Vascular Smooth Muscle Cell Calcium Sensitivity Is Decreased During Lipopolysaccharide‐Mediated Inflammation.

Abstract

Sepsis is associated with microvascular hyporeactivity to agonists and may be reflective of reduced Ca2+-sensitivity within smooth muscle cells. We hypothesize that impaired vasoreactivity during LPS-mediated inflammation is associated with decreased Ca2+ sensitivity in small mesenteric resistance arteries (SMRA). SMRAs (190–220 μm) isolated from LPS-treated (15 mg/kg ip, 18 hours) and saline-treated control mice were mounted on a pressure myograph, superfused, and loaded with fura-2. Arteriolar diameter and global intracellular Ca2+ were simultaneously measured. Smooth muscle Ca2+-sensitivity of SMRAs was assessed by stepwise increases in extracellular Ca2+ (0 to 2 mM) under depolarizing conditions (120 mM K+). SMRA isolated from mice treated with LPS demonstrated hyporesponsiveness to Ca2+. Extracellular mediated Ca2+ vasoconstriction in intact vessels resulted in an increase in EC50 (0.23 ± 0.01 mM vs 0.39 ± 0.03 mM∗) and a reduction in Emax (42.8± 1.1% vs 26.6 ± 3.4%∗). Removal of the endothelium resulted in near normal response to Ca2+. In intact vessels, LPS treatment decreases vascular smooth muscle Ca2+ sensitivity as compared to controls. NOS inhibition (L-NNA, 1 μM) restores responsiveness to Ca2+ without restoring Ca2+ sensitivity. LPS-induced inflammation results in NO-independent decrease in Ca2+-sensitivity within vascular smooth muscle cells.