Hiromi Muratani

Role of HCN4 channel in preventing ventricular arrhythmia.

Bradycardia is a trigger of ventricular arrhythmias in patients with arrhythmia including Brugada syndrome and long QT syndrome. The HCN4 channel controls the heart rate, and its mutations predispose to inherited sick sinus syndrome and long QT syndrome associated with bradycardia. We found a 4 base-insertion at the splice donor site of the HCN4 gene in a patient with idiopathic ventricular tachycardia, which was supposed to generate a truncated channel. To investigate the role of the HCN4 channel in ventricular arrhythmia, we introduced a ventricular action potential of If channel produced by HCN4 in a computer simulation model and found that the If channel generated a leaky outward current during the plateau phase of ventricular action potential. Currents through the If channel were suggested to contribute to the shortening of the action potential duration and the prevention of early after-depolarization in bradycardia. These observations suggested that the HCN4 channel played a preventive role in triggering bradycardia-induced ventricular arrhythmias.

Low Serum Cholesterol as a Risk Factor for Hemorrhagic Stroke in Men

The relation between the level of total serum cholesterol and stroke is controversial. The relation between serum total cholesterol and subtypes of stroke was examined in the participants of a community-based mass screening program in Okinawa, Japan. A total of 38,053 subjects, whose serum level of cholesterol had been determined during a mass screening carried out in 1983, were examined to see whether they had experienced stroke during a 3-year period from 1988 to 1991. Of them, 315 subjects aged 33-93 years (174 men, 141 women) had had a stroke during that period. The types of stroke were cerebral infarction in 164, cerebral hemorrhage in 111, subarachnoid hemorrhage in 19, and others in 21. In men, the odds ratio of cerebral hemorrhage was 0.71 (95% confidence interval, 0.55-0.95), and the odds ratio of cerebral hemorrhage associated with serum level of cholesterol < or =167 mg/dl, 168-191 mg/dl, 192-217mg/dl, and > or =218mg/dl were 1.00 (reference), 0.70 (0.38-1.30), 0.77 (0.55-1.08), 0.73 (0.56-0.96), respectively. Lower serum cholesterol was an independent predictor of cerebral hemorrhage in men.

Brain angiotensin II contributes to the development of hypertension in Dahl-Iwai salt-sensitive rats.

Objective: To examine the role of brain angiotensin II in the development of salt-induced hypertension in Dahl-Iwai salt-sensitive (DIS) rats. Methods: Male DIS and Dahl-Iwai salt-resistant (DIR) rats aged 5 or 6 weeks were implanted with an intracerebroventricular cannula, and either chronic intracerebroventricular infusion of 5 µg/day CV-11974, a non-peptide type-1 angiotensin II receptor antagonist or artificial cerebrospinal fluid (aCSF) was started. The rats were fed a diet containing 8% sodium chloride. Results: On day 11 or 12 of chronic infusion, DIS rats given CV-11974 intracerebroventricularly exhibited a significantly lower mean arterial pressure than DIS rats given aCSF intracerebroventricularly or intravenous infusion of CV-11974. In DIR rats, intracerebroventricular infusion of CV-11974 did not alter the mean arterial pressure. Sodium and water balances were similar in all of the groups. Plasma vasopressin and noradrenaline levels did not differ among the groups, although the plasma renin concentration was significantly lower in DIS rats given aCSF intracerebroventricularly. Arterial baroreflex control of heart rate and pressor response to intravenous injection of phenylephrine were not altered in rats given CV-11974 intracerebroventricularly. Conclusion: The integrity of the brain renin-angiotensin system is necessary for the development of salt-induced hypertension in DIS rats.

