PT  - JOURNAL ARTICLE
AU  - Böhm, M
AU  - Schmidt, U
AU  - Gierschik, P
AU  - Schwinger, R H
AU  - Böhm, S
AU  - Erdmann, E
TI  - 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.
DP  - 1994 Mar 01
TA  - Molecular Pharmacology
PG  - 380--389
VI  - 45
IP  - 3
4099  - http://molpharm.aspetjournals.org/content/45/3/380.short
4100  - http://molpharm.aspetjournals.org/content/45/3/380.full
SO  - Mol Pharmacol1994 Mar 01; 45
AB  - 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.