Production and secretion of adrenomedullin in cultured rat cardiac myocytes and nonmyocytes: stimulation by interleukin-1beta and tumor necrosis factor-alpha.

The present study investigated the secretion level and gene expression of adrenomedullin (AM), a novel vasorelaxant peptide, in cultured neonatal rat cardiac myocytes and nonmyocytes, and the effects of interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF alpha) on its production and secretion in these cells. Under serum-free conditions, both myocytes and nonmyocytes secreted immunoreactive (ir-) AM into the culture medium in a time-dependent manner. The secretion rates of ir-AM from myocytes and nonmyocytes per 10(5) cells were almost equivalent. The expression of AM messenger RNA was also observed in cultured myocytes and nonmyocytes. The peptide secretion and messenger RNA level of AM in cardiac myocytes were increased after stimulation with IL-1beta. In nonmyocytes, IL-1beta and TNF alpha remarkably augmented both the release of ir-AM into the medium and AM gene expression after 24 and 48 h of incubation. These observations indicate that cardiac ventricular cells (i.e. myocytes and nonmyocytes) actively produce AM and also suggest that cytokines such as IL-1beta and TNF alpha regulate the gene expression and secretion of this peptide in the ventricles. On the basis of these results and the findings that IL-1beta and TNF alpha are involved in heart failure and cardiac hypertrophy, AM may play a role as an autocrine/paracrine modulator in some cardiac disorders.