Kunihide Hiramatsu

Acute effects of the calcium antagonist, nifedipine, on blood pressure, pulse rate, and the renin-angiotensin-aldosterone system in patients with essential hypertension

Ten milligrams nifedipine was administered orally to young and old persons with or without hypertension, and the acute effects of nifedipine on the renin-angiotensin-aldosterone system were studied one half to 3 hours later. Nifedipine reduced blood pressure and increased pulse rate in young and old persons with or without hypertension. Simultaneously, nifedipine produced a significant increase of plasma renin activity in young persons with or without hypertension but failed to do so in old persons with or without hypertension. As a result, angiotensin I and II increased significantly in young persons but not in old persons. Hydralazine elevated aldosterone concentration by stimulating the renin-angiotensin system but nifedipine failed to do so despite its effect on the renin-angiotensin system in young individuals. Since calcium is required to secrete aldosterone, it is suggested that nifedipine blocked aldosterone secretion by the agents calcium antagonizing action.

Inhibition of Peroxisome Proliferator Signaling Pathways by Thyroid Hormone Receptor COMPETITIVE BINDING TO THE RESPONSE ELEMENT

Peroxisome proliferators (e.g. clofibric acid) and thyroid hormone play an important role in the metabolism of lipids. These effectors display their action through their own nuclear receptors, peroxisome proliferator-activated receptor (PPAR) and thyroid hormone receptor (TR). PPAR and TR are ligand-dependent, DNA binding, trans-acting transcriptional factors belonging to the erbA-related nuclear receptor superfamily. The present study focused on the convergence of the effectors on the peroxisome proliferator response element (PPRE). Transcriptional activation induced by PPAR through a PPRE was significantly suppressed by cotransfection of TR in transient transfection assays. The inhibition, however, was not affected by adding 3,5,3′-triiodo-L-thyronine (T3). Furthermore, the inhibition was not observed in cells cotransfected with retinoic acid receptor or vitamin D3 receptor. The inhibitory action by TR was lost by introducing a mutation in the DNA binding domain of TR, indicating that competition for DNA binding is involved in the molecular basis of this functional interaction. Gel shift assays revealed that TRs, expressed in insect cells, specifically bound to the 32P-labeled PPRE as heterodimers with the retinoid X receptor (RXR). Both PPAR and TR bind to PPRE, although only PPAR mediates transcriptional activation via PPRE. TR·RXR heterodimers are potential competitors with PPAR·RXR for binding to PPREs. It is concluded that PPAR-mediated gene expression is negatively controlled by TR at the level of PPAR binding to PPRE. We report here the novel action of thyroid hormone receptor in controlling gene expression through PPREs.

ACUTE EFFECTS OF COLD ON BLOOD PRESSURE, RENIN-ANGIOTENSINALDOSTERONE SYSTEM, CATECHOLAMINES AND ADRENAL STEROIDS IN MAN

1. In an attempt to study effects of cold on blood pressure and the reninangiotensin‐aldosterone system, 34 healthy young subjects with or without a family history of essential hypertension were exposed to moderate cold (4°C for 1 h) or severe cold (immersion of the hands to 0°C for 10 min). Moderate cold elevated blood pressure, aldosterone, cortisol and noradrenaline when the subjects wore summer clothing but not when the subjects wore winter clothing. Regardless of the clothing worn, skin blood flow and plasma renin activity decreased significantly in response to moderate cold but angiotensin II decreased insignificantly.

Left ventricular filling abnormalities in non-insulin-dependent diabetes mellitus and improvement by a short-term glycemic control

To determine whether left ventricular (LV) filling abnormalities in diabetes are associated with diabetic microangiopathy, and to evaluate the effect of a short-term glycemic control on the filling abnormalities, diastolic filling dynamics were assessed by pulsed Doppler echocardiography in 246 patients with non-insulin-dependent diabetics. Isovolumic relaxation time and the ratio of peak flow velocity of atrial filling wave to peak flow velocity of early filling wave (A/E) were significantly greater in diabetic patients than in age- and sex-matched control subjects. Diabetic patients with retinopathy had significantly greater isovolumic relaxation time and A/E values than those without retinopathy. A/E was significantly decreased 1 month after insulin treatment in those without, but not with retinopathy. It is concluded that LV diastolic filling is impaired in mildly hyperglycemic patients with non-insulin-dependent diabetes mellitus without severe complications, the abnormality being more intense in patients with retinopathy. A short-term glycemic control results in a marked decrease in abnormalities in patients without, but not with retinopathy.

Changes in Endocrine Activities Relative to Obesity in Patients with Essential Hypertension

The possible role of obesity in the development of hypertension was investigated in two study groups. In a population study of 961 subjects, 739 were found to be normotensive and 222 hypertensive. The prevalence of hypertension was 18.7 percent in the nonobese, and 33.2 percent in the obese subjects. Systolic and diastolic blood pressures increased progressively with the increase of relative body weight in both normotensive and hypertensive subjects. In addition, an endocrinologic study was made of 97 patients with essential hypertension; in 82, plasma renin activity (PRA) was inversely correlated with the increase of relative body weight but not with urinary Na excretion. Despite this decrease of PRA, the level of serum aldosterone was not influenced by relative body weight. Thus, the aldosterone/PRA ratio increased progressively with the increase of relative body weight. Thiazide therapy normalized this inappropriately high ratio, and reduced body weight and blood pressure. Restriction of dietary calories and salt intake had a similar effect. With a high‐salt intake in an obese subject, the aldosterone/PRA ratio is unduly increased. Apparently aldosterone contributes to the additional retention of sodium and water and thereby promotes hypertension in the presence of an expanded fluid volume.

