Sensitization of adenylate cyclase by halothane in human myocardium and S49 lymphoma wild-type and cyc- cells: evidence for inactivation of the inhibitory G protein Gi alpha.
Halothane has been reported to sensitize the myocardium towards the effects of exogenous catecholamines in patients and laboratory animals. This study was aimed at investigating the catecholamine-sensitizing effects of halothane as well as the underlying subcellular mechanisms in human myocardium. Halothane augmented the positive inotropic effect of isoprenaline but not of Ca2+. The increase of the effect of isoprenaline by halothane was more pronounced in failing myocardium, with increased Gi, than in nonfailing donor hearts. Halothane (1%) increased basal as well as isoprenaline-, NaF-, cholera toxin-, and guanylylimidodiphosphate [Gpp(NH)p]-stimulated adenylate cyclase in human myocardial membranes (p < 0.05). Treatment of membranes with pertussis toxin increased adenylate cyclase by 40% and abolished the effect of halothane. Halothane had no effect on forskolin-stimulated adenylate cyclase. The same results, i.e., a pertussis toxin-sensitive increase of adenylate cyclase stimulation by halothane, were obtained in S49 cyc-, wild-type, or recombinant Gs alpha-reconstituted cyc- cell membranes. Carbachol-stimulated guanosine-5'-O-(3-[35S]thio)triphosphate binding was not influenced by halothane, but halothane attenuated the inhibition of adenylate cyclase by Gpp(NH)p in S49 cyc- cells. These data show that halothane stimulates adenylate cyclase and sensitizes adenylate cyclase after stimulation by beta-adrenoceptor agonists and guanine nucleotides due to an impairment of Gi alpha function. This mechanism may play a role in the halothane sensitization of myocardial adenylate cyclase towards catecholamines.
Böhm
M
M
Klinik III für Innere Medizin, Universität zu Köln, Germany.
Schmidt
U
U
Gierschik
P
P
Schwinger
R H
RH
Böhm
S
S
Erdmann
E
E
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000328:Adult; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006221:Halothane / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D008223:Lymphoma / Q000201:enzymology*; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology*; D011950:Receptors, Cholinergic / Q000378:metabolism; D014407:Tumor Cells, Cultured
D011950:Receptors, Cholinergic; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D006221:Halothane