Is single oral administration of captopril beneficial in screening for primary aldosteronism

Plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were measured in 19 cases with primary aldosteronism (PA) and in 72 with essential hypertension (EHT) to differentiate the two disorders during the following conditions on normal salt diet: after overnight recumbency (basal state) and 2 hours after oral administration of 25 mg of captopril. Screening criteria were determined so that all PA patients were diagnosed as positive, and their specificities were compared with those of other conventional screening methods for PA. After captopril administration, the specificity of a criterion based on a combination of PAC and PAC/PRA ratio was 93% and positive predictive value was 79%. This criterion was superior to blood pressure response to angiotension II analog infusion, PRA on salt depletion, and to PAC on salt loading. However, higher specificity (97%) and positive predictive value (90%) were obtained from a criterion based on a combination of basal PAC and PAC/PRA ratio. Therefore, the use of a combination criterion based on PAC and PAC/PRA ratio at basal state rather than after captopril administration may give a satisfactory result in the screening for PA.

Prolonged NOS inhibition in the brain elevates blood pressure in normotensive rats

Systemic inhibition of nitric oxide synthase (NOS) evokes hypertension, which is enhanced by salt loading, partly via augmented sympathetic activity. We investigated whether inhibition of brain NOS elevates blood pressure (BP) in normotensive rats and, if so, whether the BP elevation is enhanced by salt loading. After a 2-wk low-salt (0.3%) diet, male Sprague-Dawley (SD) rats were divided into four groups. Groups 1 and 2 received a chronic intracerebroventricular infusion of 0.5 mg . kg-1 . day-1 of NG-monomethyl-L-arginine (L-NMMA), and groups 3 and 4 were given artificial cerebrospinal fluid (aCSF). Groups 1 and 3 were placed on a high-salt (8%) diet, whereas groups 2 and 4 were on a low-salt diet. On day 9 or 10, group 1 showed significantly higher mean arterial pressure (MAP) in a conscious unrestrained state (129 +/- 3 mmHg vs. 114 +/- 3, 113 +/- 1, and 108 +/- 3 mmHg in groups 2, 3, and 4, respectively, P < 0.05). On a high-salt diet, response of renal sympathetic nerve activity but not of BP to air-jet stress was significantly larger in rats given L-NMMA than in rats given aCSF (29 +/- 4% vs. 19 +/- 3%, P < 0.05). When the intracerebroventricular infusions were continued for 3 wk, MAP was significantly higher in rats given L-NMMA than in rats given aCSF irrespective of salt intake, although the difference was approximately 7 mmHg. Thus chronic inhibition of NOS in the brain only slightly elevates BP in SD rats. Salt loading causes a more rapid rise in BP. The mechanisms of the BP elevation and its acceleration by salt loading remain to be elucidated.Systemic inhibition of nitric oxide synthase (NOS) evokes hypertension, which is enhanced by salt loading, partly via augmented sympathetic activity. We investigated whether inhibition of brain NOS elevates blood pressure (BP) in normotensive rats and, if so, whether the BP elevation is enhanced by salt loading. After a 2-wk low-salt (0.3%) diet, male Sprague-Dawley (SD) rats were divided into four groups. Groups 1 and 2 received a chronic intracerebroventricular infusion of 0.5 mg ⋅ kg-1 ⋅ day-1of N G-monomethyl-l-arginine (l-NMMA), and groups 3 and 4 were given artificial cerebrospinal fluid (aCSF). Groups 1 and 3 were placed on a high-salt (8%) diet, whereas groups 2 and 4 were on a low-salt diet. On day 9or 10, group 1 showed significantly higher mean arterial pressure (MAP) in a conscious unrestrained state (129 ± 3 mmHg vs. 114 ± 3, 113 ± 1, and 108 ± 3 mmHg in groups 2, 3, and 4, respectively, P < 0.05). On a high-salt diet, response of renal sympathetic nerve activity but not of BP to air-jet stress was significantly larger in rats givenl-NMMA than in rats given aCSF (29 ± 4% vs. 19 ± 3%, P < 0.05). When the intracerebroventricular infusions were continued for 3 wk, MAP was significantly higher in rats givenl-NMMA than in rats given aCSF irrespective of salt intake, although the difference was ∼7 mmHg. Thus chronic inhibition of NOS in the brain only slightly elevates BP in SD rats. Salt loading causes a more rapid rise in BP. The mechanisms of the BP elevation and its acceleration by salt loading remain to be elucidated.

