Background-Ghrelin is a novel growth hormone (GH)-releasing peptide that may also induce vasodilation and stimulate feeding through GH-independent mechanisms. We investigated whether ghrelin improves left ventricular (LV) dysfunction and attenuates cardiac cachexia in rats with chronic heart failure (CHF). Methods and Results-Ligation of the left coronary artery or sham operation was performed; 4 weeks after surgery, rat ghrelin (100 g/kg SC BID) or saline was administered for 3 weeks. Echocardiography and cardiac catheterization were performed. Serum GH and insulin-like growth factor-1 were significantly higher in both CHF and sham rats treated with ghrelin than in those given placebo (PϽ0.05 for both). CHF rats given placebo showed an impaired increase in body weight compared with sham rats given placebo (PϽ0.05). CHF rats treated with ghrelin, however, showed a significantly greater increase in body weight than those given placebo (ϩ10% versus ϩ3%, PϽ0.05). They showed significantly higher cardiac output (315Ϯ49 versus 266Ϯ31 mL · min Ϫ1 · kg Ϫ1 , PϽ0.05) and LV dP/dt max (5738Ϯ908 versus 4363Ϯ973 mm Hg/s, PϽ0.05) than CHF rats given placebo. Ghrelin increased diastolic thickness of the noninfarcted posterior wall, inhibited LV enlargement, and increased LV fractional shortening in CHF rats (from 15Ϯ3% to 19Ϯ3%, PϽ0.05). Conclusions-Chronic subcutaneous administration of ghrelin improved LV dysfunction and attenuated the development of LV remodeling and cardiac cachexia in rats with CHF.

Previous studies have shown that plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are increased in essential hypertension. However, whether left ventricular geometry affects plasma ANP and BNP levels remains unknown. To investigate the effect of left ventricular geometry on plasma ANP and BNP levels in essential hypertension, we measured plasma ANP and BNP levels in 90 patients with essential hypertension. All patients were hospitalized, and fasting blood samples were obtained in the early morning after 30 minutes of bed rest. Plasma ANP and BNP levels were measured by immunoradiometric assay. Hypertensive patients were classified into four groups according to echocardiographic findings that showed normal geometry, concentric remodeling, eccentric hypertrophy, or concentric hypertrophy. Mean plasma ANP and BNP levels in all essential hypertensive patients were higher than those in age-matched normotensive control subjects. Plasma ANP levels in hypertensive patients with concentric remodeling, eccentric hypertrophy, and concentric hypertrophy were higher than in normotensive control subjects, although there were no differences between normotensive subjects and hypertensive patients with normal geometry. Plasma BNP levels tended to be higher in hypertensive patients with normal geometry, concentric remodeling, and eccentric hypertrophy than in normotensive control subjects; however, the differences were not significant. Plasma BNP levels and BNP/ANP ratio were specifically higher in concentric hypertrophy. There were significant correlations between ANP and left ventricular mass index, relative wall thickness, interventricular septal thickness, posterior wall thickness, and mean arterial pressure. Plasma BNP levels significantly correlated with relative wall thickness, interventricular septal thickness, posterior wall thickness, and left ventricular mass index but not with mean arterial pressure. In addition, plasma BNP levels were well correlated with ANP levels, and the slope for the linear regression model was steeper in concentric hypertrophy than in the other four groups. These results show that plasma ANP and BNP levels are increased in essential hypertensive patients with left ventricular hypertrophy. Furthermore, BNP secretion is augmented to a greater extent in concentric hypertrophy. Thus, measurement of plasma ANP and BNP levels may be useful for the detection of concentric left ventricular hypertrophy in patients with essential hypertension.

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Abstract-Atrial natriuretic peptide (ANP) may function as an endogenous regulator of cardiac hypertrophy, because the natriuretic peptide receptor has been found in the heart and because mice lacking its receptor have been shown to have a markedly elevated ventricular mass. We examined the role of endogenous ANP in cardiac hypertrophy in vitro. The effects of the blockade of endogenous ANP by its receptor antagonist, HS-142-1, on cell hypertrophy were investigated with the use of cultured neonatal rat ventricular myocytes. HS-142-1 increased the basal and phenylephrine (PE, 10 Ϫ5 mol/L)-stimulated protein syntheses in a concentration-dependent manner (1 to 300 g/mL). A significant increase in the cell size of myocytes was also induced by this antagonist. In addition, the expression levels of skeletal ␣-actin, ␤-myosin heavy chain, and ANP genes, markers of hypertrophy, were partially elevated by treatment with HS-142-1 (100 g/mL) under nonstimulated or PE-stimulated conditions. A cGMP-specific phosphodiesterase inhibitor, zaprinast (5ϫ10 Ϫ4 mol/L), and a cGMP analogue (10 Ϫ4 mol/L) suppressed the basal and PE-stimulated protein syntheses. Our observations suggest that endogenous ANP inhibits cardiac myocyte hypertrophy under basal and PE-stimulated conditions, probably through a cGMP-dependent process. ANP may play a role as an autocrine factor in the regulation of cardiac myocyte growth. Key Words: hypertrophy Ⅲ atrial natriuretic peptide Ⅲ autocrine-paracrine Ⅲ myocytes A trial natriuretic peptide (ANP) is a cardiac hormone that has an important role in the regulation of body fluid homeostasis and systemic blood pressure. 1,2 Once in the circulation, ANP binds to its specific receptor, mainly in the vascular tissue, kidney, and adrenal gland, and increases cellular cGMP levels. 3 The cGMP production induces vasodilatation, natriuresis, and diuresis.Subsequent studies have revealed the existence of natriuretic peptide receptors in cardiac cells. 4,5 Therefore, apart from acting as a circulating hormone, ANP may have some function as an autocrine and/or paracrine factor. However, the local actions of ANP on the heart itself have not been fully elucidated. Oliver et al 6 recently demonstrated with the use of knockout mouse models that the complete absence of one subtype of natriuretic peptide receptors causes marked cardiac hypertrophy, suggesting the possibility that endogenous ANP suppressively regulates the development of cardiac myocyte hypertrophy. With regard to the direct effect of ANP on cardiac hypertrophy, only one study 7 reported that exogenous ANP inhibits cardiac myocyte hypertrophy in the limited conditions. Therefore, we conducted the present study to examine the direct effect of endogenous ANP on cell hypertrophy in cultured ventricular myocytes of neonatal rats. We used a specific antagonist for natriuretic peptide receptors, HS-142-1, which competitively and selectively inhibits ANP binding to its biological (guanylyl cyclase [GC]-containing) receptor. 8 Several studies have used this antagonis...