A SUBTYPE OF ALPHA(1) ADRENOCEPTOR MEDIATES DEPRESSION OF CONDUCTION IN PURKINJE-FIBERS EXPOSED TO HALOTHANE

Background: An action of epinephrine at or adrenoceptors has been repo rted to slow conduction In Purkinje fibers exposed to halothane.In Pur kinje fibers one pharmacologically distinguishable alpha(1)-adrenocept or subtype (alpha(IB)) sensitive to the noncompetitive antagonist chlo roethylclonidine mediates decreases in automaticity Another alpha(1) s ubtype (alpha(1A)), sensitive to the competitive antagonist WB4101, in creases spontaneous rate and action potential duration by a mechanism thought to involve hydrolysis of membrane phosphoinositides by phospho lipase C, This study examined the dose-response relation and receptor- effector mechanisms underlying depression of conduction in canine Purk inje fibers by epinephrine with halothane. Methods: Conduction velocit y was determined in vitro by measuring the conduction time between act ion potentials recorded from two Purkinje fibers located about 6 mm ap art along the length of free running portions of the ventricular condu ction system, the false tendons. Velocity was evaluated at 1-min inter vals during trials of rapid exposure to different agonists in groups o f 6-12 preparations. Results: Epinephrine (0.2-5.0 mu M) transiently d ecreased Purkinje conduction velocity in a dose-related manner by as m uch as 33% (at 5 mu M epinephrine with 0.86 mM (2.8%) halothane). Velo city decreased by 5% (P less than or equal to 0.01) at an epinephrine concentration similar to ''just-threshold'' dysrhythmogenic plasma epi nephrine concentrations (0.2 mu M epinephrine with 0.46 mM halothane) reported in halothane anesthetized dogs. The decreases of conduction v elocity were blocked by prazosin but not by metoprolol, were produced by phenylephrine but not by clonidine, and were antagonized by equimol ar (0.5 mu M) concentrations of WB4101 more so (P less than or equal t o 0.01) than by chloroethylclonidine. WB4101 (0.1 mu M) produced 87% i nhibition of the response to 0.2 mu M epinephrine after chloroethylclo nidine pretreatment, indicating mediation by the alpha(1A) subtype, Ot her agonists linked to cardiac phospholipase C activation, including e ndothelin 1 (40 nm) and the muscarinic agonist carbamylcholine (1 mM), also decreased conduction velocity in fibers exposed to halothane. Co nclusions: Clinically relevant concentrations of epinephrine transient ly depress conduction in Purkinje fibers exposed to halothane by activ ating cardiac alpha(1) adrenoceptors, largely but not exclusively the WB4101-sensitive alpha(1A) subtype, reportedly coupled to stimulation of phospholipase C and generation of the second messengers diacylglyce rol and inositol trisphosphate. anesthetic potentiation of cardiac alp ha(1)-adrenoceptor effects may contribute to the generation of halotha ne-epinephrine dysrhythmias by abnormally slowing conduction and facil itating reentry.