ENDOTOXIN DISRUPTS BETA-ADRENERGIC SIGNAL-TRANSDUCTION IN THE HEART

Background: Nonsurvivors of septic shock demonstrate impaired myocardi al function refractory to the administration of beta-agonists. Methods : Using the isolated rat heart preparation, the integrity of the beta- adrenergic transduction pathway was tested (rate pressure product, rat e of contraction, rate of relaxation, and cyclic adenosine monophospha te content) using isoproterenol hydrochloride (beta-receptor agonist) or colforsin (forskolin) (adenylyl cyclase activator) stimulation foll owing intracoronary endotoxin infusion. Results: Basal rate pressure p roduct, rate of contraction, rate of relaxation, and cyclic adenosine monophpsphate concentrations were unaffected by endotoxin infusion. En dotoxin impaired increases in rate pressure product, rates of contract ion and relaxation, and cyclic adenosine monophosphate to isoprotereno l (P<.05), but the response to colforsin was unaffected by endotoxin. Conclusions: Endotoxin disrupts the myocardial response to direct beta -receptor stimulation but not to adenylyl cyclase stimulation in the i solated rat heart. Clinical Relevance: Alteration of the proximal beta -adrenoreceptor complex by endotoxin suggests that therapy of the fail ing heart during refractory septic shock may be directed to intact sit es distal in the beta-adrenergic pathway.