ROLE OF GUANYLATE-CYCLASE CGMP SYSTEMS IN HALOTHANE-INDUCED VASODILATION IN CANINE CEREBRAL-ARTERIES

The cellular mechanisms through which halothane dilates blood vessels remain largely unknown. The present studies were designed to determine the effects of 0.59 and 0.9 mM halothane (equivalent to 2.0% and 3.0%, respectively) on tissue cyclic guanosine 3,5-monophosphate (cGMP) level and guanylate cyclase enzyme activity in canine middle cerebral arteries. Rings of cerebral arteries preconstricted with 5-hydroxytryptamine (0.2-mu-M) were exposed for 15 min to low or high concentrations of halothane or for 5 min to sodium nitroprusside (50-mu-M). The vessels were instantaneously frozen by immersing them in liquid N2; they then were homogenized, and the tissue cGMP levels were determined using radioimmunoassay. Halothane produced 2.23 +/- 0.44- and 4.47 +/- 0.87-fold increases in tissue cGMP levels over control at 0.59 and 0.9 mM, respectively. Sodium nitroprusside, a nitrovasodilator, also increased the tissue cGMP level 7.80 +/- 1.36-fold over the control value. To understand better the mechanisms of halothane-induced increase of tissue cGMP level, the effects of this anesthetic agent on guanylate cyclase enzyme activity were examined. Halothane, unlike sodium nitroprusside, did not modulate the activity of the soluble guanylate cyclase enzyme. However, halothane (1.0 mM), like atrial natriuretic factor (5-mu-M), stimulated the particulate guanylate cyclase enzyme activity. LY83583 (6-anilino-5,8-quinolinedione, 10-mu-M), an agent that inhibits soluble guanylate cyclase activity, significantly reduced the response of the vessels to calcium ionophore (A23187, 0.4-mu-M), an endothelium-dependent vasodilator, without producing a significant effect on halothane-induced vasodilation. These results suggest that halothane-induced vasodilation of cerebral blood vessels is partly mediated by an increase in tissue cGMP levels. The increase in cGMP level induced by halothane results, at least in part, from activation of the particulate but not the soluble guanylate cyclase enzyme in canine middle cerebral vessels. The present study, however, does not rule out the possible interaction of halothane with the cGMP phosphodiesterase enzymes.