Circadian rhythms of urinary excretions of water and electrolytes in patients receiving total parenteral nutrition (TPN)

In order to determine whether the usual feeding pattern actually modifies the circadian rhythms of urinary excretion of water and electrolytes, we compared the circadian rhythm characteristics in patients receiving total parenteral nutrition (TPN group) with those in patients on an ordinary hospital diet (control group). Statistically significant circadian rhythms were detected in all of the urinary variables investigated herein by using the population mean-cosinor method in both groups. In addition, there were no statistically significant differences of the mesor, the %-amplitude and the acrophase between the two groups. These results suggest that the usual feeding pattern is not a main determinant in forming the circadian rhythm characteristics of human urinary variables.

Contribution of α2-adrenoceptors in caudal ventrolateral medulla to cardiovascular regulation in rat

The inhibitory action of α2-agonists on the cardiovascular neurons has been elucidated in the rostral ventrolateral medulla (RVLM) but not in the caudal ventrolateral medulla (CVLM). Our study aimed to clarify whether microinjection of clonidine into the CVLM elicits any cardiovascular effect and whether endogenous α2-adrenoceptor-mediated mechanisms contribute to the tonic activity of the CVLM neurons. In male Sprague-Dawley rats (7-9 wk old, 270-320 g) anesthetized with urethan, unilateral microinjection of 8 nmol of clonidine into the CVLM ( n = 10) increased mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) by 12.1 ± 1.8 mmHg (mean ± SE, P < 0.01) and 25.8 ± 4.8% ( P < 0.01), while heart rate (HR) remained unaltered. Unilateral microinjection of 2 nmol of SKF-86466, a selective blocker of the α2-adrenoceptors, into the CVLM ( n = 10) decreased MAP, HR, and RSNA (-11.6 ± 2.6 mmHg, -26 ± 7 beats/min, and -15.3 ± 1.7%, respectively, P < 0.01 for each). Artificial cerebrospinal fluid caused neither a cardiovascular effect nor a sympathetic response. Prior injection of SKF-86466 into the ipsilateral CVLM attenuated the effects of clonidine. Bilateral microinjection of muscimol into the RVLM abolished the effects of both clonidine and SKF-86466 injected into the CVLM. The pressor and sympathoexcitatory effects of clonidine injected into the CVLM suggest a neuroinhibitory action of the drug on the CVLM neurons. In addition,the depressor and sympathoinhibitory effects of SKF-86466 injected into the CVLM indicated that activation of α2-adrenoceptors by endogenous ligand inhibits CVLM neurons. The effects of clonidine and the α2-adrenoceptor antagonist in the CVLM require the integrity of the RVLM.The inhibitory action of alpha 2-agonists on the cardiovascular neurons has been elucidated in the rostral ventrolateral medulla (RVLM) but not in the caudal ventrolateral medulla (CVLM). Our study aimed to clarify whether microinjection of clonidine into the CVLM elicits any cardiovascular effect and whether endogenous alpha 2-adrenoceptor-mediated mechanisms contribute to the tonic activity of the CVLM neurons. In male Sprague-Dawley rats (7-9 wk old, 270-320 g) anesthetized with urethan, unilateral microinjection of 8 nmol of clonidine into the CVLM (n = 10) increased mean arterial pressure (MAP) and renal sympathetic nerve activity (RSNA) by 12.1 +/- 1.8 mmHg (mean +/- SE, P < 0.01) and 25.8 +/- 4.8% (P < 0.01), while heart rate (HR) remained unaltered. Unilateral microinjection of 2 nmol of SKF-86466, a selective blocker of the alpha 2-adrenoceptors, into the CVLM (n = 10) decreased MAP, HR, and RSNA (-11.6 +/- 2.6 mmHg, -26 +/- 7 beats/min, and -15.3 +/- 1.7%, respectively, P < 0.01 for each). Artificial cerebrospinal fluid caused neither a cardiovascular effect nor a sympathetic response. Prior injection of SKF-86466 into the ipsilateral CVLM attenuated the effects of clonidine. Bilateral microinjection of muscimol into the RVLM abolished the effects of both clonidine and SKF-86466 injected into the CVLM. The pressor and sympathoexcitatory effects of clonidine injected into the CVLM suggest a neuroinhibitory action of the drug on the CVLM neurons. In addition, the depressor and sympathoinhibitory effects of SKF-86466 injected into the CVLM indicated that activation of alpha 2-adrenoceptors by endogenous ligand inhibits CVLM neurons. The effects of clonidine and the alpha 2-adrenoceptor antagonist in the CVLM require the integrity of the RVLM.

