Hisayuki Matsuo

Inhibition of aldosterone production by α-human atrial natriuretic polypeptide is associated with an increase in cGMP production

Synthetic alpha-human atrial natriuretic polypeptide caused rapid and marked inhibition of aldosterone production in dispersed rat adrenal capsular cells. The polypeptide also slightly, but significantly, decreased cAMP production in the adrenal dispersed capsular cells, while markedly stimulating cGMP production. The cGMP production was accelerated at the concentration of alpha-human atrial natriuretic polypeptide lower than the threshold level to stimulate aldosterone production. These findings suggest that alpha-human atrial natriuretic polypeptide possibly plays a regulatory role in aldosterone production and an additional role in natriuresis through inhibition of aldosterone production. The stimulation of cGMP production by alpha-human atrial natriuretic polypeptide may be involved in the inhibitory effect of this peptide on aldosterone production.

Negative Inotropic Effect of Adrenomedullin in Isolated Adult Rabbit Cardiac Ventricular Myocytes

BACKGROUND Adrenomedullin (AM) is a potent vasodilator peptide. AM-induced vasodilatation is mediated by an increase of NO as well as cAMP. Both AM and binding sites for this peptide have been found in cardiac tissue, indicating the possible existence of an autocrine or paracrine system of AM in the heart. METHODS AND RESULTS Myocytes were isolated by use of retrograde coronary perfusion with physiological solution containing collagenase and hyaluronidase from adult rabbit ventricles. Contraction of cardiac myocytes was traced with a video motion detector, and [Ca2+]i was measured with indo 1 at 37 degrees C. The Ica was measured with a whole-cell patch clamp at 23 degrees C. AM and calcitonin gene-related peptide (CGRP), another member of the same peptide family, showed a concentration-dependent negative inotropic effect (10(-7) mol/L AM: contraction amplitude, 64 +/- 7% of control; [Ca2+]i, 52 +/- 5% of control; n = 10; 10(-6) mol/L CGRP: contraction amplitude, 64 +/- 25%; [Ca2+]i, 70 +/- 3%; n = 5; mean +/- SD). Ica was decreased to 60 +/- 39% by superfusion with AM after the cessation of NG-monomethyl-L-arginine (L-NMMA), an NO synthase inhibitor. Pretreatment with L-NMMA (10 mumol/L) abolished the negative inotropic effect of AM, whereas switching from AM+L-NMMA to AM+L-arginine (1 mmol/L) restored it. Superfusion with 8-bromo-cGMP also showed a negative inotropic effect. AM significantly increased the intracellular content of cGMP, a second messenger of NO, but not that of cAMP. AM (10 nmol/L) blunted the effect of 1 mumol/L forskolin. CONCLUSIONS AM has a negative inotropic effect and decreased both [Ca2+]i and Ica, with these effects being at least party mediated via the L-arginine-NO pathway in adult rabbit ventricular myocytes.

Plasma concentrations of α-human atrial natriuretic polypeptide and cyclic GMP in patients with heart disease☆

Plasma concentrations of immunoreactive α-human atrial natriuretic polypeptide (iα-hANP) and cyclic guanosine monophosphate (cGMP) were measured in 70 patients with heart disease. Plasma concentrations of iα-hANP were directly related to the severity of heart disease (F = 29.61, p < 0.001). Plasma concentrations of iα-hANP were well correlated with pulmonary capillary wedge pressure (PCWP; r = 0.64, p < 0.001), mean pulmonary arterial pressure (PAP; r = 0.62, p < 0.001), and mean right atrial pressure (RAP; r = 0.75, p < 0.001). Plasma concentrations of cGMP were also directly related to the severity of heart disease (F = 13.61, p < 0.001) and highly correlated with plasma concentrations of iα-hANP (r = 0.73, p < 0.001). Plasma concentrations of cGMP were also closely correlated with PCWP (r = 0.69, p < 0.001), mean PAP (r = 0.61, p < 0.001), and mean RAP (r = 0.60, p < 0.001). The iα-hANP concentrations of plasma samples obtained from the coronary sinus were approximately fourfold higher than those of samples obtained from the pulmonary artery, whereas cGMP concentrations were comparable in plasma samples obtained from either site. Elevation of cGMP concentrations following intravenous infusion of synthetic α-hANP was comparable in plasma samples obtained from the coronary sinus and the pulmonary artery. These findings suggest that elevated plasma concentrations of iα-hANP in cardiac patients result from an increase in the secretion of ANPs, which is probably accelerated by elevation of right or left atrial pressure, and that plasma concentrations of cGMP reflect circulating levels of α-hANP.

