Naotsugu Kurihara

Brain natriuretic peptide as a cardiac hormone in essential hypertension

PURPOSE A natriuretic peptide, brain natriuretic peptide (BNP), has been isolated from porcine hearts. We performed this study to determine if BNP is secreted from the heart and to identify changes, if any, in the plasma BNP concentration in essential hypertension. PATIENTS AND METHODS We measured the immunoreactive (ir) BNP concentration at intracardiac sites including the coronary sinus of five patients with heart disease during cardiac catheterization. We examined plasma ir-BNP in 48 hypertensive patients, 15 borderline hypertensive patients, and 25 normotensive subjects. RESULTS Plasma ir-BNP in the coronary sinus was greater than at other cardiac sites. The concentration was significantly higher in hypertensive subjects than in borderline hypertensive or normotensive subjects. Hypertensive patients with left ventricular hypertrophy (LVH) established by echocardiography had higher plasma ir-BNP levels than those without LVH. In the hypertensive group, plasma ir-BNP was closely correlated with the LV mass index. In these patients, BNP levels were correlated with mean arterial pressure and inversely correlated with the LV ejection fraction, although these correlations were weak. Reverse-phase high-pressure liquid chromatography showed that the major component of circulating ir-BNP in the hypertensive and normotensive subjects corresponded to authentic human BNP-32. CONCLUSIONS Human BNP-32 was secreted through the coronary sinus from the heart and may act as a cardiac hormone. Plasma BNP was increased in many of the hypertensive subjects with LVH. The increase in BNP seemed to be related to LVH or the cardiac overload associated with LVH.

Brain natriuretic peptide as a marker for hypertensive left ventricular hypertrophy: Changes during 1-year antihypertensive therapy with angiotensin-converting enzyme inhibitor

PURPOSE Secretion of brain natriuretic peptide (BNP), a cardiac hormone, is accelerated via hypertrophied ventricles in experimental hypertension. The present study examined whether regression of left ventricular (LV) hypertrophy by long-term treatment with an angiotensin-converting enzyme inhibitor (ACEI) affects plasma BNP concentration in patients with essential hypertension. PATIENTS AND METHODS Thirty-one hypertensive patients with LV hypertrophy were treated with ACEI (16 with enalapril; 15 with lisinopril) for 1 year. Serial changes were recorded in LV mass index, LV systolic function, and plasma concentrations of BNP and atrial natriuretic peptide (ANP). RESULTS ACEI therapy significantly reduced LV mass index at 6 months, and more so at 1 year. Septal and posterior wall thicknesses were also reduced. Plasma BNP and ANP were markedly elevated at study entry, but only BNP levels correlated with LV mass index. Both peptide levels declined after 6 months, and this decline was enhanced at 1 year. There was a close relation between BNP decline and LV mass index reduction overall and with enalapril and lisinopril separately. Changes in ANP and in LV mass index were not related. CONCLUSION Long-term ACEI therapy can reduce elevated plasma BNP. In this study, changes in BNP reflected the magnitude of regression of LVH. Plasma BNP may be a useful marker for LVH during antihypertensive therapy in patients with essential hypertension and LVH.

Prolonged blood pressure elevation after endothelin administration in bilaterally nephrectomized rats

The hemodynamic effect of a novel potent vasoconstrictive peptide (endothelin) on systemic blood pressure was studied in bilaterally nephrectomized and sham-operated rats under conscious and almost unrestrained condition. Following bolus IV administration of porcine endothelin, plasma endothelin concentration was measured by radioimmunoassay. After a transient decline, blood pressure was gradually elevated by endothelin administration. At 20, 30, and 40 minutes after injection, blood pressure was significantly elevated in bilaterally nephrectomized rats compared with sham-operated rats. Arterial plasma endothelin concentrations increased and rapidly decreased after injection in both rat groups. Bilateral nephrectomy significantly delayed the disappearance of endothelin from the plasma. These results suggest that the kidney plays a role in the plasma clearance of IV bolus endothelin administration and that the prolonged plasma half-life of endothelin is in part associated with the prolonged blood pressure elevation after endothelin administration in bilaterally nephrectomized rats.

