Fumiki Yoshihara

Relationship Between Left Ventricular Geometry and Natriuretic Peptide Levels in Essential Hypertension

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.

Inhibitory Regulation of Hypertrophy by Endogenous Atrial Natriuretic Peptide in Cultured Cardiac Myocytes

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(-5) mol/L)-stimulated protein syntheses in a concentration-dependent manner (1 to 300 microg/mL). A significant increase in the cell size of myocytes was also induced by this antagonist. In addition, the expression levels of skeletal alpha-actin, beta-myosin heavy chain, and ANP genes, markers of hypertrophy, were partially elevated by treatment with HS-142-1 (100 microg/mL) under nonstimulated or PE-stimulated conditions. A cGMP-specific phosphodiesterase inhibitor, zaprinast (5x10(-4) mol/L), and a cGMP analogue (10(-4) 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.

Coronary calcification in patients with chronic kidney disease and coronary artery disease.

BACKGROUND AND OBJECTIVES A close linkage between chronic kidney disease (CKD) and cardiovascular disease (CVD) has been demonstrated. Coronary artery calcification (CAC) is considered to be the causal link connecting them. The aim of the study is to determine the relationship between level of kidney function and the prevalence of CAC. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Autopsy subjects known to have coronary artery disease and a wide range of kidney function were studied. Patients without CKD were classified into five groups depending on estimated GFR (eGFR) and proteinuria: eGFR > or =60 ml/min/1.73 m(2) without proteinuria; CKD1/2: eGFR > or =60 ml/min/1.73 m(2) with proteinuria; CKD3: 60 ml/min/1.73 m(2) >eGFR > or =30 ml/min/1.73 m(2); CKD4/5: eGFR <30 ml/min/1.73 m(2); and CKD5D: on hemodialysis. Intimal and medial calcification of the coronary arteries was evaluated. Risk factors for CVD and uremia were identified as relevant to CAC using logistic regression analysis. RESULTS Intimal calcification of plaques was present in all groups, but was most frequent and severe in the CKD5D group and less so in the CKD4/5 and CKD3 groups. Risk factors included luminal stenosis, age, smoking, diabetes, calcium-phosphorus product, inflammation, and kidney function. Medial calcification was seen in a small number of CKD4/5 and CKD5D groups. Risk factors were use of calcium-containing phosphate binders, hemodialysis treatment, and duration. CONCLUSIONS It was concluded that CAC was present in the intimal plaque of both nonrenal and renal patients. Renal function and traditional risks were linked to initimal calcification. Medial calcification occurred only in CKD patients.

Ghrelin: a novel peptide for growth hormone release and feeding regulation.

Purpose of reviewA novel peptide hormone, ghrelin, has been identified from the stomach and recognized as an important regulator of growth hormone release and energy homeostasis. It is interesting to note that the stomach may play an important role in not only digestion but also pituitary growth hormone release and central feeding regulation. Thus, we summarize the recent findings on the mechanism of these effects induced by ghrelin. Recent findingsThe coadministration of ghrelin and growth hormone releasing hormone was found to have a synergistical effect on pituitary growth hormone secretion. The infusion of growth hormone releasing hormone in rats resulted in a significant increase in pituitary gene expression of ghrelin and its receptor system, suggesting that this system in the pituitary gland could modulate the regulation of growth hormone secretion by growth hormone releasing hormone. Ghrelin promoted the production of orexigenic neuropeptides (neuropeptide Y and agouti-related protein) in the hypothalamic arcuate nuclei and activated the neurons which produce these orexigenic neuropeptides, resulting in an increase in feeding and body weight. Gastric acid release and pancreatic protein secretions were also regulated by ghrelin through vagal and intrapancreatic neuronal activation, respectively. It is possible that ghrelin may participate in the regulation of cell proliferation, glucose homeostasis, and the immune system. SummaryGhrelin, secreted from the stomach, modulates growth hormone release and feeding promotion. Further elucidation of the mechanisms of ghrelin effects will help to improve the diagnosis and treatment of eating disorders and disturbed conditions of nutritional homeostasis.

Cardiac Production and Secretion of Adrenomedullin Are Increased in Heart Failure

Plasma adrenomedullin (AM) levels are reportedly increased in heart failure, but whether the cardiac production and secretion of AM is increased in heart failure remains unknown. To investigate the sites of production and secretion of AM in heart failure, we measured plasma AM levels and peptide and mRNA levels of AM in various tissues in rats with heart failure. We also examined whether the heart actually secretes AM into the circulation in patients with heart failure. We measured plasma and tissue AM levels by specific radioimmunoassay and AM mRNA by Northern blot analysis in rats with heart failure produced by aortocaval fistula. We also measured plasma AM levels in the coronary sinus and aorta in patients with left ventricular dysfunction before and after rapid right ventricular pacing. The increase in plasma AM levels in heart failure rats correlated with ventricular weight. Tissue AM levels were increased in the heart and lungs but not in the kidneys or adrenals of rats with heart failure. Similarly, tissue AM mRNA levels were also increased in the heart and lungs of heart failure rats. Plasma AM levels were higher in the coronary sinus than in the aorta in patients with left ventricular dysfunction. Rapid right ventricular pacing increased plasma atrial natriuretic peptide but not AM. These results suggest that plasma AM levels are increased in heart failure in proportion to the severity of heart failure and that cardiac production and secretion of AM is increased in heart failure rats. The lung may be another site for increased production of AM in heart failure rats. Human failing heart actually secretes AM into the circulation, and the regulation of AM secretion appears to differ from that of atrial natriuretic peptide.

