Mitsuhiro Tominaga

Decreased endothelium-dependent hyperpolarization to acetylcholine in smooth muscle of the mesenteric artery of spontaneously hypertensive rats.

The endothelium-dependent vascular relaxation to acetylcholine (ACh) in spontaneously hypertensive rats (SHR) may be impaired because of an imbalance of endothelium-derived relaxing factor and contracting factor. However, the role of the endothelium-dependent hyperpolarization remains undetermined. We examined the ACh-induced hyperpolarization and its contribution to relaxation in arteries of SHR. Membrane potentials were recorded from the mesenteric artery trunk of 6-8-month-old male SHR and also Wistar-Kyoto (WKY) rats. Endothelium-dependent hyperpolarization to ACh was unaffected by NG-nitro-L-arginine, indomethacin, or glibenclamide; was reduced by tetraethylammonium or high K+ solution; and was enhanced by low K+ solution or methylene blue, thereby indicating that hyperpolarization is not mediated by nitric oxide (endothelium-derived relaxing factor) but is presumably mediated by a hyperpolarizing factor and is due to an opening of K+ channels that probably differ from the ATP-sensitive ones. Hyperpolarizations to ACh were markedly reduced in SHR compared with findings in WKY rats (maximum, 8 +/- 1 versus 17 +/- 1 mV). In addition, under conditions of depolarization with norepinephrine (10(-5) M), the ACh-induced hyperpolarization was even less and transient in SHR, while it was large and sustained in WKY rats (6 +/- 1 versus 29 +/- 2 mV). Endothelium-dependent relaxations to ACh in arterial rings precontracted with 10(-5) M norepinephrine were far less in SHR than in WKY rats, even in the presence of indomethacin. Furthermore, high K+ solution showed smaller inhibitory effects on the relaxations in SHR than in WKY rats. Endothelium-independent hyperpolarizations and relaxations to cromakalim, a K+ channel opener, were similar between SHR and WKY rats. It would thus appear that the endothelium-dependent hyperpolarization to ACh is reduced in SHR and this would, in part, account for the impaired relaxation to ACh in SHR mesenteric arteries.

Central effect of endothelin on neurohormonal responses in conscious rabbits

It has been shown that endothelin-1 (ET-1) binding sites exist in the central nervous system and that the injection of intracerebroventricular ET-1 induces a pressor response. Therefore, we determined the neurohormonal and cardiovascular responses to intracerebroventricular ET-1 (25 pmol/kg) in conscious rabbits with chronically instrumented electrodes on the renal sympathetic nerve. Intracerebroventricular ET-1 provoked a prompt increase in arterial pressure and in renal sympathetic nerve activity within 5 minutes, and peak values were obtained at 20 and 40 minutes, respectively. Plasma epinephrine and norepinephrine reached peak values at 5-20 minutes. Plasma vasopressin and plasma glucose levels also increased significantly, but plasma osmolality, hematocrit, and serum sodium and potassium concentrations did not show any changes. Arterial blood gas analysis showed respiratory alkalosis. However, pretreatment with intravenous pentolinium (5 mg/kg), a ganglion blocking agent, abolished these neurohormonal and cardiovascular responses. Conversely, the same dose of intravenous ET-1 (25 pmol/kg) as that used in the intracerebroventricular experiment failed to cause any cardiovascular or renal sympathetic nerve responses. These results suggest that intracerebroventricular ET-1 acts in the central nervous system and causes a pressor response mainly through the enhancement of sympathoadrenal outflow.

Hypertension and ageing impair acetylcholine-induced vasodilation in rats.

