Systemic hemodynamics during sleep in young or middle-aged and elderly patients with essential hypertension.

Age-related changes in cardiovascular regulatory mechanisms may affect blood pressure homeostasis during sleep and in the daytime. This study compared systemic hemodynamics during the daytime and sleep between 12 young or middle-aged patients (young, 42.1 +/- 13.9 years old, mean +/- SD, less than 56 years old) and 12 elderly patients with essential hypertension (old, 65.3 +/- 2.8, 60 to 70 years old). They were all hospitalized and placed on a diet containing approximately 7 g sodium chloride per day. Intra-arterial blood pressure and electrocardiogram were recorded for 24 hours, and electroencephalogram and electroophthalmogram were recorded during the night with a telemetric method. Cardiac output was measured with patients in the supine position by the cuvette method during the daytime and stage 3 or 4 sleep at night. The averaged 24-hour blood pressure was similar in the two groups (140 +/- 2 [SEM]/85 +/- 3 mm Hg in the young group and 144 +/- 4/81 +/- 2 mm Hg in the old group). The reduction in mean blood pressure during sleep was also comparable in both groups (-18 +/- 2 in the young group and -20 +/- 2 mm Hg in the old group). Cardiac index was smaller in the old group than the young group during both the daytime and sleep (daytime, 2.3 +/- 0.1 versus 3.2 +/- 0.2 [L/min]/m2, P < .01; sleep, 2.1 +/- 0.1 versus 2.6 +/- 0.2 [L/min]/m2, P < .01). The reduction in cardiac index during sleep was greater in the young than the old group (P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Dietary sodium restriction impairs insulin sensitivity in noninsulin-dependent diabetes mellitus.

Dietary sodium restriction has a variety of effects on metabolism, including activation of the renin-angiotensin system. Angiotensin II has complex metabolic and cardiovascular effects, and these may be relevant to the effects of both nonpharmacological and pharmacological interventions in noninsulin-dependent diabetes mellitus (NIDDM). We have assessed the effect of dietary sodium restriction on insulin sensitivity and endogenous glucose production in eight normotensive patients with diet-controlled NIDDM who underwent hyperinsulinemic clamp studies in a randomized, double-blind, placebo-controlled cross-over protocol after two 4-day periods on sodium replete (160 mmol/day) and sodium deplete (40 mmol/day) diets. Mean +/- SD 24-h urinary sodium was 197 +/- 76.0 mmol (replete) and 67 +/- 19.5 mmol (deplete), P = 0.03. Insulin sensitivity was 42.0 +/- 11.3 mumol/kg.min (replete) and 37.0 +/- 11.6 mumol/kg.min (deplete), P = 0.04 (a reduction of 12%). Blood pressure was 130 +/- 21/78 +/- 11 mmHg (replete) and 128 +/- 12/73 +/- 10 mmHg (deplete). Dietary sodium restriction may result in a decrease in peripheral insulin sensitivity in normotensive patients with NIDDM, possibly via an elevation in prevailing angiotensin II concentrations.

Base heart rate during sleep in hypertensive and normotensive subjects.

OBJECTIVE: Many studies have reported that the resting heart rate (HR) is intimately related to the prognosis of cardiovascular disease. However, HR in the waking state is influenced by psychological and physical activity and has low reproducibility. To measure the base HR (minimum and stable HR during sleep) with ease, we developed a wristwatch-type HR recorder. We then investigated the pathophysiological significance of the base HR. SUBJECTS AND METHODS: The subjects were 158 patients (82 men and 76 women) with essential hypertension (HT) on no medication and 204 normotensive (NT) subjects (105 men and 99 women, matched for age). On the basis of pulse waves from the wristwatch-type photoelectric plethysmograph, using a blue sensor with a wavelength of 450 nm, HR was recorded easily minute by minute during sleep time. In addition, 40 (23 men and 17 women) of the HT patients were hospitalized. Their cardiac index (CI) and stroke volume index (SVI) were measured by means of the cuvette method during waking time and night-time deep sleep when their HR had reached a minimum level. RESULTS: Mean base HR (HRo) in NT subjects was 49+/-4 beats per minute (bpm) and tended to rise with increasing age (r = 0.51, P < 0.01). In HT patients, HR0 was significantly higher: 60+/-7 bpm (P < 0.01). CI of HT patients, measured during night-time deep sleep, maintained a stable value of 2.45+/-0.36 l/min per m2. SVI in patients whose HR0 was above 60 was significantly lower than that in patients whose HR0 was below 60 (37+/-4.5: 45+/-4.8 ml/m2, P < 0.01). Corresponding differences in mean HR and SVI during waking or night-time, became smaller. CONCLUSIONS: These findings suggest that there is a close relation between base HR and cardiac function caused by such conditions as age and hypertension. This relation became indistinct during waking time. Moreover, the wristwatch-type HR recorder appears to be a useful tool for measuring base HR.