Chronic kidney disease as an independent risk factor for new-onset atrial fibrillation in hypertensive patients.

Objective Chronic kidney disease (CKD) has recently been recognized to be a powerful predictor of cardiovascular morbidity and mortality. Atrial fibrillation (AF), which is a common arrhythmia in hypertensives, is associated with increased risks of cardiovascular events and death. However, the association between CKD and the onset of AF has not been fully elucidated. The present study assessed the hypothesis that CKD may influence the onset of AF in hypertensives. Methods A total of 1118 hypertensive patients (mean age, 63 years) without previous paroxysmal AF, heart failure, myocardial infarction, or valvular disease were enrolled. CKD was defined as decreased glomerular filtration rate (<60 ml/min per 1.73 m2) and/or the presence of proteinuria (≥1+). Results During follow-up periods (mean, 4.5 years), 57 cases of new-onset AF were found (1.1% per year). Kaplan–Meier curves revealed that the cumulative AF event-free rate was decreased in the CKD group (log-rank test P < 0.001). By univariate Cox regression analysis, age, smoking, left atrial dimension, left ventricular mass index, and the presence of CKD were significantly associated with the occurrence of AF. Among these possible predictors, CKD (hazard ratio 2.18, P = 0.009) was an independent determinant for the onset of AF in multivariate analysis. Advanced stages of CKD (stages 4 and 5) were strongly related to the increased occurrence of AF. Conclusion The present study demonstrated that the complication of CKD, especially progressed renal dysfunction, was a powerful predictor of new-onset AF in hypertensive patients, independently of left ventricular hypertrophy and left atrial dilatation.

Renoprotective Effect of Chronic Adrenomedullin Infusion in Dahl Salt-Sensitive Rats

The present study was designed to examine whether chronic adrenomedullin infusion has renoprotective effects in hypertensive renal failure and the mechanism by which chronic adrenomedullin infusion exerts its effects. Dahl salt-sensitive rats and Dahl salt-resistant rats were fed a high salt diet starting at 6 weeks of age. Recombinant human adrenomedullin or vehicle was infused for 7 weeks in 11-week-old Dahl salt-sensitive rats. Dahl salt-resistant rat was used as a control. After 7 weeks, untreated Dahl salt-sensitive rats were characterized by decreased kidney function, abnormal morphological findings, increased hormone levels, increased renal tissue angiotensin II levels, and altered mRNA expressions of transforming growth factor &bgr; (TGF-&bgr;) and components of the renin-angiotensin system compared with Dahl salt-resistant rats. Chronic adrenomedullin treatment significantly improved renal function (serum creatinine −87%, creatinine clearance +114%, urinary protein excretion −59%) and histological findings (glomerular injury score −54%) without changing mean arterial pressure compared with untreated Dahl salt-sensitive rats. Interestingly, long-term human adrenomedullin infusion decreased the endogenous rat adrenomedullin level (−97%) with a slight increase of human adrenomedullin level. Chronic adrenomedullin treatment also significantly inhibited the increase of plasma renin concentration (−269%), aldosterone level (−82%), and renal tissue angiotensin II levels (−60%). Furthermore, adrenomedullin infusion significantly decreased the increases of mRNA expressions of TGF-&bgr; (− 63%), angiotensin-converting enzyme (−137%), renin (−230%), and angiotensinogen (−38%) in renal cortex. These results suggest that increased endogenous adrenomedullin plays a compensatory role in chronic hypertensive renal failure and that long-term adrenomedullin infusion has renoprotective effects in this type of hypertension model, partly via inhibition of the circulating and renal renin-angiotensin system.

Effects of adrenomedullin on cultured rat cardiac myocytes and fibroblasts

The direct effects of adrenomedullin, a novel vasorelaxant peptide, on protein synthesis and atrial natriuretic peptide release in myocytes and on DNA and collagen syntheses in fibroblasts were examined using cultured ventricular cardiocytes. The protein synthesis of cardiac myocytes was not affected by adrenomedullin under non-stimulated conditions. Endothelin-1-induced protein synthesis in myocytes was slightly but significantly elevated by adrenomedullin. Likewise, the secretion of atrial natriuretic peptide from myocytes stimulated by endothelin-1 was increased by adrenomedullin. In cardiac fibroblasts, adrenomedullin clearly inhibited DNA synthesis and collagen production in a dose-dependent manner under both basal and angiotensin II-stimulated conditions. DNA and collagen syntheses by cardiac fibroblasts were suppressed by both 8-bromo cAMP and forskolin. Furthermore, a cAMP-specific phosphodiesterase inhibitor decreased DNA and collagen syntheses in fibroblasts and enhanced the inhibitory effects of adrenomedullin on these syntheses. Our observations suggest that adrenomedullin has opposite effects on cultured cardiac myocytes and fibroblasts and that the effects of adrenomedullin at least on fibroblasts are probably mediated through a cAMP-dependent pathway. As adrenomedullin is produced and secreted from both types of cardiac cells, adrenomedullin may play a role as an autocrine/paracrine modulator in the process of cardiac remodeling, mainly by suppressing mitogenesis and collagen synthesis in fibroblasts.

