Vascular contribution of adrenomedullin to microcirculatory improvement in experimental colitis

Abstract

The effect of adrenomedullin (AM), a peptide that has demonstrated vasodilatory activity, was studied in the colon and small mesenteric arteries of rats in a chronic model of inflammatory bowel disease. AM (50 ng/kg/day) was administered i.p. daily, starting 24h after trinitrobenzensulfonic acid (TNBS, 30 mg) instillation. After 14 days, rats were sacrificed, colons were macroscopically analyzed and biochemical parameters (myeloperoxidase activity, cytokines, cyclooxygenase-2 (COX-2) as well as inducible nitric oxide synthase (iNOS) expression) were determined. Vascular function of small mesenteric arteries was assessed by addition of phenylephrine (10⁻⁸ to 10⁻⁴ mol/L) and participation of COX and NOS pathways was also evaluated by using different inhibitors: indomethacin, NS-398, L-NNA, and 1400 w. Chronic AM treatment significantly reduced colonic macroscopic damage and inflammation markers. TNBS instillation induced COX-2 and iNOS expressions in colon and small mesenteric arteries; AM treatment decreased COX-2 expression only in microvessels from rats with colitis. An attenuation of phenylephrine-induced contraction was detected in small mesenteric arteries from both TNBS and AM-treated rats. COX and NOS inhibitors altered the contractile ability of phenylephrine in small mesenteric arteries from TNBS rats, suggesting the involvement of COX-2 and iNOS derived factors in the deleterious effect of TNBS on vascular reactivity; AM administration was able to reduce such alteration. Finally, treatment with the peptide significantly reduced colonic nitric oxide (NO) levels, without affecting plasma concentration. In conclusion, AM showed beneficial effects in the restoration of vascular function through the regulation of vasoactive products derived from COX-2 and iNOS.