Sadayoshi Komori

Administration-time-dependent effects of diltiazem on the 24-hour blood pressure profile of essential hypertension patients

The aim of this study was to identify differences in the patterns of efficacy and duration of effect by diltiazem given in different dosage forms and schedules. Blood pressure (BP) and heart rate (HR) were monitored before and after treatment by ambulatory blood pressure monitoring for 48 h every 30 min. Patients were divided for treatment assignment into 4 groups -nocturnal BP dippers and nondippers. In dipper hypertension, diltiazem-retard at 08:00 (n = 7) had the most marked antihypertensive effects during nighttime rest (SBP; 136 +/- 14/118 +/- 9 mmHg, p < 0.01 before vs. after treatment). Diltiazem-retard at 19:00 (n = 6) exerted greatest effect during daytime activity (152 +/- 7/139 +/- 6, p < 0.01) with inhibition of the morning BP rise. Diltiazem (t.i.d., n = 5) had the best effect during daytime activity (151 +/- 16/136 +/- 9, p < 0.05). However, in nondipper hypertensive patients, diltiazem (t.i.d., n = 8) had the most pronounced antihypertensive effects during nightly rest (144 +/- 12/127 +/- 12, p < 0.05). Evening medication with diltiazem retard appears to be more efficacious than the other dosage schedules.

QT Dispersion in Dipper- and Nondipper-Type Hypertension

The aim of this study was to identify the relationship of QT dispersion on 12-lead electrocardiograms and left ventricular mass index on echocardiograms associated with the circadian rhythm of blood pressure (BP). Heart rate and BP were monitored every 30 min for 48 h in 62 patients with essential hypertension using an ambulatory BP monitoring device. The patients were divided into four groups according to gender and circadian BP pattern (nocturnal BP dipper or nondipper). The patients were classified as dippers if their daytime BP decreased by at least 10% during the night and all the other subjects were classified as nondippers. Age, body mass index, and 48-h mean BP were similar among the four groups. During the night-rest period, the systolic and diastolic BP were significantly decreased in dipper-type hypertensives. The maximum QTc interval and QTc dispersion were longer in nondippers than in dippers. Left ventricular mass index (LVMI) had a tendency to increase in nondippers. The nocturnal reduction of BP significantly correlated with QTc dispersion and LVMI. The QTc dispersion significantly correlated with LVMI and interventricular septum thickness.

Effect of imidapril in dipper and nondipper hypertensive patients: comparison between morning and evening administration.

The purpose of the study was to identify differences in the patterns of efficacy and duration of effects of imidapril administered at different times of the day (morning versus evening) in dipper and nondipper hypertensive patients. Twenty patients with untreated hypertension were classified into two groups: dippers (n = 9) and nondippers (n = 11). Imidapril (10 mg) was given at 07:00 or 18:00 for 4 weeks in a crossover fashion. Blood pressure (BP) and heart rate (HR) were monitored before and after morning and evening treatment every 30 min for 48h by ambulatory BP monitoring (ABPM). In dipper hypertension, the mean 48h BP was reduced with both doses. The decrease in the diurnal BP was stronger when the drug was administered in the evening than morning, but without significant difference. In nondipper hypertension, the systolic BP decreased at night with both doses, but the extent of the nocturnal reduction in systolic BP was greater after morning therapy. There were no significant differences in the decrease in BP during the day or night between the morning and evening administrations. When imidapril was administered in the morning, its serum concentration reached a maximum at 16:00, and when the drug was administered in the evening, it reached a maximum at 6:00. In dipper hypertension, the time taken for the blood concentration of imidapril to reach a maximum changed depending on its time of administration, and the time when the maximum antihypertensive effect of the drug appeared was different. In nondipper hypertension, decreases in the BP were confirmed at night regardless of the time of administration; this might be caused by angiotensin converting enzyme (ACE) inhibitors effectively blocking the BP from increasing by activating the parasympathetic nervous system. Therefore, when assessing the effectiveness of antihypertensive agents, factors such as the various patterns of BP before therapy and administration time must be considered. (Chronobiology International, 17(2), 209–219, 2000)

Coronary arterial involvement and QT dispersion in Kawasaki disease

For the early detection of myocardial ischemia in patients with severe involvement of the coronary arteries after Kawasaki disease, a method with high sensitivity and low cost is desirable because these patients require frequent follow-up and diagnostic tests. For this purpose, electrocardiographic, echocardiographic, Holter, and stress testing or angiography are repeated. However, these tests have some limitations due to cost, convenience, or sensitivity. It is uncertain that increased QT dispersion would exactly indicate progression of myocardial ischemia after Kawasaki disease, but this is the first study to present that QT dispersion of > or = 60 ms had higher sensitivity for detection of severe involvement of coronary artery after Kawasaki disease. This study is limited due to the small number of patients; larger prospective studies are required to clarify the usefulness of QT dispersion analysis in detecting the progression of myocardial ischemia after Kawasaki disease.

