Adjunctive vasodilator therapy in the treatment of murine ischemia

Potent vasoconstrictors such as angiotensin II and vasopressin have been implicated as mediators of persistent vasoconstriction after reversible superior mesenteric artery (SMA) occlusion. Neither captopril (CAP), an angiotensin-converting enzyme (ACE) inhibitor, nor papaverine (PAP), a vasodilator, has proven effective in reversing this vasoconstriction when employed singly. The present study examined the combined effect of these agents in reducing mortality in a murine model of acute mesenteric ischemia. The SMAs of 106 adult male Sprague-Dawley rats were totally occluded for 85 minutes. Test agents were given intravenously at reperfusion over a 90- minute period. Survival rates were assessed at 48 hours. CAP was given as a single bolus (0.3 mg/kg) and PAP (0.5 mg/kg/h) as an infusion. Aortic and SMA blood flows were measured pretreatment and posttreatment in a separate group of 19 animals treated with CAP and PAP as single agents. χ2 analysis and analysis of variance were used to test differences with p ≤0.05 accepted as significant. PAP alone as an adjunct resulted in a significant increase in 48-hour survival (57% versus 19%, p ≤0.005). PAP in combination with CAP produced the best outcome in this model (87% versus 19%, p ≤0.005). Aortic blood flow decreased, whereas SMA blood flow increased after treatment both with CAP and with PAP, but not significantly. The combination of an intravenously administered vasodilator with either glucagon or an ACE inhibitor was the most effective adjunctive therapy in this mesenteric ischemia model. There was no evidence that an inotropic effect, rather than SMA vasodilation, was the responsible mechanism of action.