Endothelium-independent Vasoconstricting and Vasodilating Actions of Halothane on Rat Mesenteric Resistance Blood Vessels

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Abstract
Background: Whether volatile anesthetics produce changes in vascular resistance and blood flow because of direct effects on vascular tissue is unclear. Direct vasoconstricting and vasodilating actions have been demonstrated in isolated conductance arteries in vitro, but there is little information regarding direct effects on the small vessels that mediate resistance and flow changes in vivo. Methods: We investigated the actions of halothane on 50-200 microM branches of the rat mesenteric artery that were cannulated and studied in vitro. The vessels were pressurized to 60 mmHg, and vascular dimensions were continuously monitored using a computer-based real-time image analysis system. The vessel bath was perfused with HCO3(-)-buffered saline (37 degrees C) equilibrated with 95% O2/5% CO2 (+/- halothane). The vascular endothelium was mechanically removed before cannulation in some vessels. Results: In unstimulated vessels, halothane had a concentration-dependent vasoconstricting action (EC50 = 0.45 mM approximately 1.5 vol% at 37 degrees C) that was largely transient and was similar to that produced by caffeine. Both halothane and caffeine constrictions were unaffected by bath [Ca2+], nifedipine (1 microM) or Cd2+ (100 microM) and were abolished by ryanodine (10 microM). In addition, caffeine responses were attenuated by halothane in a concentration-dependent manner (EC50 = 1.6 mM). In vessels preconstricted with KCl (40 mM) or phenylephrine (10(-6) M), halothane produced transient constriction followed by concentration-dependent vasodilation. Ryanodine, which abolished halothane constrictions, had little effect on the amplitude of KCl- or phenylephrine-induced constrictions or the vasodilating action of halothane. Removal of the endothelium likewise had little effect on the vasoconstricting or the vasodilating actions of halothane in unstimulated, KCl- or phenylephrine-constricted vessels. Halothane completely relaxed KCl and phenylephrine constrictions with EC50 values of 0.36 mM (1.2% at 37 degrees C) and 0.75 mM (2.5%), respectively, in intact vessels before ryanodine; 0.25 mM (0.8%) and 0.59 mM (1.9%) in intact vessels after ryanodine; and 0.52 mM (1.7%) and 0.67 mM (2.2%) in endothelium-denuded vessels. Conclusions: Halothane has endothelium-independent vasoconstricting and vasodilating actions in isolated mesenteric resistance blood vessels. The vasoconstricting action appears to involve halothane-induced Ca2+ release from caffeine/ryanodine-sensitive intracellular store(s). The vasodilating action in phenylephrine- or KC1-constricted vessels is independent of the Ca(2+)-releasing action and most likely involves an effect(s) on sarcolemmal-dependent Ca2+ signaling (e.g., extracellular Ca2+ influx) and/or Ca2+ activation of contractile proteins. The magnitude of both the vasoconstricting and the vasodilating actions of halothane in these vessels at clinically relevant concentrations suggests these direct actions contribute to the overall cardiovascular effects of halothane in vivo.

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