Circadian variation of haemodynamics in patients with essential hypertension: comparison between early morning and evening.

OBJECTIVE: An increased incidence of cardiovascular accidents in the morning has been reported, but the reason why is not clear. We measured 24-h haemodynamics and focused on its change in the morning. DESIGN: To study the circadian variation of haemodynamics, we recorded 24-h direct blood pressure and electrocardiogram using a telemetry method, in 21 untreated inpatients with essential hypertension, and measured cardiac output using the dye-dilution method in the morning, in the evening and during sleep. We also determined the beat-to-beat cardiac output (using the pulse-contour method), the total peripheral resistance and the ratio of low- to high-frequency components (using power spectral analysis of the R-R interval during 24 h), and made comparisons between morning and evening values. RESULTS: Both systolic and diastolic blood pressure increased rapidly in the early morning. Although the comparison of blood pressure between morning and evening showed no difference, total peripheral resistance and low- to high-frequency ratio were significantly higher in the morning than in the evening, but cardiac output was lower in the morning. CONCLUSIONS: Sympathetic nervous activity and vascular resistance seem to be higher in the morning than in the evening, and these haemodynamic changes may stress the cardiovascular system.

Effect of dietary sodium on platelet alpha 2-adrenoceptors in young normotensive men with or without a family history of hypertension.

OBJECTIVE: To study the effects of genetics on the response of platelet alpha 2-adrenoceptors to a change in salt intake. METHODS: Biochemical measurements and radioligand binding assays in platelets were performed in 11 normotensive male university students with a family history of essential hypertension (FH+) and in 17 students without a family history of hypertension (FH-). The 28 students were fed a high-sodium diet for 7 days and a low-sodium diet for 7 days. RESULTS: In FH+ subjects the number of alpha 2-adrenergic receptors on platelet membrane fractions increased significantly from the high-sodium diet to the low-sodium diet, even though plasma noradrenaline concentrations tended to increase with the low-sodium diet. There was no change in the number of alpha 2-adrenoceptors in the FH--group. In both groups the radioligand binding affinity was decreased during a low-sodium period compared with in a high-sodium period. CONCLUSION: In the FH+ subjects the change in platelet alpha 2-adrenoceptors associated with altered sodium status was similar to that seen in patients with salt-sensitive hypertension, suggesting that there is a genetic susceptibility to sodium.

Fosinopril. Clinical pharmacokinetics and clinical potential.

Fosinopril is a phosphorus-containing ester prodrug of an angiotensin-converting enzyme (ACE) inhibitor. It is hydrolysed mainly in the gastrointestinal mucosa and liver to the active diacid, fosinoprilat, which has unique pharmacological properties. The majority of the active moieties of other ACE inhibitors are excreted in the urine. This means that an adjustment in either the dosage and/or the administration interval is needed in patients with moderate to severe renal dysfunction, in order to reduce drug accumulation and the possibility of an excessive decrease in blood pressure or other adverse effects. On the other hand, fosinoprilat is excreted both in urine and bile (as with temocaprilat, zofenoprilat and spiraprilat), and thus an adjustment of dosage and/or administration interval may be unnecessary in patients with moderate to severe renal dysfunction, as impaired renal function influences little of the pharmacokinetics of fosinoprilat. Furthermore, the available evidence suggests that the pharmacokinetic variables of fosinoprilat in patients receiving haemodialysis were similar to those in patients with moderate to severe renal dysfunction. Dosage modifications or supplemental dose administration following dialysis may be unnecessary. The hypotensive effect of the combination of fosinopril and a diuretic is synergistic. Pharmacokinetic interactions with fosinopril are unlikely in patients receiving thiazide or loop diuretics. Fosinopril has beneficial effects for patients with hypertension and left ventricular hypertrophy because it produces an adequate reduction in blood pressure and reversal of left ventricular hypertrophy. There are a large number of studies of the pharmacokinetics of fosinopril. However studies of its pharmacokinetic drug interactions with other drugs are far fewer. Further investigations are needed in several clinical settings.

Blood pressure during sleep: antihypertensive medication.