Plasma adrenomedullin as an indicator of prognosis after acute myocardial infarction

OBJECTIVE To elucidate whether prognosis after acute myocardial infarction can be predicted by measuring plasma adrenomedullin, a novel vasorelaxant peptide. PATIENTS AND DESIGN Plasma adrenomedullin concentrations on day 2 after myocardial infarction were measured in 113 patients with myocardial infarction with other clinical and haemodynamic variables related to mortality. RESULTS During a mean follow up period of 25 months, 16 patients died of cardiac causes. Plasma adrenomedullin concentrations on day 2 increased significantly in patients with myocardial infarction compared with controls (mean (SD), 12.3 (8.8) v 4.9 (1.0) pmol/l, p < 0.001). Plasma adrenomedullin correlated negatively with left ventricular ejection fraction on admission (r = −0.47, p < 0.001), although it did not significantly correlate with any other haemodynamic variable. By univariate Cox proportional hazards analysis, plasma adrenomedullin, age, coronary reperfusion, maximum creatine kinase concentrations, pulmonary congestion, pulmonary capillary wedge pressure, cardiac index, and left ventricular ejection fraction were all significantly related to mortality. Among the non-invasive variables, only plasma adrenomedullin was an independent predictor of mortality after myocardial infarction (p < 0.05). The Kaplan–Meier survival curves based on the median plasma adrenomedullin concentration (10.3 pmol/l) showed that patients with high plasma adrenomedullin had a higher mortality than those with low plasma adrenomedullin (p < 0.01). CONCLUSIONS Plasma adrenomedullin on day 2 after myocardial infarction is strongly associated with long term mortality, and thus may complement standard prognostic indicators.

Ventricular Adrenomedullin Levels Correlate With the Extent of Cardiac Hypertrophy in Rats

We investigated the pathophysiological significance of adrenomedullin (AM) in the development of left ventricular hypertrophy (LVH). LVH was produced by aortic banding (AB) in rats. The left ventricular weight/body weight (LV/BW) ratio, ventricular AM peptide and mRNA levels, and hemodynamics were measured at 1, 3, 7, and 21 days after the operation. Both LV/BW ratio and ventricular AM levels showed a significant increase from 1 day after the operation in the AB rats versus the sham-operated rats. Both increased in a time-dependent manner. The ventricular AM levels correlated with the LV/BW ratio (r=0.76, P<0.01). The AM mRNA levels were highly expressed at 1 day after the operation in the AB rats but showed no difference from 3 to 21 days after the operation between the AB and sham groups. The plasma AM levels showed a peak at 1 day after the operation in both groups. Then, we treated AB rats with an angiotensin-converting enzyme inhibitor (quinapril) in 2 doses (1 and 10 mg. kg-1. d-1) for 21 days. The quinapril treatment attenuated similarly both the LV/BW ratio and the ventricular AM levels. We also assessed the effects of AM and hydralazine administration for 7 days on the LV/BW ratio and hemodynamics of AB rats. Both AM and hydralazine administration reduced the blood pressure by approximately 10% compared with the nontreated AB rats, but a reduction of the LV/BW ratio was observed only in the AM-treated group (P<0.05). These results suggest that ventricular AM levels are elevated by chronic pressure overload in a time-dependent manner concomitant with the extent of LVH and that AM may play a pathophysiological role in the development of LVH in chronic pressure overload.

