Touichi Kawabe

Sepsis alters vessel contraction by adrenoceptor-induced nitric oxide and prostanoid

BACKGROUND Alpha-adrenergic agents contract vascular smooth muscle (VSM) and stimulate endothelial release of secondary factors which modulate VSM contraction. Our study examined constrictor prostanoid (cPN) and nitric oxide (NO) as secondary factors which could alter alpha-1 adrenoceptor-mediated contraction during sepsis. METHODS Sepsis was induced in rats by inoculation of an implanted sponge with Escherichia coli and Bacteroides fragilis. Aortic rings at 24 h from septic (n = 21) and control (n = 21) rats were suspended in physiological salt solution (PSS) with or without blockers to NO (N(G)-monomethylarginine), cPN (mefenamic acid, MFA), or thromboxane A2 (SQ29548). Contraction dose-response curves were generated to determine maximal contraction force (F(max)) and pD2 (sensitivity) to phenylephrine in each experimental group. RESULTS Sepsis increased F(max) to phenylephrine (PHE) (1.18 vs 0.90 g, SEM 0.0703). COX inhibition reduced the F(max) in control (0.63 vs 0.90 g, SEM 0.0675) but not in septic animals (1.19 vs 1.18 g, SEM 0.0433). TXA2 receptor inhibition did not alter F(max) in control (1.017 vs 0.973 g, SEM 0.0959) or septic animals (1.28 vs 1.12 g, SEM 0.0823). NOS inhibition enhanced the F(max) in both nonseptic (2.03 vs 0.83 g, SEM 0.0523) and septic rats (1.96 vs 1.15 g, SEM 0.0526), but did less so in the septic animals. CONCLUSIONS PHE-induced F(max) is determined by a balance between PHE-stimulated VSM alpha-adrenoceptor activity, and PHE-stimulated endothelial release of cPN and NO. Sepsis enhances total PHE-induced F(max) by increasing VSM alpha-adrenoceptor activity and reducing PHE-stimulated endothelial release of dilator NO. Sepsis abolishes the PHE-stimulated endothelial release of cPN. PHE-stimulated cPN is not thromboxane A2, but could be a nonprostanoid dilator in the lipoxygenase (HETE) or cytochrome P450 (EET) pathways.

Role of neutrophils on shock/resuscitation-mediated intestinal arteriolar derangements

Adequate resuscitation from hemorrhagic shock that preserves hemodynamics is associated with a generalized and progressive intestinal arteriolar vasoconstriction and hypoperfusion coupled with impairment of the endothelium-dependent dilation response. This study was performed to investigate the role of neutrophils on the postresuscitation intestinal arteriolar derangements. Experiments were performed in anesthetized rats 24 h after neutrophil depletion. Neutropenia was induced with antineutrophil serum by tail vein injection. Rats injected with rabbit serum lacking anti–rat neutrophil antibody served as controls. Hemorrhagic shock was 50% of mean arterial pressure for 60 min. Resuscitation was with the shed blood returned plus 2 volumes of saline. A nonhemorrhage group served as control. Intravital videomicroscopy of the terminal ileum was used to measure microvascular diameter and centerline red cell velocity. Endothelial function was assessed from the response to the endothelium-dependent dilator acetylcholine (10−9 to 10−4 M). Regardless of neutrophil count, hemorrhagic shock caused selective vasoconstriction of inflow A1 arterioles (−21.49 ± 0.67%) from baseline, which was not seen in the premucosal A3 vessels (pA3, dA3). At 2 h postresuscitation, there was a generalized vasoconstriction from baseline diameter in A1 (−21.26 ± 2.29%), pA3 (−22.66 ± 5.02%), and dA3 (−17.62 ± 4.84%). Neurophil depletion caused a significant reset of baseline A1 blood flow from 701 ± 90 nL/s to 978 ± 90 nL/s and attenuated the postresuscitation hypoperfusion. This occurred independently of the A1 diameter change. Hemorrhagic shock/resuscitation caused impairment of the endothelium-dependent dilation response irrespective of neutrophil count. This study demonstrates that neutrophils do not contribute to the hemorrhagic/resuscitation-mediated intestinal arteriolar derangements, but appear to possess a role in the intestinal arteriolar blood flow regulation under normal and low flow states possibly via a rheologic effect.