RESUMEN
BACKGROUND: In human ventricular myocardium, contractile force increases at higher stimulation frequencies (positive force-frequency relation). In failing hearts, the force-frequency relation (FFR) is negative. Data on the effect of volatile anesthetics on FFR are very limited. METHODS: The authors obtained left ventricular tissue from 18 explanted hearts from patients undergoing cardiac transplantation and tissue of 8 organ donors. The negative inotropic effect of halothane, isoflurane, and sevoflurane on isometric force of contraction of isolated muscle preparations at a stimulation frequency of 1 and 3 Hz and the effect of each anesthetic on the FFR were studied. Ryanodine and verapamil were studied for comparison. In addition, the effect of the anesthetics on Ca(2+)-dependent (3)H-ryanodine binding was investigated. RESULTS: In nonfailing myocardium, halothane was the strongest negative inotropic compound, and the positive FFR was not affected by either drug. In failing myocardium, halothane also showed the strongest negative inotropic effect, but the positive shape of FFR was restored by halothane and ryanodine. In contrast, isoflurane, sevoflurane, and verapamil did not change FFR. Only halothane shifted the Ca(2+)-dependent (3)H-ryanodine binding curve toward lower Ca(2+) concentrations. CONCLUSION: In nonfailing human myocardium, none of the anesthetics affect FFR, but halothane is the strongest negative inotropic compound. In failing myocardium, halothane, but not isoflurane or sevoflurane, restores the positive shape of FFR. Both the more pronounced negative inotropic effect of halothane and the restoration of the positive shape of FFR in failing myocardium in the presence of halothane can be explained by its interaction with the myocardial sarcoplasmic reticulum calcium-release channel.
Asunto(s)
Anestésicos por Inhalación/farmacología , Halotano/farmacología , Isoflurano/farmacología , Éteres Metílicos/farmacología , Contracción Miocárdica/efectos de los fármacos , Rianodina/farmacología , Retículo Sarcoplasmático/fisiología , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio/efectos de los fármacos , Cardiomiopatías/metabolismo , Técnicas de Cultivo , Interacciones Farmacológicas , Estimulación Eléctrica , Humanos , Miocardio/metabolismo , Rianodina/metabolismo , Retículo Sarcoplasmático/efectos de los fármacos , Sevoflurano , Vasodilatadores/farmacología , Verapamilo/farmacologíaRESUMEN
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. CONCLUSION: Halothane, but not isoflurane, impairs the beta-adrenergic responsiveness in rat myocardium by reducing the agonist affinity of the beta-adrenoceptors.