DIFFERENT SECRETION PATTERNS OF ADRENOMEDULLIN, BRAIN NATRIURETIC PEPTIDE, AND ATRIAL NATRIURETIC PEPTIDE DURING EXERCISE IN HYPERTENSIVE AND NORMOTENSIVE SUBJECTS

The purpose of this study was to investigate the effect of exercise on plasma concentrations of adrenomedullin, brain natriuretic peptide (BNP), and atrial natriuretic peptide (ANP) in patients with essential hypertension (n = 15) and in normotensive controls (n = 10). Exercise consisted of two fixed workloads, 40 and 80 watts of work load using a supine bicycle ergometer. Plasma levels of all three peptides at rest were significantly higher in hypertensives than in controls. Plasma concentrations of ANP increased with exercise in both groups and had greater increments in hypertensive patients than in normotensives. Plasma concentrations of BNP increased only in patients with hypertension and the levels of increase correlated with basal plasma BNP levels (r = 0.94, p < 0.001) and with left ventricular mass (r = 0.62, p < 0.01) determined by echocardiography. In contrast, plasma adrenomedullin did not change with exercise in either group. These results suggest that secretion patterns of these peptides are regulated by different mechanisms and that the amount and kind of peptides mobilized by exercise may depend on the underlying diseases or pathophysiologic condition.

Role of endogenous atrial natriuretic peptide in DOCA-salt hypertensive rats. Effects of a novel nonpeptide antagonist for atrial natriuretic peptide receptor.

BackgroundTo explore roles of endogenous atrial natriuretic peptide (ANP) in blood pressure and volume regulation, we examined the effects of a newly developed ANP antagonist, HS-142-1 (HS) in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Methods and ResultsWe examined 1) the effects of HS on ANP- or brain natriuretic peptide (BNP)-induced reductions in renal vascular resistance (RVR) of rat isolated perfused kidneys, 2) the effects of HS on cyclic GMP (cGMP) production in rat cultured vascular smooth muscle cells pretreated with ANP or BNP, and 3) the renal and systemic effects of HS in DOCA-salt-treated rats and control rats. We found that 1) HS dose-dependently reversed ANP- or BNP-induced decreases in RVR; 2) ANP or BNP at 100 nM caused an eightfold increase in cGMP production. These increases in cGMP were inhibited by HS in a dose-dependent fashion, and 300, μg/ml HS decreased cGMP to the control level. HS alone did not influence RVR or cGMP production; and 3) DOCA-salt rats showed higher plasma concentrations of ANP (198 versus 75 pg/ml) and BNP (23.7 versus 2.7 pg/ml, each p<0.01) than the control rats. Bolus administration of 8 mg/kg HS elevated blood pressure by 8% (p<0.01). This rise in blood pressure was attributed to an increase in systemic vascular resistance (+14%, p<0.05). Conversely, urinary excretion of sodium (-41%), glomerular filtration rate (-27%), and plasma (-77%) and urinary cGMP (-69%, each p<0.01) were decreased by administration of 8 mg/kg HS. These effects were dose dependent in DOCA-salt rats but slight or negligible in the control rats. ConclusionThese results suggest that endogenous ANP and BNP may be involved in the regulation of blood pressure and body fluid volume in DOCA-salt rats in which ANP and BNP secretion is augmented.

Role of endogenous atrial natriuretic peptide in regulating sodium excretion in spontaneously hypertensive rats. Effects of neutral endopeptidase inhibition.

To explore whether pathophysiological plasma levels of atrial natriuretic peptide (ANP) actually involve sodium excretion in spontaneously hypertensive rats (SHR), we examined the in vivo and ex vivo effects of ANP and an endopeptidase inhibitor, thiorphan, on urinary sodium excretion and the elimination rate of ANP. We found the following: 1) The basal plasma ANP level was higher in 16-week-old SHR than in Wistar-Kyoto (WKY) rats (109±10 [SEM] versus 63±4 pg/ml, p<0.001). Thiorphan (30 mg/kg i.v.) significantly increased plasma ANP by 60% in both SHR and WKY rats. However, increases in urinary sodium excretion (+290% versus +130%, p<0.05) and cyclic GMP (+160% versus +60%, p+0.05) were greater in SHR than in WKY rats. Urinary excretion of ANP was markedly increased by thiorphan, and its increase was greater in SHR than in WKY rats. 2) The thiorphan-induced natriuresis was substantially attenuated by antiserum for ANP but not by a bradykinin receptor antagonist 3) Isolated SHR kidneys excreted 50% less sodium than WKY rat kidneys at perfusion pressures of 100 and 160 mm Hg (p<0.05). Urinary sodium excretion was increased at the perfusate ANP level of 100 pg/ml, a concentration similar to the SHR plasma ANP (+70% at 160 mm Hg). 4) After bolus administration of ANP to the isolated kidney, the ANP concentration of the recirculating perfusate decreased rapidly in a log-linear fashion. Pretreatment with thiorphan significantly prolonged the elimination half-life of ANP to a greater degree in the SHR kidney than in the WKY rat kidney (+75% versus +36%, p<0.05). Thus, endogenous ANP may keep the pressure-natriuresis curve to the left and consequently facilitate sodium excretion in SHR. Moreover, the enzymatic degradation of ANP seems to be increased in SHR kidneys.

