Inhibition of adenylate cyclase by general anesthetics in toad urinary bladder

Abstract

General anesthetic agents modulate the adenylate cyclase-cyclic[c]AMP system in several tissues. The anesthetics methohexital and methoxyflurane selectively inhibit vasopressin-stimulated water flow in the toad urinary bladder, leaving urea permeability unaltered. The site of action of the drugs was studied. Both anesthetics inhibited vasopressin-stimulated adenylate cyclase activity over a wide range of vasopressin concentrations. Fluoride-stimulated activities were unaffected by either anesthetic. Both anesthetics diminished the vasopressin-related increment in intracellular cAMP levels. Phosphodiesterase activities were unaltered. The long-acting barbiturate phenobarbital inhibited both vasopressin-stimulated water flow and adenylate cyclase. The concentration of phenobarbital required for both of the effects was 10-20 times that required for the more lipid-soluble barbiturate methohexital; apparently partition into membrane lipid may be essential for the barbiturate effects on vasopressin stimulation of both transport and adenylate cyclase. Apparently the anesthetics tested inhibit vasopressin-stimulated water flow by reducing stimulation of adenylate cyclase, primarily by interfering with the hormone-receptor or receptor-catalytic subunit interactions. Substantial vasopressin stimulation of water and urea permeabilities were demonstrated under conditions in which adenylate cyclase or cAMP level enhancement was not measured. Apparently the cAMP pool or pools related to control of water and urea permeabilities may be small compared to total cell cAMP content, or that some portion of vasopressin''s effect on water or urea or both may be mediated by a cAMP-independent mechanism.