Halothane, but not isoflurane, impairs the beta-adrenergic responsiveness in rat myocardium.
BACKGROUND
The aim of this study was to identify the mechanisms by which halothane and isoflurane change the myocardial beta-adrenergic signal transduction pathway.


METHODS
The authors investigated the influence of volatile anesthetics on the isometric force of contraction of rat papillary muscles. Concentration-response curves for isoproterenol and epinephrine were studied under control conditions and in the presence of halothane or isoflurane. In radioligand receptor-binding studies, the beta-adrenoceptor affinities for isoproterenol and epinephrine were investigated with and without guanosine triphosphate. In addition, the isoproterenol-induced cyclic adenosine monophosphate accumulations in viable cardiomyocytes in the absence and in the presence of halothane were determined by radioimmunoassays.


RESULTS
The half-maximal positive inotropic effect of isoproterenol was reached at a half-maximal effective concentration (EC50 value) of 68 nM (33-141 nM; n = 10). A minimum alveolar concentration of 1.3 halothane reduced the positive inotropic potency of isoproterenol (EC50 = 158 nM [118-214 nM; n = 10; P < 0.01 vs. control]), whereas isoflurane did not changed it. This observation held true when the force of contraction was stimulated with epinephrine. Halothane (1.3 minimum alveolar concentration) depressed beta-adrenoceptor high-affinity binding and beta-adrenoceptor agonist affinity in radioligand binding assays, an effect not seen with isoflurane. Halothane shifted the intracellular cyclic adenosine monophosphate response curve of isoproterenol to the right.


CONCLUSIONS
Halothane, but not isoflurane, impairs the beta-adrenergic responsiveness in rat myocardium by reducing the agonist affinity of the beta-adrenoceptors.
Schotten
U
U
Medical Clinic I, University Hospital of the RWTH Aachen, Germany.
Schumacher
C
C
Sigmund
M
M
Karlein
C
C
Rose
H
H
Kammermeier
H
H
Sivarajan
M
M
Hanrath
P
P
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D006221:Halothane / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D007530:Isoflurane / Q000494:pharmacology*; D007545:Isoproterenol / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000378:metabolism*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011943:Receptors, Adrenergic, beta / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D000318:Adrenergic beta-Agonists; D018685:Anesthetics, Inhalation; D011943:Receptors, Adrenergic, beta; D007530:Isoflurane; D000242:Cyclic AMP; D007545:Isoproterenol; D006221:Halothane