Naoki Okuda

Cause of residual hypertension after adrenalectomy in patients with primary aldosteronism.

The cause of residual hypertension after adrenalectomy for primary aldosteronism (PA) is unknown. The purpose of this study is to investigate the characteristic pathological kidney features associated with PA. Between 1977 and 1999 at our hospital, 26 patients with PA caused by a unilateral adrenal cortical adenoma (Conns syndrome) underwent unilateral adrenalectomy with concurrent open-wedge renal biopsy. Patients were categorized into two groups: (1) those with normotension with diastolic blood pressure less than 90 mm Hg who were not administered antihypertensive drugs, and (2) those with residual hypertension with diastolic blood pressure of 90 mm Hg or greater who were administered medication for 6 months after surgery. Thirteen patients were cured of hypertension postoperatively, and 12 patients were administered antihypertensive medications. Glomerulosclerosis, renal arteriolosclerosis, and preoperative left ventricular mass (LVM) index were worse in the group with residual hypertension than in that with normotension (17.8% +/- 7.8% versus 9.6% +/- 3.8%; P = 0.01; 2.5 +/- 0.5 versus 1.6 +/- 0.4, Baders grade; P = 0.005; and 165 +/- 31 versus 139 +/- 24 g/m(2); P = 0.02, respectively). Severity of tubulointerstitial injury, preoperative duration of hypertension, preoperative severity of proteinuria, plasma aldosterone level, and serum potassium concentration were not significantly different between the two groups. In conclusion, severity of glomerulosclerosis and arteriolosclerosis and LVM are related to blood pressure after adrenalectomy in patients with PA.

Angiotensin blockade and the progression of renal damage in the spontaneously hypertensive rat

The pathophysiological role of angiotensin II in the development of renal sclerosis was investigated in 5/6-nephrectomized, 12-week-old male spontaneously hypertensive rats. After 1 week of a control period, nephrectomized rats received one of the following treatments for 4 weeks: the selective nonpeptide angiotensin II type 1 receptor antagonist TCV-116 (1 mg/kg per day), the angiotensin converting enzyme inhibitor delapril (30 mg/kg per day), hydralazine (15 mg/kg per day), or vehicle. Urinary protein and albumin excretions and systolic blood pressure were determined every week. Rats with reduced renal mass treated with vehicle had a poor survival rate (30%). Although TCV-116, delapril, and hydralazine treatment significantly improved the survival rate for 4 weeks, hydralazine failed to improve proteinuria and albuminuria as well as the decline in renal function compared with delapril or TCV-116. Histological examination revealed that both TCV-116 and delapril protected glomeruli from sclerosis, whereas hydralazine did not improve histological findings (5%, 7%, and 30% of glomeruli were affected, respectively). These results indicate that angiotensin II plays a dominant role through its type 1 receptor in the pathogenesis of renal deterioration by hypertension.

Autonomic function in hypertensive patients with neurovascular compression of the ventrolateral medulla oblongata

OBJECTIVE To study whether abnormalities of autonomic function exist in patients with essential hypertension and neurovascular compression (NVC) of the medulla oblongata. SUBJECTS AND METHODS We studied 25 untreated patients with essential hypertension (13 men and 12 women, 27-74 years old). High-resolution magnetic resonance imaging and magnetic resonance angiography were used to detect NVC. Twenty-four-hour ambulatory monitoring of blood pressure and electrocardiogram were performed, and the power spectrum of heart rate variability was analyzed. On a separate day, various autonomic activity tests, including mental stress, hand grip, cold pressor, and Valsalva maneuver were performed. Baroreflex sensitivity was calculated from changes of blood pressure and R-R interval during phenylephrine infusion. A clonidine suppression test was also performed, with measurement of plasma catecholamine levels. RESULTS Fourteen of 25 patients (56%) had NVC (C group), and 11 patients did not have NVC (NC group). There were no significant differences in age, sex, family history, or duration of hypertension between the C and NC groups. Average 24-h systolic blood pressure was similar between the two groups, although 24-h diastolic blood pressure was higher in the C group than the NC group. Daytime, night-time, and 24-h heart rate was significantly higher in the C group than in the NC group. Night-time low frequency/high frequency ratio was slightly higher in the C group. Plasma norepinephrine levels were significantly higher (467 +/- 217 versus 299 +/- 122 pg/ml), and baroflex sensitivity was slightly lower in the C group than in the NC group. Responses of blood pressure and heart rate to mental stress, cold pressor, hand grip, Valsalva maneuver, phenylephrine infusion, and clonidine tests were not significantly different between the two groups. CONCLUSIONS NVC of the medulla oblongata was frequently found in patients with essential hypertension. Patients with NVC appeared to have enhanced sympathetic nervous activity compared with those without the compression.

