Hirotaka Fujita

Effect of morning and bedtime dosing with cilnidipine on blood pressure, heart rate, and sympathetic nervous activity in essential hypertensive patients

Cilnidipine has a blocking action against N-type calcium channels as well as L-type calcium channels. We studied the effect of morning and bedtime dosing on circadian variation of blood pressure (BP), heart rate (HR), and activity of the autonomic nervous system, using an open randomized crossover study in 13 essential hypertensive patients. An automated device allowed 24-hour monitoring of ambulatory BP and HR and the power spectrum of the R-R interval, at the observation period, the morning dosing regimen, and the bedtime dosing regimen. Morning dosing and bedtime dosing with cilnidipine reduced the average systolic BP over 24 hours, during daytime, and during nighttime. The average HR and the average LF/HF ratio over 24 hours, during daytime, and during nighttime, were similar for the three periods. Both morning and bedtime dosing reduced the maximum systolic BP in the early morning and suppressed the morning rise of BP, which were accompanied by partial inhibition of the increase in LF/HF ratio. Our results show that cilnidipine administered once daily is an efficient antihypertensive drug regardless of the time of dosing, without reflex tachycardia and increase in sympathetic nervous activity, and with partial inhibition of the morning activation of the sympathetic nervous system.

Different Effects on Inhibition of Cardiac Hypertrophy in Spontaneously Hypertensive Rats by Monotherapy and Combination Therapy of Adrenergic Receptor Antagonists and/or the Angiotensin II Type 1 Receptor Blocker under Comparable Blood Pressure Reduction

To confirm that α1, β adrenoceptor antagonists and angiotensin II type 1 receptor blockers (ARBs) have different abilities to attenuate progressive cardiac hypertrophy despite their comparable lowering of blood pressure, we compared the effect of these agents alone or in combination on hypertensive cardiac hypertrophy. Eight-week-old spontaneously hypertensive rats (SHR) were divided into 7 groups. Single administration of doxazosin, atenolol, or losartan, or half-dose combinations of these drugs were given orally for 6 weeks. The control group did not receive any drugs. The heart weight-to-body weight ratio (HW/BW), left ventricular mass index (LVMI), plasma brain natriuretic peptide (BNP) and left ventricular BNP mRNA expression were measured after 6-week administration. Blood pressure did not differ among the drug-treated groups, all of which showed lower blood pressure than the control group. The HW/BW and LVMI of the drug-treated groups, except the doxazosin group, were lower than in the control group. Moreover, the LVMI values of the groups receiving losartan were significantly lower than those in the groups without losartan (p<0.05). Plasma BNP of the drug-treated groups was lower than that in the control group (p<0.05). The left ventricular BNP mRNA expression of the drug-treated groups, except the doxazosin group, was lower than that in the control group. The atenolol group showed a higher level of BNP mRNA than the groups receiving losartan monotherapy or combination therapies (p<0.05). In conclusion, the ARB had the strongest attenuating effect on the development of hypertensive cardiac hypertrophy, and the α1 and β adrenergic receptor blockers were more effective in combination than as monotherapies in SHR.

Oxidative stress in the Dahl salt-sensitive hypertensive rat.

Oxidative stress has been proposed as important in the pathogenesis of hypertension. Measurement of 8-iso prostaglandin F2α(8-ISO) is introduced for evaluating oxidative stress in vivo. 8-ISO is the major urinary metabolite of F2-isoprostanes and is formed nonenzymatically from the attack of superoxide radicals on arachidonic acid. We examined the oxidative stress level in the Dahl salt-sensitive (Dahl-S) rats and the Dahl salt-resistant (Dahl-R) rats. Dahl-S and Dahl-R rats were fed either a high salt diet (8% NaCl; HS) or low salt diet (0.3% NaCl; LS) for 3 weeks, and systolic blood pressure (SBP) and 24-hr urinary excretion of 8-ISO (U-8-ISO) were measured. In Dahl-S rats, the high salt diet induced hypertension (139 ± 3 mmHg in LS versus 186 ± 2 mmHg in HS, p < .05) and significantly increased the U-8-ISO (24.9 ± 3.6 ng/24 hr in LS versus 63.2 ± 14.6 ng/24 hr in HS, p < .05). No significant difference in blood pressure or U-8-ISO was observed between high-salt and low-salt treated Dahl-R rats. U-8-ISO concentration was correlated with SBP in all four experimental groups (r = 0.866). Moreover, urinary 8-hydroxy-2′-deoxyguanosine (U-8-OHdG), which is one of the most commonly used markers for evaluation of oxidative stress, was higher in Dahl-S-8% rats than in Dahl-S-0.3% rats (136.1 ± 48.4 ng/24 hr in LS versus 322.8 ± 46.7 ng/24 hr in HS, p < .05), and U-8-OHdG was correlated with SBP (r = 0.681) in Dahl-S rats. These results suggest oxygen radicals are involved in the pathogenesis of hypertension.