Stimulation of brain natriuretic peptide release from the heart by thyroid hormone

This study was designed to examine the involvement of thyroid hormone in the release of brain natriuretic peptide (BNP) from the heart. We measured plasma immunoreactive BNP (ir-BNP) concentrations in patients with untreated hyperthyroidism. We also measured BNP values in experimental rats with hyperthyroidism induced by thyroxine (T4) and in rats with hypothyroidism induced by propylthiouracil (PTU). The in vitro effects of triiodothyronine (T3) and T4 on the release of BNP were examined in newborn rat atrial and ventricular myocytes in primary culture. Plasma BNP levels were increased in hyperthyroid patients compared with normal control subjects. Plasma BNP levels were increased in hyperthyroid rats and decreased in hypothyroid rats compared with euthyroid rats. Plasma BNP level was correlated with serum T4 level in hyperthyroid patients and hyperthyroid rats. A major component of ir-BNP in plasma from hyperthyroid patients was human BNP-32 and that in plasma from hyperthyroid rats was rat BNP-45. T4 and T3 stimulated release of ir-BNP from both cultured atrial and ventricular myocytes in a dose-dependent manner. Plasma BNP concentration is frequently increased in hyperthyroidism, and thyroid hormone may regulate BNP release from both atrial and ventricular myocytes.

Effect of hypoxia on plasma immunoreactive endothelin-1 concentration in anesthetized rats

The present study was designed to examine the possible influence of hypoxia on plasma immunoreactive (ir) endothelin-1 concentrations in anesthetized rats. Plasma ir-endothelin-1 concentration, blood pressure, heart rate, and arterial gas levels were measured 1 and 2 hours after exposure to normoxic (20% O2), mildly hypoxic (16% O2), and severely hypoxic (12% O2) gas. Mean blood pressure and heart rate were significantly decreased and the plasma ir-endothelin-1 concentration was significantly increased in severely hypoxic rats after both 1 and 2 hours. In mildly hypoxic rats, the plasma ir-endothelin-1 concentration was also increased, but this value was not statistically significant. The plasma ir-endothelin-1 concentration was inversely correlated with arterial blood PO2 in the three study groups (normoxic, mildly hypoxic, and severely hypoxic rats) after 1 hour (n = 18, r = -.74, P less than .01), and after 2 hours (n = 18, r = .71, P less than .01). Our results indicate that severe hypoxia increased the plasma ir-endothelin-1 level in anesthetized rats. The observed increase in plasma ir-endothelin-1 level may represent a compensatory mechanism against the blood pressure reduction associated with severe hypoxia.

The Macrolide Antibacterial Roxithromycin Reduces Bronchial Hyperresponsiveness and Superoxide Anion Production by Polymorphonuclear Leukocytes in Patients with Asthma

We investigated the effects of a macrolide antibacterial, roxithromycin, on the generation of free radicals by peripheral polymorphonuclear leukocytes (PMNs) and on the severity of bronchial hyperresponsiveness. Ten asthmatic patients were treated for 3 months with roxithromycin, 150 mg orally once daily; such treatment significantly reduced the production of superoxide anion by PMNs (p = 0.0029) and reduced the bronchial hyperreactivity (p = 0.0016), as compared with results in healthy controls. Most of the patients required at least 2 months of treatment with roxithromycin for clinical improvement. We conclude that long-term, low-dose administration of roxithromycin may be useful in treatment of patients with bronchial asthma.

Plasma endothelin-1 level in chronic obstructive pulmonary disease: relationship with natriuretic peptide.