Effect of adrenomedullin on cAMP and cGMP levels in rat cardiac myocytes and nonmyocytes.

The purpose of the present study was to determine if cardiac myocytes and nonmyocytes secrete adrenomedullin, to investigate the effects of adrenomedullin on cAMP and cGMP levels in cardiac myocytes and nonmyocytes, to study the effect of calcitonin gene-related peptide (CGRP) receptor antagonist CGRP-(8-37) and adrenomedullin-specific receptor antagonist, adrenomedullin-(22-52) on response to adrenomedullin and CGRP. Neonatal (days 1-2) cardiac myocytes and nonmyocytes were prepared from the ventricle of Wistar rats. Not only cardiac myocytes, but also nonmyocytes secrete almost equal amounts of adrenomedullin into the media. Both adrenomedullin and CGRP increased the cAMP levels, not the cGMP levels, both in the myocytes and nonmyocytes. In myocytes, CGRP-(8-37), almost completely inhibited the adrenomedullin- and CGRP-induced cAMP formation. In nonmyocytes, CGRP-(8-37) completely inhibited the cAMP levels induced by adrenomedullin and CGRP. More profound antagonistic effect of CGRP-(8-37) on cAMP levels induced by adrenomedullin was observed in nonmyocytes than in myocytes. In contrast, antagonistic effect of adrenomedullin-(22-52) for adrenomedullin-stimulated cAMP formation was considerably less potent than CGRP-(8-37) both in myocytes and nonmyocytes. Adrenomedullin-(22-52) did not affect the cAMP formation induced by CGRP either in myocytes or nonmyocytes. These results suggest that myocytes and nonmyocytes secrete adrenomedullin and that adrenomedullin increases cAMP levels possibly via different receptors in myocytes and nonmyocytes.

Cardiovascular and renal effects of adrenomedullin in rats with heart failure

Plasma adrenomedullin (AM), a novel hypotensive peptide, has been shown to increase in heart failure (HF). This study sought to examine the cardiovascular and renal effects of intravenous infusion of AM in HF rats and sham-operated rats (control) using two doses of AM that would not induce hypotension. Rat AM-(1-50) was intravenously administered at rates of 0.01 (low) and 0.05 (high) μg ⋅ kg body wt-1 ⋅ min-1. Low-dose AM increased urine flow (+21% in HF, +29% in control) and urinary sodium excretion (+109% in HF, +123% in control) without changes in any hemodynamic variables. In contrast, high-dose AM slightly decreased mean arterial pressure (-3% in HF, -5% in control) and significantly increased cardiac output (+20% in HF, +12% in control). Infusion of high-dose AM resulted in significant decreases in right ventricular systolic pressure (-11%) and right atrial pressure (-28%) only in HF rats. High-dose AM significantly increased glomerular filtration rate (+10% in HF, +16% in control) and effective renal plasma flow (+25% in HF, +46% in control) as well as urine flow and urinary sodium excretion. In summary, intravenous infusion of AM exerted diuresis and natriuresis without inducing hypotension and, in the higher dose, produced beneficial hemodynamic and renal vasodilator effects in rats with compensated HF.Plasma adrenomedullin (AM), a novel hypotensive peptide, has been shown to increase in heart failure (HF). This study sought to examine the cardiovascular and renal effects of intravenous infusion of AM in HF rats and sham-operated rats (control) using two doses of AM that would not induce hypotension. Rat AM-(1-50) was intravenously administered at rates of 0.01 (low) and 0.05 (high) microg. kg body wt-1. min-1. Low-dose AM increased urine flow (+21% in HF, +29% in control) and urinary sodium excretion (+109% in HF, +123% in control) without changes in any hemodynamic variables. In contrast, high-dose AM slightly decreased mean arterial pressure (-3% in HF, -5% in control) and significantly increased cardiac output (+20% in HF, +12% in control). Infusion of high-dose AM resulted in significant decreases in right ventricular systolic pressure (-11%) and right atrial pressure (-28%) only in HF rats. High-dose AM significantly increased glomerular filtration rate (+10% in HF, +16% in control) and effective renal plasma flow (+25% in HF, +46% in control) as well as urine flow and urinary sodium excretion. In summary, intravenous infusion of AM exerted diuresis and natriuresis without inducing hypotension and, in the higher dose, produced beneficial hemodynamic and renal vasodilator effects in rats with compensated HF.