Objective To investigate the influence of hypertension and ageing on the in vivo effect of acetylcholine on blood pressure and regional vascular conductance and the inhibitory effect of NG-monomethyl-L-arginine (L-NMMA), an inhibitor of nitric oxide synthesis, on the effects of acetylcholine. Methods Male spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats aged 3–4, 7–8 and 20–26 months, were anaesthetized with pentobarbital. After sino-aortic denervation, regional blood flow in the left common carotid, superior mesenteric, right renal and right femoral arteries was measured with pulsed Doppler flowmeters. After pretreatment with indomethacin (2 mg/kg intravenously), bolus injections of acetylcholine (0.03, 0.1 and 0.3 μg/kg intravenously) were given with or without L-NMMA (20 mg/kg intravenously). Results Dose-dependent hypotensive responses to acetylcholine were significantly smaller in SHR than in WKY rats in each age group. Ageing reduced the hypotensive effect of acetylcholine in both SHR and WKY rats. In rats aged 3–4 and 7–8 months acetylcholine-induced increases in regional vascular conductances were significantly smaller in SHR than in WKY rats. Ageing reduced acetylcholine-induced increases in regional vascular conductances in WKY rats. L-NMMA had little effect on the responses to acetylcholine in both SHR and WKY rats. Sodium nitroprusside had similar effects in SHR and WKY rats and in age groups within each strain. Conclusion The in vivo vasodilatory action of acetylcholine, which appeared to be partly independent of nitric oxide, was impaired by hypertension and age.

Long-Term Compliance with Salt Restriction in Japanese Hypertensive Patients

The purpose of the present study was to investigate the long-term compliance with salt restriction in Japanese hypertensive patients. Subjects included 389 patients, 230 women and 159 men, mean age 58±11 years, who underwent successful 24-h home urine collection more than three times over an interval of a year. Urinary salt, potassium, and creatinine were measured. Additionally, family history, habitual alcohol intake, smoking habit, physical activities, and job status were assessed by use of a questionnaire. During the follow-up period (average 3.5 years), participants underwent urine collection 4.6 times in average. Urinary salt excretion at the last visit was significantly lower than that at the first visit (8.7±3.4 vs. 9.6±4.1 g/day; p<0.01). Urinary potassium excretion also decreased significantly during this period (from 2.0±0.7 to 1.9±0.7 g/day; p<0.05). Among the mean 4.6 urine collections, 45.2% (men 34.6%, women 52.6%) of the patients successfully achieved <6 g (100 mmol of sodium)/day of salt excretion on at least one occasion. The rate of achievement of averaged urinary salt excretion <6 g/day dropped to 10.3% (men 4.4%, women 14.3%). Only 2.3% (men 0.6%, women 3.5%) of the patients achieved <6 g/day on all occasions. There were no significant differences in age, habitual alcohol intake, smoking habit, physical activities, or job status between patients who complied with the salt-restricted diet and those who did not. Results suggest that long-term compliance with salt restriction is poor in Japanese hypertensive patients. Since no specifically defining characteristics were found in the compliant patients, repeated measurements of urinary salt excretion seem to be important to encourage salt restriction.

Ambulatory Blood Pressure Monitoring in Patients with Essential Hypertension Treated with a New Calcium Antagonist, Cilnidipine

Cilnidipine (FRC-8653), a new dihydropyridine calcium antagonist, was given to 14 hospitalized patients with essential hypertension, and 24-hour ambulatory blood pressure (BP) monitoring was performed. Once-daily administration of cilnidipine (5–20 mg) for 1–3 weeks decreased the 24-hour average BP significantly from 149 ± 4/88 ± 2 mmHg to 141 ± 3/82 ± 2 mmHg without any change in the pulse rate. The decrease in ambulatory BP by cilnidipine was evident during the daytime (156 ± 4/93 ± 2 mmHg to 143 ± 5/84 ± 2 mmHg, p > 0.01 for systolic BP and p > 0.01 for diastolic BP), while it was mild during nighttime (141 ± 4/80 ± 2 mmHg to 133 ± 4/76 ± 3 mmHg, p > 0.05 for systolic and ns for diastolic BP). The decrease in the ambulatory BP over the whole day and during the nighttime was significantly correlated with the basal ambulatory BP levels. When the subjects were divided into the high ambulatory BP (n = 7) and low ambulatory BP (n = 7) groups, the BP reduction by cilnidipine was evident throughout 24 hours in the high ambulatory BP group, while it was mild and significant only during daytime in the low ambulatory BP group. In summary, once-daily cilnidipine exerts a sufficient and prolonged reduction of BP without an increase in the pulse rate in patients with hypertension. The potency of cilnidipine to decrease ambulatory BP may depend on the basal ambulatory BP level. Cilnidipine is thus a useful antihypertensive drug that may not cause an excessive decrease in BP or a reflex tachycardia.