To investigate whether excessive reduction of blood pressure (BP) by antihypertensive medications correlates with myocardial infarction, especially during sleep in elderly patients, we used telemetry and cuvette dye-dilution methods to assess the direct BP and the hemodynamics of 68 inpatients with essential hypertension during wakefulness and sleep. There were 25 patients greater than or equal to 60 years old (OH-group) and 43 were less than or equal to 59 years old (YH-group). Of the OH-group, 36% showed high BP during the day, with marked decreases (minimum BP less than 110/70 mm Hg) during sleep. Average cardiac index (CI) of the OH-group was low during wakefulness and extremely low during slow-wave sleep. Changes of mean BP in the OH-group correlated with changes in total peripheral vascular resistance index (TPRI) during sleep, but this correlation was not observed in the YH-group. The antihypertensive effects on nocturnal BP of the various medications was: central adrenergic inhibitors less than or equal to beta blockers with intrinsic sympathomimetic activity less than or equal to alpha (alpha beta) blockers less than or equal to angiotensin-converting enzyme inhibitors less than or equal to calcium antagonists. Because BP and CI were found to be very low and TPRI seems to play an important role in BP regulation in sleeping elderly patients, excessive antihypertensive medication may be harmful to this subgroup. However, because the effects on nocturnal BP differ among various antihypertensive treatments, further research is required on the relation between antihypertensive medication and the hemodynamics of sleeping elderly hypertensive patients.

A study of the effects of delapril, a new angiotensin converting enzyme inhibitor, on the diurnal variation of arterial pressure in patients with essential hypertension using indirect and direct arterial pressure monitoring methods.

In order to investigate the effect of delapril, a new angiotensin converting enzyme inhibitor, on the diurnal variation of arterial pressure in patients with essential hypertension, this study examined 24 h arterial pressure using an indirect or a direct monitoring system. When the effect of twice-a-day administration of delapril at daily doses of 30 to 90 mg was examined using the indirect monitoring system in 12 outpatients, delapril decreased systolic and diastolic arterial pressures significantly only at limited points during the day. However, each of the averaged 24 h daytime and nighttime arterial pressures showed significant reductions. The 24 h intraarterial pressure monitoring demonstrated that delapril decreased systolic and diastolic arterial pressure at most of the measurement points. The arterial pressure reductions during daytime and nighttime were not significantly different, that is, there was no excessive reduction in nighttime arterial pressure. Heart rate and its variability were virtually unaffected by the delapril treatment in either monitoring study. No adverse reactions were observed in the indirect or direct monitoring studies. Thus, it is concluded that twice-a-day administration of delapril at daily doses of 30 to 90 mg brings about a safe and stable antihypertensive effect, without affecting the diurnal variation of arterial pressure.

Enhanced inhibitory effect of alpha 2-adrenoceptor stimulation on the formation of cAMP in glomeruli of spontaneously hypertensive rats.

Renal alpha 2-adrenoceptors are known to be increased in spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto rats (WKY). To investigate whether this difference affects the second messenger system, we examined the effect of alpha 2-adrenoceptor stimulation on the formation of cAMP in microdissected glomeruli and proximal convoluted tubules obtained from the kidneys of SHR and WKY. The formation of glomerular cAMP, which was stimulated by parathyroid hormone (PTH), was inhibited by alpha 2-adrenoceptor stimulation. In contrast, the inhibitory effect of alpha 2-adrenoceptor stimulation on PTH-induced cAMP formation in proximal convoluted tubules was not significantly different between SHR and WKY. These results confirm the inhibitory action of alpha 2-adrenoceptors on the formation of cAMP in glomeruli and proximal tubules and suggest that the greater inhibitory effect on glomerular cAMP formation in SHR may reflect an increase in alpha 2-adrenoceptor density in SHR kidneys.

Trandolaprilat, an angiotensin-converting enzyme inhibitor, is not excreted in bile via an ATP-dependent active transporter (cMOAT).

