Regulation of adrenomedullin gene expression in the rat heart

Adrenomedullin (AM), a novel vasorelaxant 52 amino acid peptide, was found from human pheochromocytoma in 1993. AM gene is expressed in various tissues, including heart. Although hemodynamic overload and rapid ventricular pacing are known to alter the expression of the AM gene, it has not yet been established whether wall stretch acts directly or via local paracrine and autocrine factors liberated in response to hemodynamic load. The aim of the present study was to examine AM gene expression in response to acute and chronic mechanical stress in the hearts of normal and hypertensive rats in vivo. The second purpose was to study the mechanism(s) involved in the induction of the AM gene expression. The acute increased workload of the heart was produced by the infusion of vasopressin (AVP), and the involvement of angiotensin II (Ang II) and endothelin-1 (ET-1) in the early activation of AM gene expression was studied. The acute increase in left ventricular AM gene expression occured within 2 h, whereas in the left atrium the induction of AM gene expression was observed earlier, at 30 min. The induction of left atrial and ventricular AM gene expression was shown to be Ang IIand ET-1-independent by using Ang II receptor type 1 (AT1) antagonist (losartan) and mixed ET-1 receptor types A and B antagonist (bosentan), respectively. AT1 receptor antagonism and angiotensin converting enzyme (ACE) inhibition for 10 weeks were used to evaluate the chronic regulation of AM gene expression in normotensive and hypertensive rats. The decreases in systolic blood pressure and cardiac hypertrophy induced by losartan and enalapril treatments had no effect on ventricular AM gene expression. The expression of AM, ANP and BNP was differently regulated both in the left ventricle and atria in response to AT1 receptor antagonism and ACE inhibition. Moreover, C-type natriuretic peptide (CNP), a selective agonist of natriuretic peptide receptor type B (NPRB), was infused for 2 weeks in normotensive rats to examine the effects of CNP on cardiac AM gene expression. CNP infusion increased left ventricular and plasma ir-CNP levels, and those increases were associated with significant decreases in AM and BNP mRNA levels. In conclusion, AM was shown to react rapidly against increased cardiac workload, and cardiac wall stretch seemed to be a major stimulus for the early induction of AM gene expression in the left ventricle and atrium, mimicking the rapid induction of proto-oncogenes in response to hemodynamic stress. The acute induction of left atrial and ventricular AM gene expression was shown to be Ang IIand ET-1-independent. During chronic cardiac overload, AM synthesis was an insensitive marker of chronic changes in hemodynamic load or myocyte hypertrophy. CNP was shown to have a paracrine role in the regulation of left ventricular AM gene expression. The cardiac secretion of AM was small, at least in the acute phase of cardiac pressure load, suggesting a paracrine and/or autocrine role for AM in the regulation of cardiac function.