Shock/sepsis/trauma/critical careSepsis alters vessel contraction by adrenoceptor-induced nitric oxide and prostanoid1
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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2017, Pharmacological ReportsCitation Excerpt :All aortic preparations were equilibrated in the K–H solution for about 45 min with washing out of the tissues every 15 min [16]. After this period phenylephrine was added in cumulative concentrations (10−9 to 3 × 10−5 Molar [M]) into the organ baths and for each concentration of phenylephrine, the increase in recorded changes of contraction amplitudes were expressed as grams of tension [17,18]. The EC50 values as an indicator of potency and Emax values as an indicator of efficacy were obtained from the dose–response data using GraphPad Prism 5 software (GraphPad, UK).
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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.