The Inhibitory Effects of Carvedilol Against Arrhythmias Induced by Coronary Reperfusion in Anesthetized Rats

Background: Previous study has shown the antiarrhythmic effects of carvedilol on isolated rat hearts, but little is known about the mechanism of this protective action. This article examines the inhibitory effect of carvedilol against arrhythmias induced by reperfusion in anesthetized rats. In addition, the results are compared with those with propranolol, super oxide dismutase (SOD) plus catalase, and a combination of both in order to elucidate the mechanism of the protective actions. Methods and Materials: Ninety percent of the rats in the control group showed lethal ventricular fibrillation (VF). Carvedilol at the doses of 0.03, 0.1, and 0.3 mg/kg significantly reduced the incidence of lethal VF to 0%, 0%, and 10%, respectively ( P < .05). In contrast, propranolol at the doses of 0.3, 1.0, and 3.0 mg/kg and SOD (35,000 units/kg) plus catalase (400,000 units/kg) did not reduce the incidence of lethal VF (80%, 60%, 70%, and 70%, respectively). However, administration of a combination of propranolol (1.0 mg/kg) and SOD plus catalase completely inhibited the occurrence of lethal VF to 0% ( P < .05). Conclusion: These results indicate that carvedilol has the inhibitory effect against reperfusion arrhythmias in rats and suggest that the mechanism of action of this compound is related to the combined effects of beta-blocking and antioxidant.

Protein kinase C is involved in cardioprotective effects of ischemic preconditioning on infarct size and ventricular arrhythmia in rats in vivo

Protein kinase C (PKC) has been known to play an important role in ischemic preconditioning (IP). This study was designed to examine whether the translocation of PKC is associated with the cardioprotective effects of IP in vivo on infarct size and ventricular arrhythmias in a rat model.Using anesthetized rats, heart rate, systolic blood pressure, infarct size and ventricular arrhythmias during 45 min of coronary occlusion were measured. PKC activity was assayed in both the cytosolic and cell membrane fraction . Brief 3-min periods of ischemia followed by 10 min of reperfusion were used to precondition the myocardium. Calphostin C was used to inhibit PKC.Infarct size was significantly reduced by IP (68.1 (2.5)%, mean (S.E.) vs. 45.2 (3.4)%, p < 0.01). The reduction in infarct size by IP was abolished by pretreatment with calphostin C. The total number of ventricular premature complex (VPC) during 45 min of coronary occlusion was reduced by IP (1474 (169) beats/45 min vs. 256 (82) beats/45 min, p < 0.05). The reduction the total number of VPC induced by IP was abolished by the administration of calphostin C before the episode of brief ischemia. The same tendency was observed in the duration of ventricular tachycardia and the incidence of ventricular fibrillation. PKC activity in the cell membrane fraction transiently increased immediately after IP (100 vs. 142%, p < 0.01) and returned to baseline 15 min after IP. Pretreatment with calphostin C prevented the translocation of PKC.The translocation of PKC plays an important role in the cardioprotective effect of IP on infarct size and ventricular arrhythmias in anesthetized rats.

What time is the "biologic zero hour" of circadian variability?

Most ambulatory blood pressure monitoring (ABPM) studies have used a mechanical clock as the reference time, but there is no biologic background for assuming that midnight by the mechanical clock is zero hour by the biologic clock. The aim of this study was to determine the biologic zero hour as the zero reference time by evaluating the circadian rhythm of blood pressure, heart rate, and activity. Twenty healthy medical students (18 men, 2 women, mean age 26 years old) were recruited and blood pressure, heart rate, and physical activity were monitored simultaneously by an ABPM device every 30 min for 48 h. Four concepts of zero time were selected in this study and analyzed regarding biologic zero hour: 24:00 by the mechanical clock (clock time); the time of awakening, based on a diary (diary time); the time of a sudden increment in physical activity in the morning (activity time); and the middle of the total sleeping time, based on the diary (midsleeping time). The awakening time is a better individual index than the mechanical clock, and the midsleeping time as the zero reference point is better than the awakening time. We assessed the reproducibility of the data regarding the circadian troughs between the first and second day. The reproducibility of the day-to-day variation of the blood pressure and heart rate was poor. The reproducibility of physical activity was fairly good, but the magnitude of activity was small. A 48-h monitoring profile is superior to a 24-h monitoring period.