Ultrastructural studies on the phenotypic modulation of human intimal smooth muscle cells

The present study was carried out to clarify the mechanism of intimal thickening at the ostia of celiac and superior mesenteric arteries. The cell components involved in the process were analyzed under electron microscope. Autopsy samples from cases without significant atherosclerotic diseases were examined and the percentages of smooth muscle cells in either synthetic or contractile state, macrophages, and foam cells in the intima of mesenteric and celiac arteries were calculated. Smooth muscle cells in the synthetic state were predominant in the proximal region and those in the contractile state were predominant in the distal region. Few macrophages were present in both regions. The intima in the proximal and distal regions of celiac arteries in autopsy samples was further divided into three layers and the percentages of various smooth muscle cell phenotypes in each layer were calculated and compared in patients at different ages. In the proximal region, the phenotype of the smooth muscle cells changed from the synthetic to the contractile state from the deeper to the superficial layers with the advance of age. In the distal region, the contractile state was dominant regardless of the age. These results suggest that the phenotypic modulation of human intimal smooth muscle cells is reversible dedifferentiation-redifferentiation process; this phenomenon plays an important role in the initiation of atherosclerosis.

Lipoxygenase inhibition decreases neointimal formation following vascular injury.

Our aim was to assess the potential role of lipoxygenase (LO) products in neointimal formation following vascular injury. We investigated the effect of LO pathway inhibition, by phenidone, on the concentration of 12- and 5-hydroxyeicosatetraenoic acid (12- and 5-HETE) in rat whole blood and in aortic tissue. We also examined the effect of phenidone on myoneointimal formation in balloon-injured rat carotid arteries. Phenidone significantly decreases the concentration of HETEs in aortic tissue, and decreases neointimal size even though there is no difference in the BrdU index. These data indicate that the LO product participates in developing neointima following balloon-induced vascular injury, and that the LO blocker phenidone decreases neointimal size possibly by suppressing migration of smooth muscle cells.

Cardiac Rupture Complicating Hemorrhagic Infarction after Intracoronary Thrombolysis

An 80‐year‐old woman with acute myocardial infarct intracoronary thrombolysis by a large dose of urokinase four hours after the onset of chest pain. Despite the patient having no chest pain after intracoronary thrombolysis and her general condition being stable, she died suddenly on the 4th hospital day. Autopsy revealed hemopericardium due to cardiac rupture, which occurred at the center of the transmural hemorrhagic infarction of the anteroseptal wall. The massive hemorrhagic infarction was promoted by reperfusion from thrombolytic therapy. She had also classic risk factors for cardiac rupture, such as hypertension, senility, female gender, and first acute myocardial infarct. Therefore, the present case demonstrated that hemorrhagic infarction increased the incidence of cardiac rupture.

Renoprotective effect and cost-effectiveness of using benidipine, a calcium channel blocker, to lower the dose of angiotensin receptor blocker in hypertensive patients with albumiuria

In hypertensive patients with chronic renal disease, angiotensin receptor blockers (ARBs) are among the first-line drugs, and calcium channel blockers (CCBs) are recommended as a second line. We examined the effects of two therapeutic strategies using ARBs and benidipine, a CCB, on blood pressure (BP), urinary albumin excretion (UAE), and cost-effectiveness in hypertensive patients with albuminuria. Patients whose BP was 140/90 mmHg or higher despite treatment with low- or medium-dose ARBs were assigned randomly to two groups. In Group A (n=14), the ARB dose was maximized and then benidipine was added until BP targets were reached (<130/85 mmHg). In Group B (n=18), benidipine was administered first and then the ARB dose was increased until BP targets were reached. The BP targets were achieved by ARB alone in 36% of Group A patients and by the addition of benidipine in 83% of Group B patients. Finally, BP decreased in each group, reaching the targets in 93% of Group A patients and 94% of Group B patients after a 4-month therapeutic period. UAE was decreased in both groups after a 4-month therapeutic period compared to the allocation period (−33±6% in Group A, −31±6% in Group B; p<0.001, respectively). The monthly drug cost was higher (11,426±880 vs. 8,955±410 yen, p=0.012) and the cost-effectiveness of antihypertensive treatment was lower (p=0.003) in Group A than in Group B. We conclude that the addition of benidipine to low- or medium-dose ARB is, in light of the renal protection and the cost-effectiveness of this approach, a useful therapeutic strategy for controlling BP in hypertensive patients with albuminuria.

Amlodipine suppressed cardiac gene expression of brain natriuretic peptide, transforming growth factor-β1 and fibronectin mediated by aldosterone in male stroke-prone spontaneously hypertensive rats

Objectives  Amlodipine, a calcium channel blocker (CCB), is one of the most common antihypertensive medicines in Japan. We evaluated whether the calcium channel blocker confers cardiac protection through the renin–angiotensin–aldosterone system in male stroke‐prone spontaneously hypertensive rats (SHR‐SP).