Single Oral Administration of Captopril may not bring an Improvement in Screening of Primary Aldosteronism

Plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were measured in 19 cases with primary aldosteronism (PA) and 72 with essential hypertension (EHT) to differentiate the two disorders in the following conditions: after overnight recumbency (basal state) and after oral administration of captopril. Screening criteria were determined in order to pick up all of PA patients as positive. After the captopril administration, the specificity of a criterion based on the combination of PAC and PAC/PRA ratio was 93% and positive predictive value 79%. This criterion was superior to other conventional screening methods. However, higher specificity (97%) and positive predictive value (90%) were obtained from a combination criterion based on the basal PAC and PAC/PRA ratio. The single oral administration of captopril may not bring an improvement in the screening of PA.

Long-term survival of chronic dialysis patients in comparison to that of stroke and acute myocardial infarction patients

AbstractBackground. There are no data comparing the long-term survival of chronic dialysis patients with that of acute myocardial infarction (AMI) or stroke patients. We obtained outcome data from two community-based registries, one for dialysis patients and one for patients who suffered an AMI or stroke. Methods. Patients were entered into the registries between April 1, 1988, and March 31, 1991, in Okinawa, Japan. Only patients who survived for 28 days after starting dialysis or after the onset of AMI and stroke were studied. A total of 646 chronic dialysis patients, 747 AMI patients, and 3809 stroke patients were followed up until March 1, 1999. Survival rates were compared between the dialysis patients and those suffering AMI or stroke, based on Cox proportional hazard analysis, and relative risk (95% confidence interval [CI]) of death was estimated after adjusting for sex and age at onset. Results. The relative risk (95% CI) of death for AMI and stroke patients was 0.39 (0.33–0.46) and 0.40 (0.36–0.46), respectively, when the death risk of dialysis patients was taken as reference (1.00). The relative risk for patients with cerebral hemorrhage was 0.44 (0.38–0.50), with the value being 0.40 (0.35–0.46) for patients with cerebral infarction, and 0.37 (0.28–0.49) for those with subarachnoid hemorrhage. Conclusions. Survival in dialysis patients is clearly worse than that in AMI and stroke patients. Specific factors leading to the higher mortality rate in dialysis patients remain to be determined.

Sympathetic Response to Oral Glucose Load is Altered in Hypertensive Subjects

Blood pressure, plasma norepinephrine (NE) and epinephrine (E) levels in responses to oral glucose load (OGTT) and to head-up tilting (Tilt) were measured in 14 hypertensive (HT) and 17 normotensive subjects (NT). In response to OGTT, NE significantly increased within 30 minutes (+25 +/- 8%; p less than 0.05) in NT, followed by a decline to the basal level, while it remained unchanged in HT (+5 +/- 8%). E decreased similarly during OGTT in both groups. Mean blood pressure, however, fell only in HT (-3.3 +/- 1.1%; p less than 0.05) but did not change in NT. Blood pressure, NE and E responses to Tilt did not differ between NT and HT. These results suggest that hypertensive subjects have some defects in sympathetic activation in response to glucose loading.