A subtype of alpha 1 adrenoceptor mediates depression of conduction in Purkinje fibers exposed to halothane.
BACKGROUND
An action of epinephrine at alpha adrenoceptors has been reported to slow conduction in Purkinje fibers exposed to halothane. In Purkinje fibers one pharmacologically distinguishable alpha 1-adrenoceptor subtype (alpha 1B) sensitive to the noncompetitive antagonist chloroethylcholinidine mediates decreases in automaticity. Another alpha 1 subtype (alpha 1A), sensitive to the competitive antagonist WB4101, increases spontaneous rate and action potential duration by a mechanism thought to involve hydrolysis of membrane phosphoinositides by phospholipase C. This study examined the dose-response relation and receptor-effector mechanisms underlying depression of conduction in canine Purkinje fibers by epinephrine with halothane.


METHODS
Conduction velocity was determined in vitro by measuring the conduction time between action potentials recorded from two Purkinje fibers located about 6 mm apart along the length of free running portions of the ventricular conduction system, the false tendons. Velocity was evaluated at 1-min intervals during trials of rapid exposure to different agonists in groups of 6-12 preparations.


RESULTS
Epinephrine (0.2-5.0 microM) transiently decreased Purkinje conduction velocity in a dose-related manner by as much as 33% (at 5 microM epinephrine with 0.86 mM (2.8%) halothane). Velocity decreased by 5% (P < or = 0.01) at an epinephrine concentration similar to "just-threshold" dysrhythmogenic plasma epinephrine concentrations (0.2 microM epinephrine with 0.46 mM halothane) reported in halothane-anesthetized dogs. The decreases of conduction velocity were blocked by prazosin but not by metoprolol, were produced by phenylephrine but not by clonidine, and were antagonized by equimolar (0.5 microM) concentrations of WB4101 more so (P < or = 0.01) than by chloroethylclonidine. WB4101 (0.1 microM) produced 87% inhibition of the response to 0.2 microM epinephrine after chloroethylclonidine pretreatment, indicating mediation by the alpha 1A subtype. Other agonists linked to cardiac phospholipase C activation, including endothelin 1 (40 nM) and the muscarinic agonist carbamylcholine (1 mM), also decreased conduction velocity in fibers exposed to halothane.


CONCLUSIONS
Clinically relevant concentrations of epinephrine transiently depress conduction in Purkinje fibers exposed to halothane by activating 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 diacylglycerol and inositol trisphosphate. Anesthetic potentiation of cardiac alpha 1-adrenoceptor effects may contribute to the generation of halothane-epinephrine dysrhythmias by abnormally slowing conduction and facilitating reentry.
Turner
L A
LA
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee 53226, USA.
Vodanovic
S
S
Hoffmann
R G
RG
Kampine
J P
JP
Bosnjak
Z J
ZJ
D000818:Animals; D003864:Depression, Chemical; D004146:Dioxanes / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000494:pharmacology; D006221:Halothane / Q000494:pharmacology*; D066298:In Vitro Techniques; D011690:Purkinje Fibers / Q000187:drug effects* / Q000502:physiology; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects* / Q000502:physiology; D010738:Type C Phospholipases / Q000502:physiology
D004146:Dioxanes; D018340:Receptors, Adrenergic, alpha-1; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; D010738:Type C Phospholipases; D006221:Halothane; D004837:Epinephrine