IK independent class III actions of MS-551 compared with sematilide and dofetilide during reperfusion in anaesthetized rats.

1 The antiarrhythmic and haemodynamic effects of three class III antiarrhythmic drugs, MS‐551, sematilide and dofetilide, were examined in the coronary artery, ligation‐reperfusion model of pentobarbitone‐anaesthetized rats, a species deficient in functional cardiac IK. MS‐551 is a non‐selective potassium channel blocker, while both sematilide and dofetilide are selective delayed rectifier potassium (K) channel (IK) blockers. 2 Before coronary ligation, 3 and 10 mg kg−1 MS‐551 decreased the heart rate by 6% (P < 0.01) and 12% (P < 0.01), and increased mean arterial pressure (MAP) by 14% (P < 0.05) and 33% (P < 0.01), respectively. Sematilide at 10 and 30 mg kg−1 also decreased the heart rate by 4% (P < 0.01) and 9% (P < 0.01), respectively, and the higher dose of 30 mg kg−1 decreased MAP by 29% (P < 0.01). Dofetilide, 1 mg kg−1, decreased the heart rate (P < 0.01), but had no significant effect on MAP. 3 The QT interval was increased by 10% (P < 0.01) and 31% (P < 0.01), when 3 and 10 mg kg−1 MS‐551 were given. Sematilide and dofetilide had no effect on the QT interval. 4 Immediately after reperfusion, lethal ventricular fibrillation (VF) was induced in 80% of the saline group. MS‐551 at 3 and 10 mg kg−1, reduced the incidence of lethal VF to 50% and 20% (P < 0.05). Neither dofetilide 1 mg kg−1 nor sematilide (10 and 30 mg kg−1) decreased the incidence of lethal VF (70%, 80% and 50%, respectively). None of the three drugs had any effect on the occurrence of reperfusion‐induced VT or the total incidence of VF. However, 10 mg kg−1 MS‐551 delayed the onset of reperfusion‐induced VF (27 ± 5 s compared with 12 ± 2 s of the control group, P < 0.05). 5 In conclusion, in rats which are deficient in cardiac IK MS‐551 prolonged the QT interval and reduced the incidence of sustained VF after reperfusion. Blockade of channels other than IK might participate in the defibrillatory effect of MS‐551. Sematilide and dofetilide, which are selective IK blockers, did not increase the QT interval nor did they show antiarrhythmic effects. Mechanisms other than K channel block may be involved in the different effects of the three drugs on blood pressure.

Relation between QT interval dispersion and heart rate.

Because the relation between QT dispersion (QTd) and heart rate (HR) are different from that between QT interval and HR, QTd could be overadjusted at a high HR and be underadjusted at a slow HR if we use Bazetts formula to adjust QTd. HR adjustment of QTd is not needed to evaluate repolarization dispersion.

Protective effect of γ-glutamylcysteinylethyl ester on dysfunction of the selenium-deficient rat heart

We investigated the protective effect of intracellular GSH against cardiac dysfunction in selenium (Se)-deficient neonatal rats and cultured fetal rat myocytes. A Se-deficient diet with or without daily subcutaneous injections of gamma-glutamylcysteinylethyl ester (gammay-GCE) (a membrane-permeating GSH precursor) was given to rats from gestation day 4 via the dam to postnatal day 14. Se deficiency induced a 62% incidence of electrocardiographic abnormalities such as sinus arrhythmias or extrasystole, a 63% reduction in dP/dt in the left ventricle, and an increase in thiobarbituric acid reacting substances (TBARS), but no ultrastructural cardiac lesions were observed. Administration of gamma-GCE increased the intracellular GSH concentration ([GSH]i) of both neonatal rat hearts and cultured fetal rat cardiac myocytes. gamma-GCE-like sodium selenite prevented the cardiac dysfunction and the TBARS increment. gamma-GCE also prevented H2O2 toxicity in the cultured myocytes. The Vmax, but not the Km, for GSH of Se-dependent GSH peroxidase (Se-Gpx) activity in Se-deficient rat heart homogenates was one-third that of normal rat heart homogenates. Although gamma-GCE did not affect the Se-Gpx Vmax and Km for GSH, it did induce a substantial and significant increase in [GSH]i, which was postulated to increase the velocity of H2O2 decomposition by Se-Gpx activity 1.6-fold. These data suggest that the increase in [GSH]i may have played a role in preventing the TBARS increase and cardiac dysfunction in Se-deficient rats.