Subacute sepsis impairs vascular smooth muscle contractile machinery and alters vasoconstrictor and dilator mechanisms.

INTRODUCTION

Sepsis results in hyporesponsiveness to alpha-adrenergic stimulation. This is thought to be mediated by the release of vasoactive compounds from the septic endothelium or by the direct effect of sepsis on vascular smooth muscle (VSM) contractile mechanics and machinery. Previous studies have used lethal models of sepsis or endotoxemia to examine this phenomenon. The present study utilizes a clinically relevant, nonlethal model of soft tissue infection to determine the effects of sepsis on alpha-adrenergic mechanisms. We hypothesize that subacute sepsis causes impaired alpha-adrenergic vascular responsiveness by a combination of effects on adrenergic constrictor mechanisms, endogenous dilator tone, and VSM contractile function.

METHODS

Male Sprague-Dawley rats underwent implantation of a 2 x 2-cm2 gauze sponge into a subcutaneous pocket created at the base of the tail. Five days after implantation, sepsis (S) was induced by inoculation of the sponge with 10(9) CFU Escherichia coli and Bacteroides fragilis. Controls (C) were inoculated with saline. Thoracic aortic harvest was performed 24 and 48 h after sponge inoculation for organ bath ring studies. Receptor-mediated (phenylephrine) and nonreceptor-mediated (KCl) maximum force of contraction (Fmax) was measured. Vessel sensitivity (pD2) to phenylephrine, acetylcholine, and KCl was calculated from dose-response curves.

RESULTS

At 24 h, sepsis resulted in a lower Fmax to phenylephrine (1.15 for C vs 0.5 for S, P < 0.05 by ANOVA), despite an increase in vessel sensitivity (pD2) to alpha-adrenergic stimulation (6.70 for C vs 6.88 for S, P < 0.05 by ANOVA). Fmax to KCl was lower in septic animals at 24 h (3. 50 for C vs 2.77 for S, P < 0.05 by ANOVA) and sensitivity to acetylcholine (pD2) was markedly increased (6.56 for C vs 7.23 for S, P < 0.05 by ANOVA). At 48 h, the impairment in Fmax to alpha-adrenergic stimulation (2.29 for C vs 1.72 for S, P < 0.05 by ANOVA) and KCl (3.5 for C vs 3.08 for S. P < 0.05 vs 24 h C by ANOVA) persisted without any change in sensitivity to phenylephrine or acetylcholine.

CONCLUSIONS

Subacute sepsis results in an early suppression of maximum contractile force despite an increase in adrenergic receptor sensitivity (pD2). This may be secondary to an elevation in dilator sensitivity combined with a direct effect of sepsis on VSM contractile mechanisms. Later in the septic process, however, alpha-adrenergic hyporesponsiveness ( downward arrow Fmax) is primarily due to changes in VSM contractile machinery.