Adenosine and nitric oxide regulate regional vascular resistance via interdependent and independent mechanisms during sepsis

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Objective: Adenosine receptor blockade increases regional resting vascular resistance during sepsis. In healthy subjects, part of adenosine's actions are mediated via stimulation of nitric oxide synthase. Because nitric oxide synthase activity is thought to be a major contributor to altered vascular tone in sepsis, we tested the hypothesis that some of the nitric oxide-mediated resting regional resistance during sepsis is secondary to endogenous adenosine stimulation of nitric oxide synthase. Design: Prospective, randomized, controlled experiment. Setting: Shock-trauma and basic science laboratory. Subjects: Male Sprague-Dawley rats. Interventions: Twenty-four hours after sepsis or sham induction, rats were separated into two groups (n = 6 to 10 in each group). Group 1 received a 10-min infusion of the adenosine antagonist 8-sulfophenyltheophylline (0.9 mg/kg · min) followed by a 10-min infusion of L-nitro-arginine-methyl ester (0.5 mg/kg · min). Group 2 similarly received L-nitro-arginine-methyl ester followed by 8- sulfophenyltheophylline in the presence of L-nitro-arginine-methyl ester. Measurements and Main Results: Hemodynamic and blood flow measurements (microspheres) were made before infusions, 10 mins after the administration of each single-agent infusion, and 10 mins after combined-agent infusions were administered. No significant resistance alterations were observed in nonseptic rats. In septic rats, adenosine receptor blockade alone increased hepatosplanchnic and skeletal muscle vascular resistance, but no further increases were seen when L-nitro-arginine-methyl ester was added. Nitric oxide synthase inhibition alone increased hepatosplanchnic and skeletal muscle vascular resistances. When 8-sulfophenyltheophylline was added to the infusion, skeletal muscle vascular resistance increased significantly more than with L-nitro-arginine-methyl ester alone, but there were no further increases in hepatosplanchnic resistance. Renal and adipose vascular resistances increased with L-nitro-arginine-methyl ester infusions, and 8- sulfophenyltheophylline produced no effect. Conclusions: During sepsis, nitric oxide caused resting vasodilation independent of adenosine in the renal and adipose vasculature. In the hepatosplanchnic circulation, there is reciprocal adenosine-nitric oxide interaction in maintaining resting regional resistance. Skeletal muscle displayed a dual adenosine-mediated (nitric oxide-independent) and nitric oxide-mediated (adenosine receptors required) interaction to regulate resting resistance during sepsis. These data indicate that in the hepatosplanchnic and skeletal muscle vasculature, all of the resting nitric oxide-mediated vasodilation is secondary to endogenous adenosine action, but in adipose and renal vasculature, resting nitric oxide mediated vasodilation is independent of adenosine. Endogenous adenosine also appears to play a significant role in determining resting skeletal muscle resistance that is independent of nitric oxide synthase during sepsis.

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Critical Care Medicine



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This article was published in Critical Care Medicine, Volume 28, Issue 6, Pages 1931-1939.

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