Background and Objective: Endothelin-1 (ET-1) is a potent vasoconstrictor peptide produced by the vascular endothelium. The purpose of this study was to elucidate the pathophysiological role of ET-1 in patients with pulmonary hypertension secondary to chronic obstructive pulmonary disease (COPD). Method: We measured plasma ET-1 levels during right heart catheterization both at rest and during exercise on room air and while breathing oxygen in patients with COPD. In addition, we simultaneously measured plasma levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Results: Plasma ET-1 levels at rest were significantly higher in 21 patients with COPD than in 16 control subjects (p < 0.001). For COPD patients, there was no correlation between the plasma ET-1 level and pulmonary arterial pressure or pulmonary vascular resistance at rest. On the other hand, there was a significant negative correlation between plasma ET-1 level and mixed venous oxygen tension (r = –0.503, p < 0.05). Also, the plasma ET-1 level was positively correlated with those of ANP (r = 0.540, p < 0.05) and BNP (r = 0.533, p < 0.05) at baseline. Oxygen administration significantly decreased plasma ET-1 levels at rest (p < 0.05). Plasma ET-1 levels did not change significantly with exercise despite the progression of pulmonary hypertension and hypoxemia. In contrast, plasma ANP and BNP levels both increased markedly with exercise (p < 0.01). Conclusion: We conclude that in patients with COPD, the plasma ET-1 level is not affected by acute progression of pulmonary hypertension and hypoxemia during exercise, and persistent hypoxemia may be associated with an increase in the plasma ET-1 level. In addition, our findings suggest that ANP and BNP may modulate the pulmonary vascular tone by interacting with ET-1 in these patients.

Glucocorticoids and dopamine-1 receptors on vascular smooth muscle cells.

The effect of glococorticoids on the dopamine (DA)-mediated cyclic adenosine monophosphate (cAMP) by intact vascular smooth muscle cells (VSMC) was studied in rats. Cultured VSMC were obtained from renal arteries of 14-week-old Wlstar-Kyoto rats by explant method. Micromoiar concentrations of dexamethasone (DEX) pretreatment for 48 hours potentiated DA-mediated response without any change of affinity constant. However, micromoiar concentrations of aldosterone pretreatment for 48 hours had almost no effect on DA-mediated response. The DEX-induced facilitation began at 6 hours and reached maximum at 24 hours after DEX administration in a dose-dependent manner. Inhibitors of protein and RNA synthesis blocked this glucocorticoid effect. The basal activity of adenylate cyclase in DEXtreated cells was twofold higher than that in control cells. Treatment of VSMC with DEX increased cholera toxin-stimulated and forskolin-stimulated adenylate cyclase activity. However, pertussis toxin treatment did not augment or reduce the effect of DEX treatment. These results suggest that glucocorticoids increase DA-mediated cAMP formation by VSMC through glucocorticoid type II receptors and the induction of protein synthesis and that the activation of the catalytic unit may play some role in this facilitation.

Atrial and brain natriuretic peptides: secretion during exercise in patients with essential hypertension and modulation by acute angiotensin-converting enzyme inhibition.

1. This study examined whether brain and atrial natriuretic peptides (BNP, ANP) are secreted together through the coronary sinus from the heart, and whether plasma concentrations of BNP and ANP were affected by ergometric exercise in patients with essential hypertension. The effect of temocapril, a potent angiotensin‐converting enzyme (ACE) inhibitior, on plasma concentrations of these peptides was also examined.

Endothelin-Induced Renal Vasoconstriction and Increase in Cytosolic Calcium in Renal Vascular Smooth Muscle Cells

This study was designed to investigate the effects of the potent vasoconstrictor, endothelin, on renal hemodynamics in rats in vivo, and in addition, to measure intracellular calcium ion ([Ca2+]i) in monolayers of renal vascular smooth muscle cells in culture using the fura-2 method. Endothelin (1 nmol) dramatically decreased renal blood flow from 7.0 +/- 0.5 ml/min to 2.6 +/- 1.0 ml/min, whereas it increased mean arterial pressure from 100 +/- 2 mmHg to 113 +/- 7 mmHg. These alterations persisted over 20 minutes in conscious and almost unrestrained rats. Endothelin (10(-8)-10(-7) mol/l) immediately increased [Ca2+]i, although the increase by endothelin (10(-9) mol/l) was relatively slow. The increase persisted in the presence of 1 mmol/l extracellular calcium. In the absence of extracellular calcium, only a small, transient increase of [Ca2+]i was observed. These results indicate that endothelin produces renal vasoconstriction and increases the [Ca2+]i in cultured renal vascular smooth muscle cells. The latter effect is dependent mainly on extracellular calcium.