Uncoupling of coronary microvascular beta 2-adrenoceptors by Escherichia coli endotoxemia.

Abstract

Cardiovascular responses to the adrenergic stimulation are depressed in clinical and experimental endotoxemia. However, the effect of Escherichia coli endotoxemia on coronary microvascular beta-adrenergic function remains to be determined. The purpose of the present study was to test the hypothesis that endotoxemia impairs the beta-adrenoceptor- and adenosine 3'5'-cyclic monophosphate-mediated relaxation in the porcine coronary microcirculation. Coronary arterioles (80 to 170 microns internal diameter) were isolated from pigs 3 hours after intravenous administration of E. coli endotoxin (150 micrograms/kg, over 1 hour, n = 8) or Ringer's lactate (control, n = 8). Arterioles were studied in vitro in a pressurized, partially contracted, no-flow state by videomicroscopy. Precontracted (30% to 50% of baseline diameter with acetylcholine) control coronary arterioles dilated in response to either the nonselective beta-adrenoceptor agonist, isoproterenol, the Gs-protein activator, sodium fluoride, or the adenylate cyclase activator, forskolin. After 3 hours of endotoxemia, the relaxation responses to isoproterenol and sodium fluoride were significantly reduced, but the relaxation response to forskolin was preserved. The beta 2-adrenoceptor blocker, ICI-118, 551, markedly reduced the relaxation of control microvessels induced by isoproterenol, whereas the beta 1-adrenoceptor blocker, atenolol, caused only a slight reduction in isoproterenol-induced relaxation. beta 2-Adrenoceptors appear to predominate over beta 1-adrenoceptors in the coronary microcirculation. E. coli endotoxemia impairs beta 2-adrenoceptor-mediated relaxation in the porcine coronary microcirculation, apparently because of changes proximal to adenylate cyclase in the signal transduction pathway.