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Abstract
BackgroundTransient receptor potential (TRP) ion channels have emerged as key components contributing to vasoreactivity. Propofol, an anesthetic is associated with adverse side effects including hypotension and acute pain upon infusion. Our objective was to determine the extent to which TRPA1 and/or TRPV1 ion channels are involved in mediating propofol-induced vasorelaxation of mouse coronary arterioles in vitro and elucidate the potential cellular signal transduction pathway by which this occurs.MethodsHearts were excised from anesthetized mice and coronary arterioles were dissected from control C57Bl/6J, TRPA1-/-, TRPV1-/- and double-knockout mice (TRPAV-/-). Isolated microvessels were cannulated and secured in a temperature-controlled chamber and allowed to equilibrate for 1 hr. Vasoreactivity studies were performed in microvessels pre-constricted with U46619 to assess the dose-dependent relaxation effects of propofol on coronary microvascular tone.ResultsPropofol-induced relaxation was unaffected in vessels obtained from TRPV1-/- mice, markedly attenuated in pre-constricted vessels obtained from TRPA1-/- mice and abolished in vessels obtained from TRPAV-/- mice. Furthermore, NOS inhibition with L-NAME or endothelium denuding abolished the proporfol-induced depressor response in pre-constricted vessels obtained from all mice. In the absence of L-NAME, BKCa inhibition with penitrem A markedly attenuated propofol-mediated relaxation in vessels obtained from wild-type mice and to a lesser extent in vessels obtained from TRPV1-/-, mice with no effect in vessels obtained from TRPA1-/- or TRPAV-/- mice.ConclusionsTRPA1 and TRPV1 appear to contribute to the propofol-mediated antagonism of U46619-induced constriction in murine coronary microvessels that involves activation of NOS and BKCa.
Highlights
Transient receptor potential (TRP) ion channels have recently emerged as key regulators of vasomotor tone [1,2,3,4,5,6] and many general anesthetic agents modulate vasomotor tone [7,8,9,10]
Propofol-induced relaxation was unaffected in vessels obtained from TRPV1-/- mice, markedly attenuated in pre-constricted vessels obtained from TRPA1-/- mice and abolished in vessels obtained from TRPAV-/- mice
In the absence of L-NAME, BKCa inhibition with penitrem A markedly attenuated propofol-mediated relaxation in vessels obtained from wild-type mice and to a lesser extent in vessels obtained from TRPV1-/, mice with no effect in vessels obtained from TRPA1-/- or TRPAV-/- mice
Summary
Transient receptor potential (TRP) ion channels have recently emerged as key regulators of vasomotor tone [1,2,3,4,5,6] and many general anesthetic agents modulate vasomotor tone [7,8,9,10]. Our laboratory and others have demonstrated that anesthetic agents activate and/or modulate TRPA1 and/or TRPV1 ion channel sensitivity to agonist activation in sensory neurons and heterologous expression systems [11,12,13,14,15,16]. Numerous studies have demonstrated that propofol-mediated activation of TRPA1 in sensory neurons and heterologous expression systems [11, 14], no studies have addressed the extent to which propofol modulate vasomotor tone in microvascular beds via direct interactions with TRP ion channels. Our objective was to determine the extent to which TRPA1 and/or TRPV1 ion channels are involved in mediating propofolinduced vasorelaxation of mouse coronary arterioles in vitro and elucidate the potential cellular signal transduction pathway by which this occurs
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