Antiproteinuric effect of an N-type calcium channel blocker, cilnidipine

The objective of the present study was to determine antiproteinuric effect of an N-type calcium channel blocker—cilnidipine. Subjects were 43 essential or renal hypertensive subjects who had been taking calcium channel blockers other than cilnidipine for at least 6 months. All patients had proteinuria greater than 0.2 g/day in spite of fair blood pressure control (< 150/90 mmHg). Calcium channel blockers in 25 patients (62 ± 3 years) were switched to cilnidipine (cilnidipine group), whereas other 18 patients (58 ± 3 years) continued to take originally prescribed calcium channel blockers (control group). The 24-hr urine collections were done at baseline and after 6 months of the follow-up period. Baseline characteristics including age, blood pressure levels, body mass index and creatinine clearance were similar between cilnidipine and control groups. Urinary protein excretion also was comparable between cilnidipine (0.61 ± 0.10 g/day) and control (0.86 ± 0.17 g/day) groups. Urinary protein significantly decreased after 6 months in cilnidipine group (− 0.21 ± 0.11 g/day, − 36%, p < 0.01), whereas it did not change in control group (+ 0.01 ± 0.15 g/day, 0.4%, ns). There were no significant changes in blood pressure, serum creatinine, creatinine clearance, estimated protein intake, and urinary salt excretion during the follow-up period in either group. The reduction of urinary protein by cilnidipine was evident in essential hypertensives (− 54 ± 9%, n = 18, p < 0.01) but not in renal hypertensives (+ 10 ± 35%, n = 7, ns). Results suggest that cilnidipine has an antiproteinuric effect especially in patients with essential hypertension.

Association between hyperinsulinemia and intima-media thickness of the carotid artery in normotensive men.

Objectives To determine whether hyperinsulinemia is associated with early atherosclerosis in normotensive men of a work site population. Design and methods Six hundred and seventeen subjects were screened from 8678 male transport workers for the further examination of cardiovascular disease and diabetes. Subjects aged less than 40 years, those with hypertension or diabetes, or both, and those being administered medications for hyperlipidemia were excluded. Finally, 164 normotensive, nondiabetic subjects were enroled. The intima-media thickness (IMT) was measured by B-mode ultrasonography with a 7.5 MHz probe. Electrocardiography, a 75 g oral glucose-tolerance test (OGTT) and blood chemistry measurements were also performed. The sum of insulin values (ΣIRI) and the ratio of the sum of insulin values to blood glucose levels (ΣIRI/ΣBG) in the 75 g OGTT were used as markers of hyperinsulinemia. Results The mean age of the subjects was 52 ± 5 years (mean ± SD). In a univariate analysis, IMT was associated with age, systolic blood pressure, body mass index, ΣIRI, and ΣIRI/ΣBG. Multivariate analysis showed that age, total cholesterol, and SIRI (or ΣIRI/ΣBG) were independent risk factors for IMT. Conclusions These results suggest that, in addition to age and total cholesterol, hyperinsulinemia as assessed by an OGTT is associated with early atherosclerosis in normotensive, nondiabetic men of a work site population.

Disparate circadian variations of blood pressure and body temperature in bedridden elderly patients with cerebral atrophy

