Toshihiko Takenaka

Short-Acting Nifedipine and Diltiazem Do Not Reduce the Incidence of Cardiac Events in Patients With Healed Myocardial Infarction

BACKGROUND The administration of calcium antagonists to patients with healed myocardial infarction is a controversial treatment. This study was conducted to elucidate the effect of short-acting nifedipine and diltiazem on cardiac events in patients with healed myocardial infarction. METHODS AND RESULTS A controlled clinical open trial of 1115 patients with healed myocardial infarction was carried out between 1986 and 1994. The patients included 595 who received no calcium antagonist, 341 who received short-acting nifedipine 30 mg/d, and 179 who received short-acting diltiazem 90 mg/d. The primary end points were cardiac events, which were defined as fatal or nonfatal recurrent myocardial infarction; death from congestive heart failure; sudden death; and hospitalization because of worsening angina, congestive heart failure, or premature ventricular contractions. Cardiac events occurred in 51 patients (8.6%) in the no-calcium-antagonist group and 54 (10.4%) in the calcium-antagonist group (odds ratio, 1.24; 95% CI, 0.83 to 1.85), demonstrating that the calcium antagonists did not reduce the incidence of cardiac events. Subgroup analysis revealed no beneficial effects of these drugs for reducing cardiac events in patients with such complications as hypertension or angina pectoris. CONCLUSIONS This study showed that use of short-acting nifedipine and diltiazem in this postmyocardial infarction population was associated with a 24% higher cardiac event rate, but this strong adverse trend did not reach statistical significance.

Tissue Angiotensin II Concentration in the Heart and Kidneys in Transgenic Tsukuba Hypertensive Mice

Tsukuba hypertensive mice (THM) are transgenic mice carrying both human renin and angiotensinogen genes, and possessing an overexpressing human renin-angiotensin system. The aim of this study is to evaluate the angiotensin II concentration in the heart and kidney in THM. Twenty-week-old male THM and control C57BL/6 mice (C57) were used. Each group consisted of 3 mice. For each mouse, systolic blood pressure, heart to body weight ratio, renal glomerular sclerosis index and angiotensin II concentration in the heart and kidney were measured. Systolic blood pressure of THM was about 40 mmHg higher than that of C57. Heart to body weight ratio and renal glomerular sclerosis index were significantly higher in THM than those in C57. The angiotensin II concentration in THM was about 4 times higher in the heart and about 5 times higher in the kidney compared with that in C57. These results suggest that accelerated tissue angiotensin II production, significant cardiac hypertrophy and renal glomerular sclerosis all occur because of hypertension.

Significant role of the increase in renin-angiotensin system in cardiac hypertrophy and renal glomerular sclerosis in double transgenic tsukuba hypertensive mice carrying both human renin and angiotensinogen genes.

Tsukuba hypertensive mice (THM) are a hypertensive model prepared by mating a transgenic mice with human renin gene and a transgenic mice with human angiotensinogen gene. In the present study, we examined effects of renin-angiotensin system (RAS) on cardiac hypertrophy and renal disorders using Tsukuba hypertensive mice. While THM showed an increase of about 30 mmHg in systolic pressure compared to C57BL/6 mice employed as normal control animals, the increase in blood pressure was not observed in the mice to which either gene was transferred. Urinary volume, water intake volume, urinary albumin excretion, heart to body weight ratio and renal glomerular sclerosis index increased significantly in THM, but none of these parameters showed a significant difference from the C57 mice when they were examined in mice to which either of the genes was transferred. In contrast, when lisinopril was administered to THM, all the parameters decreased significantly without lowering the systolic pressure. From these findings, it was demonstrated that RAS was playing a significant role in cardiac hypertrophy and renal disorders of THM and that lisinopril had inhibitory effects on cardiac hypertrophy and renal glomerular sclerosis by inhibiting RAS.

Incidence of cancer in postmyocardial infarction patients treated with short‐acting nifedipine and diltiazem

Recent reports suggest a possible link between nifedipine (but not diltiazem) and an increased risk of cancer in patients being treated with calcium antagonists.

Mechanism of Taurine Natriuresis in Rats

Taurine, a sulfur containing amino acid, is abundant in many organs and tissues in mammals1. However, its physiological significance has been hardly understood. We reported that daily urinary taurine excretion significantly decreased in patients with essential hypertension, and administration of taurine increased urinary kallikrein and decreased blood pressure2. In the field of experimental hypertension animal, administration of taurine also showed antihypertensive effect in spontaneously hypertensive rats (SHR)3 and in a stroke-prone substrain (SHR-SP)4, in which the deficiency of taurine metabolism was demonstrated3,5. Since urinary kallikrein has a positive correlation with urinary kinin6, it seems that taurine stimulates kallikrein activity to increase the quantity of kinin produced in the kidney.

Tissue-localized angiotensin II enhances cardiac and renal disorders in Tsukuba hypertensive mice.

