EFFECTS OF HALOTHANE ON EDRF CGMP-MEDIATED VASCULAR SMOOTH-MUSCLE RELAXATIONS

Background. Halothane has been reported to inhibit endothelium-depende nt relaxation in a variety of vessels. These studies were done to dete rmine whether this inhibition is caused by interference with synthesis , release, or action of endothelium-derived relaxing factor (EDRF) on cyclic guanosine monophosphate (cGMP) levels within the vascular smoot h muscle. Methods. Rat aortic rings were suspended in aerated Krebs so lution (37-degrees-C) and were contracted to a stable plateau with EC6 0-70 norepinephrine (NE). Relaxations caused by acetylcholine (ACh; 1 x 10(-8) - 1 X 10(-6) M), nitric oxide (NO; 5 X 10(-9) - 1 X 10(-6) M) , or nitroglycerin (NG; 2 X 10(-9) - 3 x 10(-7) m) in rings contracted with NE were compared in the presence and absence of halothane. Tissu e cGMP contents were measured using a radioimmunoassay method. Results :In the presence of halothane (0.5, 1.0, and 2.0 MAC), the ACh-induced relaxations were significantly attenuated in a concentration-dependen t manner, an effect that was reversible. Halothane (2 MAC) significant ly attenuated NO-induced relaxations at all concentrations and NG-indu ced relaxations at low concentrations (5 x 10(-9) - 3 x 10(-8) M) but not at higher concentrations (1 X 10(-9) - 3 x 10(-7) m) in denuded ve ssels. Nitric oxide-stimulated (5 x 10(-8) - 5 X 10(-6) M) cGMP conten t was significantly attenuated by halothane (2 MAC) at NO concentratio ns between 1 X 10(-7) and 5 X 10(-6) M. Conclusions. Nitric oxide, eit her endogenous or exogenous, interacts with the enzyme guanylate cycla se to stimulate the production of cGMP. Halothane interfered with the relaxations caused by NO (in rings without endothelium) and decreased the NO-stimulated cGMP content. These results suggest that the site of action of halothane in attenuating endothelium-dependent relaxation i n the rat aorta is within the vascular smooth muscle, rather than on t he synthesis, release, or transit of the EDRF from the endothelium and that its action may involve an interference with guanylate cyclase ac tivation.