Effects of dexamethasone and L-canavanine on the intracellular calcium-contraction relation of the rat tail artery during septic shock.
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 Ca2+ 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 Ca2+-sensitive dye fura 2 in vitro. Intracellular Ca2+ concentration and perfusion pressure were measured simultaneously. The rightward shift of the perfusion pressure-intracellular Ca2+ mobilization curve after norepinephrine stimulation subsequent to CLP indicates decreased intracellular Ca2+ 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 Ca2+). We conclude that CLP lowers vasomotion by lowering intracellular Ca2+ sensitivity, which can be restored with glucocorticoid treatment. The involvement of inducible NOS does not solely account for the sepsis-induced reduction in Ca2+ sensitivity of contraction.
Mansart
Arnaud
A
Pharmacology Laboratory, Pharmacology Faculty, Nancy University, and Intensive Care Unit, University Central Hospital, France.
Bollaert
Pierre-Edouard
PE
Giummelly
Philippe
P
Capdeville-Atkinson
Christine
C
Atkinson
Jeffrey
J
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000502:physiology*; D002172:Canavanine / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000503:physiopathology*; D013623:Tail / Q000098:blood supply; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology
D005938:Glucocorticoids; D009569:Nitric Oxide; D002172:Canavanine; D003907:Dexamethasone; D001120:Arginine; D052247:Nitric Oxide Synthase Type II; D002118:Calcium