Mechanism of cardiac dysfunction in hearts from endotoxin-treated rats.
Myocardial performance was assessed in isolated perfused working hearts 3 hr after in vivo endotoxin administration (LD50-6 hr) to rats. Hearts removed from endotoxin-treated rats developed approximately 70% of the peak systolic pressure and 50% of the cardiac output (45% of the aortic flow and 50% of the coronary flow) at 25 cm H2O left atrial filling pressure (LAFP) compared to hearts from vehicle-injected controls. Hearts from endotoxin-treated rats were also characterized by decreased mechanical responsiveness to isoproterenol challenge at a high LAFP. These data suggest that myocardial dysfunction associated with endotoxin shock persists in vitro under conditions in which flow returning to the heart is not a limiting factor. Cyclic AMP accumulation was reduced in myocytes from endotoxin rats in response to 1 microM isoproterenol (29% of control values) and 1 microM forskolin (35% of control values) in both the absence and presence of phosphodiesterase inhibition with 0.2 mM isobutylmethylxanthine. Adenylate cyclase activity in crude membrane preparations of ventricular tissue from endotoxin-treated rats was unresponsive to challenge by isoproterenol and was reduced to 65% of control values by 100 micron GppNHp and by 10 mM NaF. Maximal specific binding of (-)[3H]dihydroalprenolol was decreased in membranes from endotoxin (56 +/- 2 fmol/mg) compared to control (64 +/- 2 fmol/mg) rats (P less than 0.05) but with similar antagonist affinities. These results suggest a decreased adrenergic responsiveness in myocytes and ventricular membrane preparations from endotoxin rats that may be linked to the reduction in myocardial adrenergic responsiveness during endotoxemia.
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D004731:Endotoxins / Q000633:toxicity; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D010477:Perfusion; D051381:Rats; D011919:Rats, Inbred Strains; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D012772:Shock, Septic / Q000378:metabolism*
D004731:Endotoxins; D011943:Receptors, Adrenergic, beta; D000242:Cyclic AMP; D000262:Adenylyl Cyclases; D007545:Isoproterenol