Effects of dexamethasone and L-canavanine on the intracellular calcium-contraction relation of the rat tail artery during septic shock

1 Pharmacology Laboratory, Pharmacy Faculty, Nancy University, and 2 Intensive Care Unit, University Central Hospital, Nancy, France Submitted 19 September 2005 ; accepted in final form 27 March 2006 The intracellular mechanism by which sepsis lowers vascular reactivity and the subsequent reversal by dexamethasone or nitric oxide synthase (NOS) inhibitors remain unclear. We measured the sensitivity of contraction of the rat tail artery to intracellular Ca 2+ in a model of polymicrobial septic shock. At 22 h after cecal ligation and puncture (CLP), rats were treated with an anti-inflammatory glucocorticoid (dexamethasone, 1 mg/kg ip), an inducible NOS inhibitor ( L -canavanine, 100 mg/kg ip), or saline. At 24 h after CLP, endothelium-denuded, perfused segments of tail artery were loaded with the intracellular Ca 2+ -sensitive dye fura 2 in vitro. Intracellular Ca 2+ concentration and perfusion pressure were measured simultaneously. The rightward shift of the perfusion pressure-intracellular Ca 2+ mobilization curve after norepinephrine stimulation subsequent to CLP indicates decreased intracellular Ca 2+ sensitivity of contraction. The relation was restored by dexamethasone (which also restored in vivo blood pressure and flow), but not by L -canavanine (which restored perfusion pressure by further mobilization of intracellular Ca 2+ ). We conclude that CLP lowers vasomotion by lowering intracellular Ca 2+ sensitivity, which can be restored with glucocorticoid treatment. The involvement of inducible NOS does not solely account for the sepsis-induced reduction in Ca 2+ sensitivity of contraction. glucocorticoid; nitric oxide; sepsis Address for reprint requests and other correspondence: P. E. Bollaert, Service de Réanimation Médicale, Hôpital Central, Ave. de Lattre de Tassigny, 54035 Nancy Cedex, France (e-mail: pe.bollaert{at}chu-nancy.fr )