Decreased vasopressin responsiveness in vasodilatory septic shock–like conditions

OBJECTIVE:To determine the effect of vasodilatory septic shock–like conditions on vasoconstricting responses to vasopressin and norepinephrine in isolated resistance arteries. DESIGN:Prospective, randomized animal study. SETTING:University research laboratory. SUBJECTS:Male adult Sprague-Dawley rats. INTERVENTIONS:Small mesenteric arteries (outside diameter, 50–150 μm) were cannulated and studied in vitro under physiologic conditions. A vasodilatory septic shock–like state was produced by treatment with the nitric oxide (NO) donor, S-nitroso-N-acetylpenicillamine (SNAP), and the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX). Vasoconstricting concentration-response relationships were determined for norepinephrine and vasopressin before and after application of SNAP or SNAP+ IBMX. Synergism between low-dose vasopressin and norepinephrine and between low-dose norepinephrine and vasopressin was determined before and after SNAP or SNAP+IBMX. MAIN RESULTS:Norepinephrine and vasopressin produced concentration-dependent contractions (half-maximal effective concentration [EC50] = 2.5 μM and 3.9 nM, respectively) that were significantly inhibited by 1 μM SNAP (EC50 = 3.6 μM and 8.1 nM, respectively) or 100 μM SNAP + 10 μM IBMX (EC50 = 10 μM and 8.2 nM, respectively). Low-dose vasopressin significantly increased the responsiveness to norepinephrine (EC50 = 0.5 μM) just as a low-dose norepinephrine significantly enhanced the vasopressin response (EC50 = 2.3 nM). The synergistic effects of low-dose vasopressin and norepinephrine, or low-dose norepinephrine and vasopressin, were also significantly inhibited by 1 μM SNAP (EC50 = 2.5 μM and 4.2 nM, respectively) or 100 μM SNAP + 10 μM IBMX (EC50 = 9 μM and 8.4 nM, respectively). CONCLUSIONS:Vasoconstriction produced by vasopressin or norepinephrine, and the synergistic vasoconstriction produced by the combinations, was inhibited in vasodilatory septic shock–like conditions. Thus, in addition to the well-described vasopressin deficiency in vasodilatory septic shock, these studies indicate that decreased vasopressin responsiveness further contributes to a state of relative vasopressin insufficiency in this condition.