Preservation of the right atrial appendage improves reduced plasma atrial natriuretic peptide levels after the maze procedure

OBJECTIVES The present study was conducted to determine whether preservation of the right atrial appendage lessens the decrease of plasma atrial natriuretic peptide levels after the maze procedure and whether the increase of plasma atrial natriuretic peptides improves the ability of the kidneys to excrete the fluid load after the operation. METHODS We evaluated 42 patients who underwent the maze procedure. The right atrial appendage was preserved in 22 patients but not in 20. Blood samples were obtained before and after the operation for measurement of atrial natriuretic peptides. To evaluate the influence of atrial natriuretic peptides on the ability of the kidneys, we also measured body weight, fluid balance, and the doses of furosemide and dopamine administered after the operation. RESULTS The restoration to sinus rhythm at 1 month after was comparable in the two groups. Plasma atrial natriuretic peptide levels significantly increased after the operation in patients in whom the right atrial appendage was preserved (1 day after: 23.4 +/- 17.8 vs 3 days after: 42.7 +/- 23.6 and 7 days after: 36.3 +/- 23.7 pg/mL, P <.05) but not in patients in whom the right atrial appendage was not preserved (1 day after: 20.0 +/- 19.6, 3 days after: 28.5 +/- 19.3, and 7 days after: 23.0 +/- 16.1 pg/mL). Furthermore, plasma atrial natriuretic peptide levels were significantly lower in patients in whom the right atrial appendage was not preserved than in patients in whom the right atrial appendage was preserved at 3 and 7 days after the operation. The fluid balance during the first 7 days of the postoperative period was comparable in the two groups, although the total dose of dopamine used in the same period was significantly smaller in patients in whom the right atrial appendage was preserved than in patients in whom the right atrial appendage was not preserved (155.3 +/- 119.0 vs 244.9 +/- 129.0 microg/kg, P <.05). CONCLUSIONS The present study showed that preservation of the right atrial appendage lessens the decrease of plasma atrial natriuretic peptide levels after the maze procedure and that increased plasma atrial natriuretic peptides may improve the ability of the kidneys to excrete the fluid load after the operation.

Estimation of the secretion rate of atrial natriuretic peptide from the coronary sinus in coronary artery disease

Although atrial natriuretic peptide (ANP) is known to be secreted through the coronary sinus into the systemic circulation, its actual secretion rate has not been thoroughly investigated. The immunoreactive ANP concentrations in plasma samples from the ascending aorta and coronary sinus in 11 patients with the coronary artery disease were measured and the coronary sinus flow rate using the continuous thermodilution method was simultaneously determined at the time of sampling. These variables were also determined during the intravenous infusion of synthetic alpha-human ANP at 0.025 microgram/kg.min in 7 of the 11 patients. In the basal state, the plasma concentration of ANP was 61 +/- 6 (standard error) pg/ml in the aorta and 541 +/- 40 pg/ml in the coronary sinus, and the coronary sinus flow index was 57.3 +/- 12.3 ml/min.m2. Thus, the secretion rate of ANP was determined to be 14.4 +/- 2.8 ng/min.m2. The secretion rate of ANP correlated significantly with the plasma concentration of ANP in the aorta (r = 0.65, p less than 0.05). The ANP infusion, which decreased pulmonary artery wedge pressure from 8.0 +/- 0.6 to 6.3 +/- 0.4 mm Hg (p less than 0.01), elevated the plasma concentrations of ANP in the aorta and coronary sinus by 701% (p less than 0.001) and 33% (p less than 0.05), respectively, and decreased the secretion rate of ANP by 40% (p less than 0.05). These results suggest that the circulating plasma concentration of ANP may reflect the secretion rate of ANP and that an increase in circulating ANP directly or indirectly reduces ANP secretion.