DIFFERENTIAL CONTROL OF VASCULAR TONE AND HEART RATE BY DIFFERENT AMINO ACID NEUROTRANSMITTERS IN THE ROSTRAL VENTROLATERAL MEDULLA OF THE RAT

1. To test the hypothesis that a central mechanism may play a role in the minimal reflex tachycardia noted in response to peripheral converting enzyme inhibition, we compared the effects of intravenous (i.v.) ceronapril (CER) with nitroglycerin (NTG) on neurotransmitter release in the rostral ventrolateral medulla (RVLM), using an in vivo microdialysis method in pentobarbital anaesthetized rats.

Predominance of Nocturnal Sympathetic Nervous Activity in Salt-Sensitive Normotensive Subjects

To assess the relation between salt sensitivity and autonomic nervous function by power spectral analysis of heart rate variability in normotensive subjects, low and high salt diets were given to 13 normotensive men (aged 25 to 39 years) for 4 days each. Autonomic function was assessed by power spectral analysis of R-R intervals based on an autoregressive algorithm from 24-h Holter electrocardiogram. Subjects whose mean blood pressure was increased more than 3 mm Hg by high salt diet were defined as salt sensitive (SS, n = 5), and the remainder as salt resistant (SR, n = 8). Using the low frequency (LF, 0.1 Hz) and high frequency (HF, 0.25 Hz) components, the LF to total power ratio (%LF) was used as a marker of sympathetic activity, and the HF to total power ratio (%HF) as a marker of parasympathetic activity. Compared to the daytime, SR revealed a decrease in %LF and an increase in %HF during the night on both diets. In SS, these circadian changes were observed only during low-salt diet. During the night, SS showed a higher %LF and a lower %HF than SR. Plasma catecholamines tended to be decreased by the high sodium diet in SR but not in SS subjects. These results suggest that the persistent nocturnal predominance of sympathetic nervous activity in a salt-sensitive men may contribute to the subsequent increase of blood pressure in these subjects.

Tetranuclear copper(II) complexes. Copper(II) complexes of schiff bases derived from histamine and salicylaldehyde or 2-pyridinecarbaldehyde

Abstract Reaction of copper(II) ions with the Schiff bases derived from histamine and salicylaldehyde or 2-pyridinecarbaldehyde were investigated in acidic and basic media. The copper(II) complexes obtained from the reactions in acidic solutions were mononuclear complexes I and II, while those from the reactions in basic solutions were tetranuclear complexes III and IV, in which the four copper(II) ions were tetrahedrally arranged. A study on magnetic property (4.2–300 K) of the tetranuclear complexes by the Faraday method suggested the presence of antiferromagnetic interactions between the four copper(II) ions.

Effects of a low-energy diet and an insulin-sensitizing agent on ambulatory blood pressure in overweight hypertensive patients

Objective To clarify the role of insulin resistance and hyperinsulinaemia in the pathogenesis of obesity-related hypertension. Design An open study comparing the effects of weight reduction by low-energy diet and treatment with troglitazone, an insulin-sensitizing agent. Setting A tertiary teaching hospital. Patients Thirty overweight hypertensive patients (15 men and 15 women, mean age 61 years, mean body mass index 29.1 kg/m2). Interventions Fifteen patients were assigned to a weight-reduction programme by low-energy diet (3360 kJ/day) for 3 weeks; the remaining 15 patients were treated with troglitazone (400 mg/day) for 8 weeks. Main outcome measures Casual and ambulatory blood pressures, glucose and lipid metabolism, and insulin sensitivity. Results The baseline values of body mass index, fasting and post-glucose plasma insulin, and casual and ambulatory blood pressures were comparable between the two groups. Weight reduction (4.1 ± 0.3 kg, mean ± SEM) was associated with significant decreases in plasma insulin, blood glucose, homeostasis model assessment (HOMA) insulin resistance index, serum triglyceride, casual blood pressure (7.7 ± 2.3/3.9 ± 1.4 mmHg) and 24 h blood pressure (8.3 6 1.9/ 4.3 ± 1.1 mmHg). Treatment with troglitazone caused comparable decreases in the metabolic parameters and HOMA index, but did not change casual or 24 h blood pressure (0.8 ± 3.4/0.8 ± 2.1 and 1.5 ± 2.4/1.0 ± 1.9 mmHg, respectively). Conclusions Insulin resistance/hyperinsulinaemia may not have an important role in the pathogenesis of obesity-related hypertension. The antihypertensive effect of weight reduction seems to be mediated mainly by other mechanisms.