Trandolapril is the prodrug of an angiotensin-converting enzyme (ACE) inhibitor. It has been proposed that its active metabolite, trandolaprilat, is mainly excreted in bile, but this has not been clearly demonstrated. Recently it has been reported that temocaprilat, an active metabolite of the ACE inhibitor temocapril, is effectively excreted in bile via an ATP-dependent active transporter (canalicular multispecific organic anion transporter: cMOAT). To investigate whether trandolaprilat has the pharmacological ability to affect the cMOAT system in a manner similar to temocaprilat. The lipophilicity of trandolaprilat and temocaprilat was measured to determine the n-octanol-water partition coefficients. The dose-dependent inhibition of the up-take of [3H]-estradiol-17beta-D-glucuronide and [3H]-2,4-dinitrophenyl-S-glutathione, which are good substrates for cMOAT, in canalicular membrane vesicles (CMVs) prepared from Sprague-Dawley rats was determined in the presence of trandolaprilat and temocaprilat. The partition coefficient of trandolaprilat (log Po/w - 1.1) was about 30 times higher than that of temocaprilat (log Po/w - 2.5). The uptake of [3H]-estradiol-17beta-D-glucuronide and [3H]-2,4-dinitrophenyl-S-glutathione was dose-dependently inhibited by the presence of temocaprilat, but trandolaprilat had no effect on the transport of [3H]-estradiol-17beta-D-glucuronide or [3H]-2,4-dinitrophenyl-S-glutathione into CMVs even at concentrations as high as 200 microM. It could be concluded that trandolaprilat has a higher lipophilicity than temocaprilat. But the hepatobiliary excretion system via cMOAT may not contribute to the excretion of trandolaprilat in bile.

Cough-challenge trial with a new angiotensin-converting enzyme inhibitor, imidapril.

This study was conducted to examine whether imidaprilat, an active diacid of the angiotensin-converting enzyme (ACE) inhibitor imidapril, preferentially inhibits angiotensin I degradation rather than bradykinin degradation, and whether imidapril is less active than other ACE inhibitors in inducing cough in patients with hypertension. The effect of imidaprilat on the inhibition of pressor response to angiotensin I and augmentation of depressor response to bradykinin was compared with that of enalaprilat and captopril in anesthetized rats. To determine the incidence of cough associated with imidapril, patients with a history of ACE inhibitor-induced dry cough were enrolled in a randomized, open-labeled, crossover trial with two 6-week periods to be treated with imidapril or amlodipine, a calcium-channel blocker. The recurrence of cough was assessed during both treatments. In the animal study, there were no significant differences in the ratio of inhibition of pressor response to angiotensin I and the augmentation of depressor response to bradykinin among the ACE inhibitors. In the cough-challenge trial, a total of 60 patients with hypertension were enrolled in the study. Cough and cough related symptoms recurred in 98.3% of the patients (59/ 60) during imidapril therapy. In contrast, only two patients reported cough during treatment with amlodipine. These results indicate that imidapril has no selectivity in inhibiting angiotensin I- and bradykinin-degradation in rats, and that clinically it is not different from other ACE inhibitors in inducing cough in patients with hypertension.

Identification of an alpha 2-adrenoceptor in human coronary arteries by radioligand binding assay.

A single high affinity binding site for an alpha 2-adrenoceptor in human coronary arteries was identified by radioligand binding assay. Human coronary arteries were obtained at autopsy within 6 hours of death. A crude membrane solution was incubated with (3H)-rauwolscine at 25 degrees C for 30 min. The binding of (3H)-rauwolscine was rapidly saturable and reversible. Kd was 1.2 +/- 0.2 (SE) nM and Bmax 22 +/- 3 fmol/mg protein. This is the first study which has shown the presence of an alpha 2-adrenoceptor in human coronary arteries using a radioligand binding assay method.

Measurement of plasma active renin by solid phase radioimmunoassay using monoclonal antibodies.

A direct radioimmunoassay (RIA) for plasma active renin concentration (ARC) was evaluated by using plasma samples obtained from hospitalized normal volunteers and hypertensive patients. The direct renin RIA was performed by using a pair of anti-renin monoclonal antibodies and a sandwich method. It is suggested that an agitator should be used during the incubation, because the magnetic solid phase was precipitated and could not be suspended well in plasmas. Further, the thawed reagents should not be used for the assay. A highly significant correlation (r = 0.96, p less than 0.01) was found between ARC and enzymatic activity of renin (PRA) in plasma samples obtained from hypertensive patients. The mean values of ARC were 22.8 +/- 3.6 pg/ml in normal subjects, 22.5 +/- 5.3 in patients with EH having medium levels of PRA, 113.7 +/- 11.7 in patients with renovascular hypertension, and undetectable in patients with primary aldosteronism. The results indicated good and reliable performance of the direct renin RIA, which is clinically useful to investigate the renin-angiotensin system.

Measurement of plasma total renin by the anti-human renin monoclonal antibodies.

