Chronic administration of adrenomedullin attenuates hypoxic pulmonary vascular structural remodeling and inhibits proadrenomedullin N-terminal 20-peptide production in rats

Adrenomedullin (ADM) is a novel cardiovascular-active peptide involved in vasodilation, reducing blood pressure and inhibiting vascular smooth muscle cell migration and proliferation. Previous research showed that ADM might be involved in the development of pulmonary hypertension. In this study, we investigated the effect of ADM subcutaneously administered by mini-osmotic pump (300 ng/h) on pulmonary hemodynamics and pulmonary vascular structure in hypoxic rats, as well as the influence of ADM on the proadrenomedullin N-terminal 20-peptide (PAMP) protein and mRNA expressions and its plasma concentrations. The results showed that ADM obviously decreased mean pulmonary artery pressure and the ratio of right ventricular mass to left ventricular plus septal mass in hypoxic rats. Chronic infusion of ADM lessened the muscularization of small pulmonary vessels, attenuated relative medial thickness and relative medial area of pulmonary arteries, and alleviated the ultrastructural changes in pulmonary arteries of hypoxic rats. ADM inhibited the proliferation of pulmonary artery smooth muscle cells, represented by a decrease in the expression of proliferative cell nuclear antigen (PCNA) in the pulmonary artery. Meanwhile, plasma PAMP concentration and the expression of PAMP protein and mRNA by pulmonary arteries in rats of hypoxia with ADM group were markedly decreased compared with those in hypoxic group. The results suggest that ADM ameliorated the development of hypoxic pulmonary vascular structural remodeling. Intramolecular regulation of ADM may play an important role in the regulation of hypoxic pulmonary hypertension by ADM.