PROADRENOMEDULLIN-DERIVED PEPTIDES

Posttranslational processing of the adrenomedullin gene product result s in the formation of at least two biologically active peptides, adren omedullin (AM) and proadrenomedullin N-20 terminal peptide (PAMP). Pro duced predominantly in the vasculature, both peptides are potent hypot ensive agents, albeit via unique mechanisms of action. The gene is tra nscribed in a variety of other tissues including brain, pituitary, and kidney. Numerous actions have been reported most related to the physi ologic control of fluid and electrolyte homeostasis. In the kidney, AM is diuretic and natriuretic, and both AM and PAMP inhibit aldosterone secretion by direct adrenal actions. In pituitary gland, both peptide s at physiologically relevant doses inhibit basal ACTH secretion, agai n by apparently differing mechanisms. Additionally, AM antagonizes CRH -stimulated ACTH release. The peptides are produced in numerous brain sites, including hypothalamus and brainstem. Inhibition of AVP release has been reported and the physiologic significance of AM's ability to inhibit water drinking and salt appetite has been established. Thus t he peptides appear to act in brain and pituitary gland to facilitate t he loss of plasma volume, actions which complement their hypotensive e ffects in the blood vessel. Interestingly, direct cardiac effects (pos itive inotropism and chronotropism) and CNS actions (sympathostimulati on) have been reported, leading to the hypothesis that these peptides also can exert important cardioprotective effects, helping to prevent vascular collapse during states of high AM secretion such as sepsis. ( C) 1998 Academic Press.