Role of adrenal androgens in the development of arteriosclerosis as judged by pulse wave velocity and calcification of the aorta.

To evaluate the role of adrenal androgens in the development of arteriosclerosis, serum dehydroepiandrosterone sulfate (DHEAS), dehydroepiandrosterone (DHEA), aortic calcification and pulse wave velocity (PWV) were measured in 69 males and 119 females without overt cardiovascular disease. The steroids decreased with age in both sexes, and the reduction was significantly steeper in younger (< or = 40 years) than in older (> 40 years) subjects only in females. When adjusted for age, the steroids were significantly lower in subjects with aortic calcification than in those without it, and the PWV was significantly slower in the latter. Adrenal androgens appear to retard the development and/or progression of arteriosclerosis.

Diminution of early insulin response to glucose in subjects with normal but minimally elevated fasting plasma glucose. Evidence for early beta-cell dysfunction

Aim Systematic analysis of β‐cell function in Japanese health examinees.

Proteinuria and renal function during antihypertensive treatment for essential hypertension.

In an attempt to determine the effects of antihypertensive treatment on proteinuria and renal function, these factors were studied in 155 patients with essential hypertension, before and during antihypertensive therapy. Slight renal impairment tended to increase with the progress of hypertension, as evidenced by a slight but significant increase in the levels of blood urea nitrogen (BUN) and serum creatinine, and by a progressive decrease in creatinine clearance. A decrease in proteinuria appeared as early as one month after initiation of treatment and continued for at least two years during treatment. Apparently the proteinuria was caused by increased glomerular pressure and by vascular damage in the glomerular vessels. In 7 patients, normalization of blood pressure resulted in an elevation of BUN and creatinine concentrations, although initial renal function did not differ significantly from that in other groups who did not show such derangement during treatment. Thus, a reduction of proteinuria seems to be a good criterion for predicting beneficial results from antihypertensive treatment.

Possible Link Between a Low Prevalence of Cardiovascular Disease and Mild Dyslipidaemia: a Study in Japanese Patients with Type 2 Diabetes

In 98 Japanese patients with Type 2 diabetes mellitus, serum total cholesterol, triglyceride, high density lipoprotein cholesterol (HDL‐C), free fatty acid (FFA), and apolipoproteins (apo) A‐I, A‐II, B, C‐II, C‐III, and E were determined. The data were compared with those in 47 normolipidaemic normal controls. The total cholesterol value of the diabetic patients was also compared to that of a general population (n = 2227). The diabetic patients were separated into those with cardiovascular disease (n = 20) and without it (n = 78) and a comparison of clinical characteristics and dyslipidaemia was also performed. The diabetic patients had slightly but significantly higher FFA, LDL‐C, apo B, C‐II, C‐III, E, and B/A‐I, and lower apo A‐I and A‐II compared to the normal controls. The total cholesterol level of the diabetic patients (5.17 ± 0.96 mmol−1) was not significantly higher than that of the general population (5.12 ± 0.91 mmol−1). By multivariate stepwise discriminant analyses, only total cholesterol significantly discriminated the patients with and without cardiovascular disease. In Japanese patients with Type 2 diabetes, a diabetic population with a very low prevalence of cardiovascular disease, high total cholesterol ís a risk factor for developing cardiovascular disease. Nevertheless, a markedly low prevalence of cardiovascular disease in Japanese with Type 2 diabetes compared to Caucasian counterparts may partly be due to the mildness of dyslipidaemia.

Echocardiographic diagnosis of subepicardial aneurysm ruptured into the right ventricle after inferior myocardial infarction

A subepicardial aneurysm is a rare complication of myocardial infarction that sometimes causes a left to right shunt at the ventricular level. We report on echocardiographic observations in two recent cases of inferior myocardial infarction complicated by rupture of a subepicardial aneurysm into the right ventricle (RV). Two-dimensional and color flow Doppler images in several planes offered diagnostic characteristics of the lesion, including discontinuity of the myocardium at the neck of the aneurysm, a narrow neck relative to the diameter of the aneurysm, and a back and forth flow at the neck of the aneurysm. These techniques also provided new findings, such as a two-chambered structure of the aneurysm and a circular flow pattern within the inner aneurysmal cavity. In addition, color flow Doppler imaging showed multiple shunt flows from the aneurysm to the RV. Echocardiographically diagnosed abnormalities were verified by and successfully treated with surgery in both cases. In conclusion, echocardiography with color flow Doppler imaging may have the potential to diagnose the anatomic and hemodynamic condition of a subepicardial aneurysm.