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

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-med iated 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 I received a 1 0-min infusion of the adenosine antagonist 8-sulfophenyltheophylline (0.9 m g/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 fol lowed by 8-sulfophenyltheophylline in the presence of L-nitro-arginine-meth yl ester. Measurements and Main Results: Hemodynamic and blood flow measurements (mic rospheres) 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 nonse ptic rats. In septic rats, adenosine receptor blockade alone increased hepa tosplanchnic and skeletal muscle vascular resistance, but no further increa ses were seen when L-nitro-arginine-methyl ester was added. Nitric oxide sy nthase inhibition alone increased hepatosplanchnic and skeletal muscle vasc ular resistances. When 8-sulfaphenyltheophylline 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 i n hepatosplanchnic resistance. Renal and adipose vascular resistances incre ased with L-nitro-arginine-methyl ester infusions, and 8-sulfophenyltheophy lline produced no effect. Conclusions: During sepsis, nitric oxide caused resting vasodilation indepe ndent of adenosine in the renal and adipose vasculature. In the hepatosplan chnic circulation, there is reciprocal adenosine-nitric oxide interaction i n maintaining resting regional resistance. Skeletal muscle displayed a dual adenosine-mediated (nitric oxide-independent) and nitric oxide-mediated (a denosine receptors required) interaction to regulate resting resistance dur ing sepsis. These data indicate that in the hepatosplanchnic and skeletal m uscle vasculature, all of the resting nitric oxide-mediated vasodilation is secondary to endogenous adenosine action, but in adipose and renal vascula ture, resting nitric oxide mediated vasodilation is independent of adenosin e. Endogenous adenosine also appears to play a significant role in determin ing resting skeletal muscle resistance that is independent of nitric oxide synthase during sepsis.