Sequential changes in autonomic regulation of cardiac myocytes after in vivo endotoxin injection in rat

We report that in vivo injection of endotoxin (EDTX, 6 mg . kg(-1)) induces cardiovascular alterations in rats that closely mimic the clinical situati on, as assessed by in vivo hemodynamic measurements in anesthetized and con scious, chronically instrumented animals. The patch-clamp technique was use d to characterize the L-type calcium current (I-Ca) and its autonomic regul ation in isolated cardiac myocytes. The density of I-Ca progressively decre ased at 12 and 36 h after EDTX injection. However, the dihydropyridine (+/- )Bay K 8644 (100 nM) enhanced I-Ca to levels similar to those in control an d EDTX-treated myocytes. In addition, the net stimulatory effect of a beta- adrenergic agonist (Isoproterenol) on I-Ca was increased 12 h after EDTX in jection. This change in the beta-adrenergic effect declined 24 h later. The potentiation in the beta-adrenergic stimulation of I-Ca was mimicked by L8 58051 (10 mu M), a direct activator of adenylyl cyclase, but not by IBMX (2 00 mu M), a phosphodiesterase inhibitor. Besides, the antiadrenergic effect of acetylcholine on I-Ca was unchanged 12 h after EDTX injection, but Incr eased 36 h after EDTX injection. These results support the hypothesis that time-dependent changes in the adenylyl cyclase pathway in cardiac myocytes may contribute, via the autonomic regulation of I-Ca, to the severity of my ocardial dysfunction during sepsis.