There have been few reports which investigated the effect of chronic administration of AM in cardiovascular disease. Khan et al. (Khan et al., 1997a) reported that chronically infused human AM (200 ng/h, for 2 weeks) had a hypotensive effect in both normotensive rats and spontaneously hypertensive rats without an increase in urinary volume or sodium excretion at a plasma AM concentration within the physiological limit. The same investigators also demonstrated that chronically infused AM (1000 ng/h, for 2 weeks) had a hypotensive effect accompanied by significant reductions of plasma renin activity and plasma aldosterone concentration in renovascular hypertensive rats at a plasma AM concentration within the physiological rang (Khan et al., 1997b). These results imply that chronic AM infusion may have beneficial effects in hypertension and its organ damage in part via inhibition of the renin-angiotensin system. We reported that chronic human AM infusion (500 ng/h) has renoprotective effects in a rat model of malignant hypertension (Nishikimi et al., 2002; Mori et al., 2002). AM infusion significantly reduced plasma renin concentration, plasma aldosterone levels and plasma endogenous rat AM levels within the physiological range of human plasma AM levels. AM decreased urinary protein excretion and improved glomerular sclerosis, according to the histological findings. AM significantly decreased the intrarenal angiotensin II levels and gene expression of TGF-beta and angiotensin converting enzyme. These results suggest that increased endogenous AM plays a compensatory role in chronic hypertensive renal failure and that long-term AM infusion has renoprotective effects in this type of hypertension model, partly via inhibition of the circulating and renal renin-angiotensin system.
(2) Heart Failure
Plasma AM levels are increased in heart failure, and acute administration of AM exerts beneficial hemodynamic, renal, and neurohormonal effects in heart failure. However, the chronic effects of AM administration on heart failure remain unknown. Rademaker et al. (Rademaker et al., 2002b) infused AM (10 ng/kg per minute) for 4
days in sheep with pacing-induced heart failure. Infusion of AM persistently increased circulating levels of the AM, in association with prompt (15 minutes) and sustained (4 days) increases in cardiac output (day 4, 27%), and reductions in peripheral resistance (30%), mean arterial pressure (13%), and left atrial pressure (24%). AM also significantly enhanced urinary sodium excretion (day 4, 3-fold), creatinine excretion (1.2-fold), and creatinine clearance (1.4-fold) over the 4 days of treatment, whereas urine volume and cAMP excretion tended to be elevated. These findings support the concept of AM as a protective hormone during hemodynamic compromise with therapeutic potential in heart failure.
We examined the effect of chronic infusion of AM (500 ng/min, for 7 weeks) on the progression of heart failure in Dahl salt-sensitive rats (Nishikimi et al., 2003). Chronic AM infusion significantly decreased left ventricular end-diastolic pressure, right ventricular systolic pressure, right atrial pressure, and left ventricular weight/body weight. AM significantly attenuated the increase in circulating renin-aldosterone, endogenous rat AM, and atrial natriuretic peptide levels. AM also decreased the myocardial tissue levels of angiotensin II and atrial and brain natriuretic peptide. These changes were associated with the improvement of cardiac output and systemic vascular resistance. Furthermore, AM improved left ventricular end-systolic elastance. These improvements were greater in the AM than in the diuretic group, although both drugs similarly decreased systolic blood pressure and increased urinary sodium excretion. Kaplan-Meier survival analysis showed that AM significantly prolonged survival time compared with those of the diuretic and vehicle treatment groups. These results suggest that endogenous AM plays a compensatory role in heart failure and that chronic AM infusion attenuates progression of left ventricular dysfunction and improves survival, at least in part, through inhibition of circulating and myocardial neurohormonal activation.
Nakamura et al. (Nakamura et al., 2002) examined the effects of long-term administration of AM on left ventricular remodeling following acute myocardial infarction. They infused human recombinant AM for 4 weeks in rats with myocardial infarction induced by left coronary artery ligation. Chronic infusion of AM reduced the heart weight/body weight, left ventricular end-diastolic pressure, plasma endogenous rat AM levels, myocyte size, and collagen volume fraction of non-infarct LV area without affecting the infarct size, indicating that continuous administration of AM could be a useful therapeutic tool for acute MI.
Okumura et al. (Okumura et al., 2004) recently examined the effect of infusion of AM on myocardial ischemia/reperfusion following acute myocardial infarction. They showed that infusion of AM significantly reduced myocardial infarct size, left ventricular end-diastolic pressure, and myocardial apoptotic death with concomitant Akt phosphorylation. However, pretreatment with wortmannin (a phosphatidylinositol 3-kinase [PI3K] inhibitor) abolished the beneficial effect of AM. Infusion of AM significantly attenuated the myocardial ischemia/reperfusion injury. They concluded that cardioprotective effects of AM on ischemia/reperfusion injury might be mainly due to antiapoptotic effects of AM via a PI3K/Akt-dependent pathway. Thus, AM may have an anti-remodeling effect in acute myocardial infarction.
(4) Pulmonary Hypertension
AM has antiproliferative effects in vascular smooth muscle cells and cardiac fibroblasts and AM also inhibits vascular smooth muscle cell migration and hypertrophy in cultured neonatal cardiac myocytes. Yoshihara et al. (Yoshihara et al., 1998) reported the beneficial effect of long-term AM infusion in pulmonary hypertension and right ventricular hypertrophy induced by the administration of monocrotaline. Chronic infusion of AM significantly lessened the increase in right ventricular systolic pressure and the ratio of right ventricular weight. AM also attenuated the medial thickening of the pulmonary artery. These results suggest that chronic infusion of AM attenuates the pulmonary hypertension and right ventricular hypertrophy in rats treated with monocrotaline at least in part via an inhibitory effect on pulmonary arterial remodeling. These findings are consistent with recent studies which showed that chronic inhalation of AM inhibited the development of pulmonary hypertension (Nagaya et al, 2003).
These findings support the concept of AM as a protective peptide in cardiovascular disease and suggest that AM administration may be a new therapeutic approach.
Was this article helpful?
Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...