effects of diltiazem retard on ambulatory blood pressure and heart rate variability in patients with essential hypertension

Background Dihydropyridine calcium antagonists increase heart rate due to reflex activation of the sympathetic nervous system, although these effects are less obvious for long‐acting agents. Objective To study the effects of diltiazem retard, a long‐acting nondihydropyridine calcium antagonist, on 24 h blood pressure, heart rate and autonomic nerve activity in patients with essential hypertension. Design Randomized crossover design. Methods Thirteen patients [five men and eight women, aged 64 ± 2 years (mean ± SEM)] were administered placebo or diltiazem retard (100‐200 mg once daily) for 4 weeks each. Ambulatory monitoring of blood pressure and heart rate, and electrocardiography were carried out at the end of each period using a multibiomedical recorder (TM‐2425). Autonomic nerve activity was evaluated by power spectral analysis of variability of heart rate using the high‐frequency component as an index of parasympathetic nerve activity and the ratio of the low‐frequency component and the high‐frequency component as an index of sympathovagal balance. Results Treatment with diltiazem retard significantly decreased 24 h average blood pressure and heart rate by 11.6 ± 3.6/5.7 ± 1.8 mmHg and 5.0 ± 1.1 beats/min, respectively. The changes in daytime and night‐time values were comparable. Diltiazem retard also significantly decreased daytime and 24 h low:high‐frequency‐component ratio (2.0 ± 0.2 versus 1.7 ± 0.2 and 1.8 ± 0.2 versus 1.6 ± 0.2, respectively). Conclusions These results indicate that diltiazem retard is effective as a once‐daily antihypertensive agent and has favorable effects on heart rate and the autonomic nervous system.

The effect of central amino acid neurotransmitters on the antihypertensive response to angiotensin blockade in spontaneous hypertension.

Objective To investigate the effects of central amino acid neurons on the antihypertensive action of a newly developed angiotensin II type 1 receptor (AT1) antagonist, CV 11974. Materials and methods We measured the release of various amino acids in the rostral ventrolateral medulla using the brain microdialysis technique. A microdialysis probe was inserted into the exposed rostral ventrolateral medulla in male spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats anaesthetized with urethane. Mean arterial pressure and the release of amino acids (glutamate, glycine, glutamine, taurine and γ-aminobutyric acid) were monitored before and after intravenous administration of CV 11974 (5 mg/kg), nitroglycerin (5 μg/kg per min) or vehicle. Results In SHR, CV 11974 decreased mean arterial pressure (-40±6 mmHg) accompanied by significant increases in the release of inhibitory amino acids, glycine (411 ± 83%) and γ-aminobutyric acid (363 ± 71%) in the rostral ventrolateral medulla, whereas intravenous nitroglycerin produced a decrease in mean arterial pressure (-35±4 mmHg) without changes in amino acid release. In WKY rats, both intravenous CV 11974 and intravenous nitroglycerin produced smaller but significant decreases in mean arterial pressure (CV 11974, −18±5 mmHg; nitroglycerin, −20±7 mmHg) without change in the release of amino acids in the rostral ventrolateral medulla. Selective perfusion of glycine or γ-aminobutyric acid into the rostral ventrolateral medulla caused a larger mean arterial pressure reduction in SHR than in WKY rats. Furthermore, the use of a specific antagonist of glycine or of the γ-aminobutyric acid receptor in the rostral ventrolateral medulla attenuated the antihypertensive response induced by the intravenous AT1 antagonist in SHR. Conclusion The present results suggest that the release of the inhibitory amino acids glycine and γ-aminobutyric acid in the rostral ventrolateral medulla contributes to the depressor action of this AT1 receptor antagonist in the genetic hypertensive rat model.

EFFECT OF PROPRANOLOL ON CENTRAL NEUROTRANSMITTER RELEASE IN WISTAR RATS ANALYSED BY BRAIN MICRODIALYSIS

1. The effect of propranolol on amino acid neurotransmitter release in the rostral ventrolateral medulla (RVLM) was examined in urethane‐anaesthetized male Wistar rats.