Submitted on September 19, 2005
Accepted on March 27, 2006
Effects of dexamethasone and L-canavanine on the intracellular calcium/contraction relationship of the rat tail artery during septic shock
Arnaud Mansart1, Pierre-Edouard Bollaert1*, Philippe Giummelly1, Christine Capdeville-Atkinson1, and Jeffrey Atkinson1
1 Pharmacology Laboratory, Pharmacy Faculty, Nancy, France; Intensive Care Unit, Hopital Central, Nancy, France
* To whom correspondence should be addressed. E-mail: pe.bollaert{at}chu-nancy.fr.
The intracellular mechanism by which sepsis lowers vascular reactivity and the subsequent reversal by dexamethasone or nitric oxide (NO) synthase inhibitors remains unclear. We measured the sensitivity of contraction of the rat tail artery to intracellular calcium in a model of polymicrobial septic shock. Rats were subjected to cecal ligation and puncture (CLP), then treated 22 hours later with an anti-inflammatory glucocorticoid (dexamethasone, 1 mg.kg-1, IP), an inducible NO synthase (iNOS) inhibitor (L-canavanine, 100 mg.kg-1, IP), or saline. Twenty-four hours after CLP, endothelium-denuded, perfused segments of the tail artery were loaded with the intracellular calcium - sensitive dye fura-2 in vitro. Intracellular calcium concentration ([Ca2+]i) and perfusion pressure were measured simultaneously. The perfusion pressure versus intracellular calcium mobilization curve following norepinephrine stimulation was shifted to the right after CLP indicating decreased intracellular calcium sensitivity of contraction. The relationship was restored by dexamethasone (which also restored in vivo blood pressure and flow) but not by L-canavanine which restored perfusion pressure by further intracellular calcium mobilization. We conclude that CLP lowers vasomotion by lowering intracellular calcium sensitivity and this can be restored with glucocorticoid treatment. The involvement of iNOS does not solely account for the sepsis-induced reduction in calcium sensitivity of contraction.
