Impairment of cardiac beta-adrenoceptor cellular signaling by decreased expression of G(s alpha) in septic rabbits

Background: Abnormalities in the beta -adrenergic control of cardiac functi on play a role in the pathogenesis of several disease states. Because circu latory failure in patients with septic shock is known to be less response t o catecholamines, we investigated whether the beta -adrenoceptor-linked sig nal transduction mechanisms are altered in the heart of a septic animal mod el Methods: Rabbits were rendered endotoxemic by an intravenous injection of 1 00 mug/kg Escherichia coti lipopolysaccharide. Three and 6 h later, the myo cardial tissues were used for the experiments. Results: The positive inotropic response to isoproterenol was significantly impaired in papillary muscles isolated from septic rabbits compared with t hose from controls. The impaired inotropic responsiveness to isoproterenol was not prevented by the nitric oxide synthase inhibitor N-G-nitro-L-argini ne, indicating no involvement of nitric oxide overproduction. Adenylate cyc lase activity stimulated with isoproterenol and 5'-guanylyl imidodiphosphat e was markedly reduced in septic myocardium. The contractile and adenylate cyclase responses to colforsin daropate, a direct adenylate cyclase activat or, were unaffected by sepsis, Radioligand binding experiments with (-)[I-1 25]iodocyanopindolol revealed no significant alteration in myocardial beta -adrenoceptor density or affinity in sepsis. Determination of cardiac G(s a lpha) level by western blotting showed a reduction of approximately 50% in sepsis. The relative content of G(s alpha) messenger RNA in septic myocardi um also was reduced from the control level by about 50%, as determined by N orthern blot analysis. Little change was found in protein and messenger RNA levels of G(1 alpha) in septic myocardium. Conclusions: Impairment of myocardial functional responsiveness to beta -ad renoceptor stimulation appears in the early stage of sepsis, The impaired r esponse to beta -adrenoceptor stimulation in the heart in this pathologic s tate may result in part from a decreased level of G(s alpha) protein which occurs at the level of gene expression.