EFFECT OF HALOTHANE ON PHENYLEPHRINE-INDUCED VASCULAR SMOOTH-MUSCLE CONTRACTIONS IN ENDOTOXIN-EXPOSED RAT AORTIC RINGS

Objectives: a) To determine the response of endotoxin-exposed vascular smooth muscle to exogenous vasoconstrictors during concomitant exposu re to an inhaled anesthetic (halothane); and b) to determine if excess nitric oxide production is responsible for any altered response. Desi gn: In vitro, prospective, repeated measures, dose-response study. Set ting: University/medical school experimental physiology laboratory. Su bjects: Adult male Sprague-Dawley rats, whose aortae were studied in a n in vitro preparation. Interventions: Thoracic aortae were excised fr om anesthetized animals and cut into 3-mm rings. After incubation in a erated organ baths containing a modified essential medium with or with out Escherichia coli lipopolysaccharide (100 mu g/mL) at 37 degrees C for 5 hrs, the rings were removed and suspended in separate baths for isometric tension recording. Phenylephrine dose-response data (10(-10) to 10(-5) M) were determined for lipopolysaccharide- and nonlipopolys accharide-treated rings. After washout and equilibration, two vessels (one each lipopolysaccharide and non-lipopolysaccharide-treated) were additionally exposed to 2% halothane and phenylephrine dose-response d eterminations were repeated for all vessels. This procedure was repeat ed for 1% halothane in a separate experiment. In some experiments, the nitric oxide synthase inhibitor, N-w-nitro-L-arginine (3 x 10(-4) M), was added to the bath after the washout from the second phenylephrine dose-response determination. Then, a third phenylephrine dose respons e determination was performed, with and without 2% halothane. Measurem ents and Main Results: Dose-response curves were evaluated using a log istic regression analysis. In addition, absolute and percentage change s in tension were compared between the first and second contractions. Exposure to lipopolysaccharide resulted in a decrease in the maximum t ension from 2.07 +/- 0.03 (controls) to 1.24 +/- 0.04 g/mg of vessel d ry weight and an increase in the dose at which the contraction is 50% of maximum (ED(50)) from 3.78 x 10(-8) to 2.05 x 10(-7) M (P < .05). E xposure to 2% halothane produced significant reductions in the maximum tensions in both groups. The lipopolysaccharide treated vessels showe d not only a proportionately larger decrease (-51 +/- 5% vs. -18 +/- 2 % in the control plus halothane group), but also a significantly great er absolute decrease (0.59 +/- 0.09 vs. 0.34 +/- 0.04 g/mg in the cont rol plus halothane group). The addition of 1% halothane produced less pronounced decreases in tension, with only an additive effect in the l ipopolysaccharide-treated vessels. The addition of N-w-nitro-L-arginin e resulted in a reversal of the lipopolysaccharide-induced decrease in tension. However, 2% halothane still had a significantly greater effe ct on the lipopolysaccharide exposed rings. Conclusions: Exposure of r at aortic rings to lipopolysaccharide in vitro decreased the contracti le response to phenylephrine. The addition of 2% halothane resulted in a more than additive decrease in tension in the lipopolysaccharide tr eated vessels. Patients in septic or endotoxic shock are sensitive to most anesthetic regimens, and some of this sensitivity may be due to a n altered vasoconstrictive response induced by lipopolysaccharide expo sure. The inability of nitric oxide synthase inhibition to reverse thi s response completely suggests that induction of nitric oxide synthase and increased production of nitric oxide are not solely responsible f or this finding.