Twenty bedridden elderly patients with normal sleep-wake cycles were studied to evaluate the circadian variations of blood pressure, pulse rate, body core temperature, cortisol, and catecholamines with a focus on their relation to cerebral atrophy. Twenty-four-hour blood pressure (BP) and pulse rate monitorings were done with simultaneous measurement of urinary bladder temperature. Urine was also collected every 4 h to measure 17-hydroxycorticosterone and catecholamines. Based on the brain CT, frontal horn index (FHI: maximal distance between bilateral frontal horns/the corresponding width of the skull) was calculated as an index of cerebral atrophy. Analysis by the cosinor method revealed that the significant circadian rhythm with nocturnal decline was observed in only 9 patients (45%) for BP and in 13 patients (65%) for pulse rate. In contrast, 19 of 20 patients (95%) showed significant circadian rhythms of bladder temperature, with the nadirs appearing between 00:06 and 06:54. In the subgroup of mild cerebral atrophy (FHI < 0.30, n = 11), BP and pulse rate fell modestly but significantly during nighttime, whereas they did not fall in the subgroup of moderate to severe cerebral atrophy (FHI > or = 0.30, n = 9). The possibility could not be excluded that the sleep disturbance might result in the relatively high BP during nighttime. Bladder temperature, 17-hydroxycorticosteroids, and catecholamines showed significant nocturnal falls in both groups. In conclusion, nocturnal fall of BP disappeared in the bedridden elderly patients with cerebral atrophy, which cannot be explained by the change in the circadian variation of the sympathetic nervous system, cortisol, or body core temperature.

Impact of antihypertensive medication adherence on blood pressure control in hypertension: the COMFORT study

BACKGROUND It has not been fully elucidated whether antihypertensive medication adherence affects blood pressure (BP) control in hypertension cases. AIM To investigate the association of adherence to antihypertensive drug regimens and BP control using data from the Combination Pill of Losartan Potassium and Hydrochlorothiazide for Improvement of Medication Compliance Trial (COMFORT) study. DESIGN An observational analysis from a randomized controlled trial. METHODS A total of 203 hypertensive subjects were randomly assigned to a daily regimen of a combination pill (losartan 50 mg/hydrochlorothiazide 12.5 mg) or two pills, an angiotensin II receptor blocker and a thiazide diuretic. Medication adherence calculated based on pill counts and BPs was evaluated at 1, 3 and 6 months after randomization. RESULTS The subjects were divided into three groups according to their adherence, i.e. relatively low-adherence (<90%; n = 19), moderate-adherence (90-99%; n = 71) and high-adherence (100%; n = 113) groups. Clinical characteristics of the subjects including BP, sex, randomized treatments and past medical history did not differ significantly among the three groups. Achieved follow-up BPs over the 6-month treatment period, which were adjusted for age, sex, baseline BP and randomized treatment, were significantly higher in the low-adherence group (135/78 mmHg) compared with the high-adherence (130/74 mmHg; P = 0.02/0.02) and the moderate-adherence (128/74 mmHg; P = 0.003/0.02) groups. CONCLUSION Low adherence to an antihypertensive-drug regimen was associated with poor BP control.

Differential modulation by mu- and delta-opioids on baroreceptor reflex in conscious rabbits.

We examined the role of central mu- and delta-opioids on both neurohormonal responses and baroreceptor reflex in conscious rabbits. Both intracerebroventricular [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin, a mu-selective agonist, and [D-Ala2,D-Leu5]-enkephalin, a delta-selective agonist, caused dose-related increases in arterial pressure and renal sympathetic nerve activity, whereas intravenous injection of the same maximum dose of these peptides as that used in the intracerebroventricular experiment did not cause any cardiovascular and neuronal responses. On the other hand, increases in plasma epinephrine, norepinephrine, and glucose levels induced by intracerebroventricular [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin were significantly greater than those by [D-Ala2,D-Leu5]-enkephalin. Both enkephalins did not cause any responses in plasma renin activity, plasma vasopressin, and serum sodium and potassium concentrations. The sensitivity of the baroreceptor reflex control of renal sympathetic nerve activity using a logistic model was enhanced by a subpressor dose of intracerebroventricular [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (10 pmol/kg) but not by [D-Ala2,D-Leu5]-enkephalin. Conversely, a mu-selective dose of intravenous naloxone (0.1 mg/kg) attenuated baroreceptor reflex sensitivity. Intravenous naloxone methobromide, which has been shown not to cross the blood-brain barrier, did not change baroreceptor reflex sensitivity, suggesting that naloxone acts at the central nervous system. In conclusion, in conscious rabbits, 1) intracerebroventricular mu- and delta-receptor agonists caused pressor responses and 2) mu-opioid agonist altered baroreceptor reflex control of renal sympathetic nerve activity and produced changes in sympathoadrenal responses.