Shock/sepsis/trauma/critical care
Sepsis alters vessel contraction by adrenoceptor-induced nitric oxide and prostanoid1

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Abstract

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 (NG-monomethylarginine), cPN (mefenamic acid, MFA), or thromboxane A2 (SQ29548). Contraction dose-response curves were generated to determine maximal contraction force (Fmax) and pD2 (sensitivity) to phenylephrine in each experimental group.

Results.

Sepsis increased Fmax to phenylephrine (PHE) (1.18 vs 0.90 g, SEM 0.0703). COX inhibition reduced the Fmax 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 Fmax 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 Fmax 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 Fmax 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 Fmax 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.

Introduction

Shock and altered blood flow to vital organs are frequent pathophysiological events during clinical systemic inflammation and are major components of the organ system failure syndrome. Vasoactive agents are often utilized to maintain blood flow to major organs, but sepsis alters vessel responses to both vasoconstrictor and vasodilator agents 1, 2. These altered responses to both intrinsic and extrinsic vasoactive agents are thought to play an important role in the alteration of blood flow to splanchnic organs during sepsis.

Recent studies have shown that vascular endothelial cells initiate secondary mechanisms to modulate the primary receptor-mediated contraction of blood vessels. Endothelial cells possess alpha-adrenergic receptors that respond to stimulation by producing both constrictor and relaxant factors, which then modulate the direct stimulus for vascular smooth muscle (VSM) contraction 3, 4. This suggests that the endothelial response to alpha-adrenergic agents might modulate VSM force development as a normal mechanism to prevent an alpha-adrenergic induced, complete closure of blood vessels.

Our present study addresses the effect of sepsis on endothelial cell modulation of alpha-1 adrenergic receptor-mediated VSM contraction. Because sepsis alters many factors which can independently affect endothelial cell and VSM function, sepsis could alter one or more mechanisms for endothelial cell modulation of VSM contraction. To test this hypothesis, we used a rat model of systemic inflammation as a result of soft tissue infection to identify the effect of sepsis on aortic ring contraction. In addition, we wanted to determine the role of the nitric oxide and prostanoid vasoactive systems as the principle modifiers of adrenergic VSM contraction during sepsis by the addition of selective inhibitors into the aortic ring preparations.

Section snippets

General animal care

Male Sprague-Dawley rats (Harlan, Indianapolis) were maintained on standard rat diet and water ad libitum for at least 1 week in AAALAC-approved facilities before use in experiments. Experimental procedures conformed to “Principles of Laboratory Animal Care” of the National Society for Medical Research and the “Guide for the Care and Use of Laboratory Animals” of the U.S. National Academy of Science as published by the National Institutes of Health (NIH publication # 80-23, revised 1987). All

Role of PHE-induced COX and NOS pathways in development of Fmax to PHE in non-septic animals

PHE, in the absence of inhibitor, induced approximately 1 g of Fmax in a 2-mm long aortic ring from nonseptic rats that had received a sponge inoculation of saline 24 h previously (Fig. 1, top panel). The amount of Fmax to PHE was decreased in the presence of the COX inhibitor MFA, but was increased in the presence of the NOS inhibitor LNMMA (Fig. 1, top panel). The amount of MFA-induced reduction in PHE-induced Fmax was the same in the presence and absence of LNMMA (Fig. 1, top panel, white

Hypothesis

Sepsis changes the vascular response to many vasoactive agents, which can alter blood flow to vital organs such that organ dysfunction will eventually occur. Part of this sepsis-induced effect involves a sepsis effect on alpha-1 adrenergic receptor-mediated contraction of vascular smooth muscle [2]. Alpha-1 adrenergic receptor agonists also appear to stimulate the endothelium to release vasodilatory NO 3, 4, 19 and vasoconstrictor prostanoid 3, 20 which modulates vascular smooth muscle

Acknowledgements

This work was partly supported by a grant from the U.S. Department of Defense and the Veterans Administration.

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    Presented in part at the Shock Society meeting, Snowbird Utah, June 4–7, 2000, and at the VA surgeons’ meeting, Houston, Texas, April 28, 2002. Supported in part by the Department of Defense.

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