Ventricular Adrenomedullin System in the Transition From LVH to Heart Failure in Rats

Abstract

Abstract-We investigated whether adrenomedullin (AM) participates in the pathophysiology during the transition from left ventricular hypertrophy (LVH) to heart failure (HF). We used the Dahl salt-sensitive (DS) rat model, in which systemic hypertension causes LVH at the age of 11 weeks, followed by HF at the age of 18 weeks. Two molecular forms of AM levels in the plasma and myocardium at the LVH stage were significantly elevated compared with those in controls, and they were further increased at the HF stage. Interestingly, the LV tissue AM-mature/AM-total ratio was higher only in the HF group than in controls and LVH. The LV tissue AM-mature/AM-total ratio, AM-mature, and AM-total concentrations had close relations with the LV weight/body weight (rϭ0. 72, rϭ0.79, and rϭ0.70, respectively; all PϽ0.001). AM gene expression was significantly increased at the LVH stage and was further increased at the HF stage. Furthermore, gene expression of AM receptor system components such as calcitonin receptor-like receptor (CRLR), receptor activity-modified protein 2 (RAMP2), and RAMP3 were significantly increased at the stage of LVH and HF. Regarding other neurohumoral factors, plasma renin and aldosterone levels were not increased at the LVH stage but were increased at the HF stage, whereas atrial natriuretic peptide was increased in both the plasma and myocardium at the LVH stage and was further increased at the HF stage. These results suggest that induction of the cardiac AM system, including the ligand, receptor, and amidating activity, may modulate pathophysiology during the transition from LVH to HF in this model. Key Words: adrenomedullin Ⅲ hypertension, sodium dependent Ⅲ hypertrophy, left ventricular Ⅲ heart failure Ⅲ rats, Dahl M any neurohumoral factors are involved in the pathophysiology of heart failure (HF). 1 Therefore, it is very important to investigate the pathophysiological roles of newly identified neurohumoral factors in HF because these studies may lead to the development of a new drug. 1 In fact, angiotensin-converting enzyme inhibitors, ␤-blockers, and angiotensin receptor blockers, which were produced in this field of research, are now used in many patients with HF and contribute to the improvement in prognosis and quality of life in this syndrome. Recent studies indicate that most patients with HF have a history of hypertension and/or left ventricular hypertrophy (LVH). 2,3 Furthermore, it has been suggested that treating high blood pressure actually prevents HF. 4 These results suggest that hypertension and LVH are the most common risk factors for HF, and they contribute a large proportion of the HF cases. 5 Therefore, it seems important to assess the derangement of neurohumoral factors during the transition from LVH to HF.Adrenomedullin (AM) is a 52-amino acid novel vasodilatory peptide that was originally discovered in human pheochromocytoma tissue. 6 AM is widely distributed in various tissues and organs, including the heart. 7 The plasma levels of AM are elevated in various pathophysiologica...

Adrenomedullin Protects Against Myocardial Apoptosis After Ischemia/Reperfusion Through Activation of Akt-GSK Signaling

“…3,[27][28][29] The mechanism by which AM exerts its effects on cardiomyocytes is not fully understood. A previous report showed that AM signaling depends on the combination of CRLR (calcitonin receptor-like receptor) and RAMP2 (receptor activity- modifying proteins), resulting in activation of the AM receptor.…”

Long-Term Administration of Rho-Kinase Inhibitor Ameliorates Renal Damage in Malignant Hypertensive Rats

“…15,16 After 3 weeks of administration of fasudil, hemodynamic studies (direct measurement of BP and heart rate) were performed with the animals under anesthesia, as reported previously. 17 Blood was obtained from the carotid artery, and the plasma was stored at Ϫ80°C until assay.…”

Response of adrenomedullin system to cytokine in cardiac fibroblasts?role of adrenomedullin as an antifibrotic factor

“…After cooling, the boiled medium was evaporated in a vacuum until dry. Immunoradiometric assay for rat AM-m and AM-total (AM-m+AM-Gly) was performed using a recently developed specific immunoradiometric assay kit (AM RIA SHIONOGI) with some modifications, as previously reported [21,25]. AM-Gly was calculated as following formula: (AM-Gly)=(AMtotal)À(AM-m).…”

“…Second, recent studies have revealed that two molecular forms of AM, an active mature form of AM (AM-m), and an intermediate inactive form of glycine-extended AM (AM-Gly), circulate in human plasma, AM-Gly being the dominant circulating form [19,20]. In addition, we have very recently shown that the major molecular form of AM in cardiac tissues is AM-m and that this form of AM is increased in left ventricular hypertrophy (LVH) and heart failure [21]. However, which molecular form of AM is predominantly secreted by cultured cardiac fibroblasts remains unknown.…”