The Role of Adrenomedullin in Cardiovascular and Renal Function.

Adrenomedullin is a potent vasodilating peptide that is expressed in tissues relevant to cardiovascular and renal function, such as the heart, kidney, aorta, lung and brain. Adrenomedullin participates in blood pressure homeostasis, and cardiovascular and renal function, as demonstrated in adrenomedullin transgenic mice and knockout mice. Using gene transfer approaches, we have shown that a single injection of adenovirus carrying the adrenomedullin gene results in a prolonged reduction of blood pressure for several weeks, and improved cardiac and renal function in pressure- or salt-induced hypertensive rat models and streptozotocin-induced diabetic rats. Adrenomedullin gene transfer also protects against cardiac and renal damages including: 1) myocardial infarction, ventricular arrhythmias and apoptosis in ischemic myocardium; 2) cardiac hypertrophy and fibrosis; 3) glomerulosclerosis, tubular disruption, protein cast accumulation in lumen, renal cell proliferation and fibrosis in the kidney; 4) neointimal hyperplasia in blood vessels induced by balloon angioplasty; 5) streptozotocin-diabetic­induced cardiac and renal glycogen accumulation, and body weight loss; and 6) cerebral ischemia-induced infarction and locomotor deficits. Adrenomedullin gene delivery results in increased cAMP, nitric oxide and cGMP levels in conjunction with significantly reduced superoxide production in the heart, kidney and brain. These results indicate that adrenomedullin plays important roles in cardiovascular and renal diseases via suppression of oxidative stress production through activation of second messengers cAMP and nitric oxide­cGMP-dependent signaling pathways. These findings provide important insights into the action of adrenomedullin as an antioxidant in protecting cardiovascular and renal dysfunction induced by hypertension, salt loading, vascular injury, diabetes and ischemia-reperfusion injury. (c) 2002 Prous Science. All rights reserved.