Reduced L-type calcium current in ventricular myocytes from endotoxemic guinea pigs

The circulatory response to gram-negative sepsis and its experimental counterpart, endotoxemia, includes a profound dysfunction in myocardial contractility that is resident to the myocyte and associated with reduced systolic free intracellular Ca2+ concentration ([Ca2+](i)). We explored the possibility that decreased systolic [Ca2+](i) in endotoxemic myocytes is correlated with reduced L-type Ca2+ current (I-Ca,I-L). Ventricular myocytes were isolated from guinea pigs 4 h after an intraperitoneal injection of Escherichia coli lipopolysaccharide (LPS; 4 mg/kg). Membrane potentials and Ca2+ currents were measured using whole cell patch-clamp methods. The action potential duration of endotoxemic myocytes was significantly shorter than control values (time to 50% repolarization: LPS, 314 +/- 23 ms; control, 519 +/- 36 ms, P < 0.05). Correspondingly, endotoxemic myocytes demonstrated significantly reduced peak I-Ca,I-L density (3.5 +/- 0.2 pA/pF) and Ba2+ current (I-Ba) density (7.3 +/- 0.5 pA/pF) compared with respective values of control myocytes (I-Ca,I-L density 6.1 +/- 0.3 pA/pF, I-Ba density 11.3 +/- 0.8 pA/pF; P < 0.05). Endotoxemia-induced reduction in peak I-Ca,I-L could not be attributed to alterations in current-voltage relationships, steady-state activation and inactivation, or recovery from inactivation. The beta-adrenoceptor agonist isoproterenol, but not the Ca2+ channel activator BAY K 8644, reversed the LPS-induced reduction in peak I-Ca,I-L, cell contraction, and systolic [Ca2+](i). These data demonstrate that part of the host response to endotoxemia involves diminished sarcolemmal I-Ca,I-L of ventricular myocytes.