Objective To evaluate the relation of tissue-localized angiotensin II (Ang II) concentration with cardiac hypertrophy and glomerulosclerosis in Tsukuba hypertensive mice (THM) carrying both human renin and angiotensinogen genes. Design Thirty THM aged 12 weeks were distributed equally to a lisinopril dosage group, a hydralazine dosage group, and an untreated group. Ten age-matched C57BL/6 mice were used as normal controls. Administration was performed for 8 weeks from 12 weeks of age. All mice were euthanized at 20 week of age, and the heart-to-body weight ratio, the renal glomerulosclerosis score, tissue Ang II concentration and tissue catecholamine concentration were measured. Results In the untreated group, a significant increase in every examination item was found as compared with that in C57BL/6 mice. In the lisinopril group, the observed value of every item was significantly lower than that in the untreated group. In the hydralazine group, tissue Ang II and catecholamine concentrations and the heart-to-body weight ratio were not different from those in the untreated group. Although the glomerulosclerosis score in the hydralazine group was significantly less than that in the untreated group, this was significantly higher than that in the lisinopril group. Conclusion Tissue Ang II concentration is more important than hypertension in causing cardiac hypertrophy, and both tissue Ang II level and hypertension are important in causing glomerulosclerosis in THM.

Enhanced angiotensin II stimulates renal disorders in transgenic Tsukuba hypertensive mice.

Tsukuba hypertensive mice (THMs) are transgenic mice carrying human renin-angiotensin system (RAS) genes. The aim of this study is to evaluate whether renal disorders are present in THMs. Twenty-week-old THMs and C57BL/6 mice (C57s) were used for this study. Each group consisted of 8 mice. Systolic blood pressure, urinary volume, water intake and urinary albumin excretion were measured in each mouse. Each mouse was then euthanized, and the renal glomerulosclerosis index and glomerular size were measured. Systolic blood pressure of THMs was about 40 mmHg higher than that of C57s. Urinary volume, water intake and urinary albumin excretion were significantly higher in THMs than in C57s. The renal glomerulosclerosis index and glomerular size were also significantly higher in THMs than in C57s. These results suggested that an enhanced renin-angiotensin system, including its hypertensive effects, stimulates albuminuria, renal glomerulosclerosis and glomerular hypertrophy in THMs.

Regulation of aldosterone receptor in rat kidney cytosol by atrial natriuretic factor.

We investigated the effect of atrial natriuretic factor (ANF) on aldosterone receptors in the kidney cytosol, because the binding of aldosterone to aldosterone receptors in the cytosol is considered a critical step of its action. Rat atriopeptin III was injected into male Sprague-Dawley rats (200-250 g) via the femoral vein while under pentobarbital anesthesia, and aldosterone receptors in the kidney cytosol were determined. The maximum binding capacity and dissociation constant were calculated by the Scatchard analysis. Maximum binding capacity of both types of aldosterone receptor (Type I, high affinity and low binding capacity and Type II, low affinity and high binding capacity) gradually decreased after ANF injection, reached the lowest level after 2 hours, and then slightly recovered. When more than 2.5 micrograms/kg of rat atriopeptin III was injected, the density of aldosterone receptors significantly decreased. Injection of 12.5 micrograms/kg of rat atriopeptin III decreased maximum binding capacity of Type I receptor from 42.3 +/- 2.4 (mean +/- SD, n = 6) to 22.8 +/- 3.2 femtomole/mg protein (n = 6) (p less than 0.01), and that of Type II receptor decreased from 388 +/- 46 to 285 +/- 30 fmol/mg protein (p less than 0.01). Dissociation constant of both types of receptors did not change significantly after ANF injection. Plasma aldosterone concentration showed no significant change after ANF injection, and a significant change was noted after ANF administration on aldosterone receptors in the experiments on adrenalectomized rats 7 days after operation. Furosemide had no significant effect on aldosterone receptors in both normal and adrenalectomized rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic Use of Continuous Dosing of Long-Term Nitrates Does Not Prevent Cardiac Events in Patients with Severe Acute Myocardial Infarction

This study was performed to investigate the effects of the chronic use of continuous, not eccentric, dosing of nitrates on cardiac events in patients with severe acute myocardial infarction. A total of 1,303 patients with healed myocardial infarction were divided into two groups: treatment with nitrates or nontreatment. Primary end points were nonfatal and fatal recurrent myocardial infarction, death from congestive heart failure and sudden death. Among the 725 patients treated with nitrates, 45 patients (6.2%) experienced cardiac events during the observation period, whereas only 17 of the 578 patients treated without nitrates (2.9%) had cardiac events. This difference was statistically significant (p < 0.01; odds ratio 2.18, 95% confidence interval 1.24–3.86). In Killip class II–IV patients, the incidence of cardiac events in patients with nitrates was significantly greater than in patients without nitrates (18.8 vs. 3.5%, p < 0.05). The chronic use of continuous, not eccentric, dosing of nitrates did not prevent cardiac events in patients with severe acute myocardial infarction.

EFFECT OF AN ANGIOTENSIN II RECEPTOR ANTAGONIST, TCV‐116, ON NEOINTIMAL FORMATION FOLLOWING BALLOON INJURY IN THE SHR CAROTID ARTERY

1. In the present study, we examined the effect of a novel angiotensin II type I receptor antagonist, TCV‐116, on carotid neointimal formation after balloon injury in SHR and WKY rats.