of vasodilation. Propofol significantly hyperpolarized VSM in small mesenteric vessels. This hyperpolarization was abolished on inhibition of KCa and KATP channel activity and on inhibition of NO and cGMP (but not cAMP). Assuming a close inverse correlation between the magnitude of VSM Em and contractile force, these results suggest that propofol induces hyperpolarization and relaxation in denervated, small mesenteric vessels by activation of KCa and KATP channels. Such channel activation may be mediated by activation of NO and cGMP, but not cAMP, second messenger pathways.