Rapid regulation of adrenomedullin in metabolically compromised vascular smooth muscle cells

Objective The prepro-adrenomedullin gene encodes the biologically active pe ptide adrenomedullin, which acts as a potent vasodilator as well as a modul ator of vascular smooth muscle cell growth, We investigated the question of whether adrenomedullin is regulated in response to metabolic perturbations in vascular smooth muscle. Materials and methods Acute inhibition of glycolysis, leading to partial de pletion of cellular ATP, was produced in cultured rat aortic vascular smoot h muscle cells by replacing glucose with 2-deoxyglucose, Solution hybridiza tion/RNase protection analysis was used to quantitate changes in expression of the prepro-adrenomedullin messenger RNA and a specific radioimmunoassay was used to assess levels of secreted adrenomedullin. Results Acute incubation of rat aortic vascular smooth muscle cells with 2- deoxyglucose caused a rapid and sustained induction of low basal levels of adrenomedullin messenger RNA, which reached twice the control levels by 1 h and four times control levels by 6 h, The induction of adrenomedullin mess enger RNA expression was dependent upon de-novo gene transcription and was reversed by the re-introduction of glucose, Despite the sustained increase in adrenomedullin messenger RNA, secretion of immunoreactive-adrenomedullin from vascular smooth muscle cells was reduced by as much as 75% and parall eled the inhibition of radiolabeled amino acid incorporation into protein d uring glycolytic inhibition; both parameters recovered towards control leve ls following re-introduction of glucose. Conclusions The rapid and reversible activation of the adrenomedullin gene and inhibition of adrenomedullin peptide release in response to metabolic i nhibition suggest that adrenomedullin represents a novel localized mechanis m that may modulate regional blood flow and vascular smooth muscle cell pro liferation in response to perturbations of normal metabolism, J Hypertens 1 999, 17:373-379 (C) Lippincott Williams & Wilkins.