Chapter 2 - Adrenomedullin

Abstract

Adrenomedullin (AM) is a potent long-acting vasodilatory peptide originally discovered in the acid extract of human pheochromocytoma tissue. Adrenomedullin and its mRNA are widely distributed in the cardiovascular system, including the ventricles, atria, blood vessels, lungs, and kidneys. The components of the AM receptor, which include calcitonin receptor-like receptor (CLR) and receptor activity modifying protein (RAMP) 2 and RAMP3, colocalize with AM in the cardiovascular system, suggesting AM serves as an important regulator of cardiovascular function. Adrenomedullin gene expression and/or immunoreactivity are increased in the ventricles of hypertrophied and failing hearts and after myocardial infarction, as are the mRNA levels of CLR, RAMP2, and RAMP3. In vitro, cardiomyocytes and cardiofibroblasts produce and secrete two molecular forms of AM, AM-mature and AM-glycine, and express CLR, RAMP2, and RAMP3. Within the heart, AM has inhibitory effects on collagen synthesis and fibroblast proliferation. In addition, AM inhibits cardiac hypertrophy and exhibits antiapoptotic, angiogenic, antiinflammatory, and antioxidant effects. Adrenomedullin also exerts inotropic effects in vitro and in vivo. Cellular signaling by AM is mediated via cyclic AMP/protein kinase A, nitric oxide/cyclic GMP, phosphoinositide 3-kinase/Akt, and/or the extracellular-signaling-regulated kinase pathway. It thus appears that AM may exert antifibrotic, antihypertrophic, and positive inotropic effects in heart failure, myocardial infarction and myocardial ischemia/reperfusion. Several pilot studies have now demonstrated the beneficial effects of AM in patients with heart failure, acute myocardial infarction, and pulmonary hypertension. Clinical trials also showed the diverse biological effects of AM.