The authors evaluated the assay performances and clinical usefulness of a newly developed solid phase radioimmunoassay (RIA) for total renin concentration (TRC) in human plasma. The direct total renin RIA was performed by a sandwich technique with a pair of anti-human renin monoclonal antibodies. Renin activation with trypsin did not change TRC. The RIA showed satisfactory assay performances and demonstrated full compatibility with a direct RIA-kit for active renin concentration (ARC) in human plasma. The values of TRC were 105.3 +/- 8.6 pg/mL in normal subjects and 136.5 +/- 14.6 pg/mL in patients with essential hypertension. The values of TRC and the ratios of ARC to TRC were high in patients with renovascular hypertension and were low in patients with primary aldosteronism. Although the TRC value in diabetic patients was 134.4 +/- 14.8 pg/mL, the ratio of ARC to TRC was low. The RIA procedure was simple since prior purification or activation of renin was not required. These results suggest that the total renin RIA and its combined use with the active renin RIA may be helpful in understanding the renin-angiotensin system in human plasma.

Clinical implications of cardiac (123)I-meta-iodobenzylguanidine scintigraphy and cardiac natriuretic peptides in patients with heart disease.

The purpose of this study was to evaluate whether or not cardiac sympathetic nerve activity, using (123)I-meta-iodobenzylguanidine ((123)I-MIBG) imaging, and cardiac natriuretic peptides (atrial and brain, ANP and BNP) were independent predictors of cardiac events, and, if so, which was the stronger predictor. Planar (123)I-MIBG images were obtained from 62 patients with heart disease. Plasma ANP and BNP levels, left ventricular ejection fraction (LVEF) by echocardiography, serum total cholesterol and triglyceride were measured. (123)I-MIBG was assessed as the heart-to-mediastinum (H/M) ratio of the delayed image and the washout rate (WoR) from the early to the delayed image. Patients were followed up for an average of 16.2 months, and 12 of 62 patients had cardiac events. Patients with events had significantly lower LVEF and H/M ratio compared with those without events. They had significantly higher WoR, ANP and BNP. By multivariate Cox proportional hazard analysis, (123)I-MIBG (H/M or WoR), ANP and BNP were independent predictors for cardiac events. Event-free survival using a Kaplan-Meier model, with a threshold value of 2.0 for H/M and 45% for WoR, showed that patients with H/M<2.0 and/or WoR>45% had a significantly poorer prognosis. These results suggest that (123)I-MIBG imaging and cardiac natriuretic peptides are useful tools for the evaluation of patients with heart disease, and that cardiac sympathetic nerve activity is a stronger predictor of cardiac events.

Complicated central effects of endothelin on blood pressure in rats.

The role of endothelin (ENT) in the control of systemic blood pressure (BP) was examined in conscious rats. Intracerebroventricular (i.c.v.) administration of ENT (0.002 or 0.2 micrograms, i.e., 0.78 or 78 pmol/2 microliters 0.9% saline) to conscious rats had complicated effects on BP. A significant fall in BP occurred in the initial 2-4 min after administration; and then after recovery toward the control level, BP decreased again within 17 min, following which a constant rise in BP occurred. In addition to the changes in BP, 3 of 9 rats which received 0.2 micrograms lapsed into severe barrel rotation-like behavior only to die 6-8 min after i.c.v. injection. It was therefore assumed that ENT had central effects on BP regulation and motor activity.

[Adrenal tumors associated with renal cell carcinoma].

We experienced two cases with renal cell carcinoma who showed enlargement of the contralateral adrenal gland. In case 1, the enlarged adrenal gland was a non-functioning adrenal adenoma, and in case 2, it was a metastatic adrenal tumor. Non-functioning adrenal adenomas are benign tumors of the adrenal cortex often found incidentally at autopsy or on computed tomography (CT) studies of the upper abdomen. Adrenal adenomas have been reported to occur in 9.5-14% of patients with renal cell carcinoma, while the incidence being 1.5-8.7% in the general population. Since metastases of renal cell carcinoma to the adrenal glands are not uncommon, it is important to distinguish between non-functioning adrenal adenomas and metastatic tumors. Therefore, we studied the incidence of adrenal tumors (including metastatic tumors and benign tumors) in patients with renal cell carcinoma who underwent the abdominal CT study in our hospital. From 1982 to 1989, CT had been performed in 67 patients with renal cell carcinoma. Six adrenal masses were identified with CT in these patients. Three out of the 6 patients probably had metastatic tumors and one of the 3 adrenal masses was pathologically diagnosed as metastatic tumor. The other three masses were benign on pathology and only one of them was pathologically diagnosed as non-functioning adrenal adenoma. The incidence of adrenal adenomas on the CT study was lower than that of previous studies based on autopsy. The reasons of this difference in results between their studies and ours are not clear.(ABSTRACT TRUNCATED AT 250 WORDS)