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

Introduction. Sepsis results in hyporesponsiveness to cu-adrenergic stimula tion, 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 h ave 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 mec hanisms. We hypothesize that subacute sepsis causes impaired alpha-adrenerg ic vascular responsiveness by a combination of effects on adrenergic constr ictor mechanisms, endogenous dilator tone, and VSM contractile function. Methods. Male Sprague-Dawley rats underwent implantation of a 2 x 2-cm(2) g auze sponge into a subcutaneous pocket created at the base of the tail. Fiv e days after implantation, sepsis (S) was induced by inoculation of the spo nge with 10(9) CFU Escherichia coli and Bacteroides fragilis. Controls (C) were inoculated with saline. Thoracic aortic harvest was performed 24 and 4 8 h after sponge inoculation for organ bath ring studies. Receptor-mediated (phenylephrine) and nonreceptor-mediated (KCI) maximum force of contractio n (F-max) was measured. Vessel sensitivity (pD(2)) to phenylephrine, acetyl choline, and KCI was calculated from dose-response curves. Results. At 24 h, sepsis resulted in a lower F-max to phenylephrine (1.15 f or C vs 0.5 for S, P < 0.05 by ANOVA), despite an increase in vessel sensit ivity (pD(2)) to cu-adrenergic stimulation (6.70 for C vs 6.88 for S, P < 0 .05 by ANOVA). F-max 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 (pD(2)) was markedly increased (6.56 for C vs 7.23 for S, P < 0.05 by ANOVA). At 4 8 h, the impairment in P,, to a-adrenergic stimulation (2.29 for C vs 1.72 for S, P < 0.05 by ANOVA) and KCI (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 con tractile force despite an increase in adrenergic receptor sensitivity (pD(2 )). This may be secondary to an elevation in dilator sensitivity combined w ith a direct effect of sepsis on VSM contractile mechanisms. Later in the s eptic process, however, a-adrenergic hyporesponsiveness(down arrow F-max) i s primarily due to changes in VSM contractile machinery. (C) 1999 Academic Press.