Eiko Takeshita

Association Between Platelet Glycoprotein Ibα Genotype and Ischemic Cerebrovascular Disease

BACKGROUND AND PURPOSE Platelets play pivotal roles in the development of ischemic cerebrovascular disease (CVD). The platelet glycoprotein (GP) Ib/IX/V complex is a receptor for von Willebrand factor, which plays a major role in the initial phase of platelet activation under high shear stress conditions. This study was designed to investigate the association between a genetic variation of this receptor and the prevalence of CVD. METHODS Two hundred patients with ischemic CVD, as confirmed by brain CT and/or MRI, and 317 age- and sex-matched control subjects without clinical evidence of CVD or cardiovascular disease were analyzed for their genotype frequencies of the (145)Thr/Met dimorphism of the alpha-chain of GPIb (GPIbalpha). RESULTS Genotypes with (145)Met (T/M and M/M) were more frequently found in the CVD patients (26.5%) than in control subjects (14.2%, P=0.0005). The genotype effect was more obvious in those <60 years of age or without acquired cardiovascular risk factors. The odds ratio for nonsmoking women <60 years of age was 10. 6 (95% confidence intervals, 2.2 to 51.7). Although the number of patients studied was small (n=24), transient ischemic attack showed the highest odds ratio (4.3, P=0.0004), followed by lacunar infarction (OR=2.2, P=0.0024) and atherothrombotic infarction (OR=1. 5, P=0.3143). Logistic regression analysis revealed that the presence of Met-allele was independently associated with CVD. CONCLUSIONS Our study suggests that the platelet GPIbalpha genotype is a genetic risk factor for ischemic CVD.

Urinary dopamine excretion in normotensive subjects with or without family history of hypertension.

To define the role of the renal dopaminergic system in the pathogenesis of essential hypertension, urinary free dopamine excretion was examined in 23 normotensive subjects who had one or more first-degree relatives with essential hypertension, and also in 36 matched control subjects without any such family history. The group urinary dopamine excretion and urinary sodium excretion were not different. However, a significant urine dopamine-sodium relationship was apparent in the controls but not in the relatives due to relatively high dopamine output in those with lower sodium excretion. The two groups were similar as regards blood pressure (BP), plasma renin activity (PRA), prolactin and catecholamines. These findings demonstrate an alteration in the urine dopamine-sodium relationship in some normotensive subjects with genetic risk of hypertension.

Cholesteryl ester transfer protein polymorphism associated with macroangiopathy in japanese patients with type 2 diabetes

A polymorphism in the gene for cholesteryl ester transfer protein (CETP) has been reported to be associated with serum cholesterol levels and risk for atherosclerotic vascular diseases, and to clarify the relationship between the gene polymorphism for CETP and macroangiopathy in diabetes mellitus, a cross-sectional study was performed. The subjects of the study were182 Japanese (age: 59.6+/-8.6 years) with type 2 diabetes and no signs of renal dysfunction, 24 of whom had macroangiopathy, and 158 of whom did not. The genotype of the subjects for the TaqIB polymorphism of CETP in intron one was analyzed by using polymerase chain reaction - restriction fragment length polymorphism. Serum CETP levels were significantly higher in the B1/B1 genotype than in the other genotypes (P<0.05). The serum CETP levels were correlated with the serum LDL cholesterol levels (P<0.01), but not with the HDL cholesterol levels. Macroangiopathy was more frequently observed in subjects with the B1/B1 genotype than in the other genotypes (odds ratio=2.953, 95% confidence interval=1.250-6.977, P=0.0136). Logistic regression analysis revealed that the CETP genotype was independently associated with macroangiopathy. The exact mechanism underlying the association remains unknown, but differences in serum CETP levels may be involved.

Increased Urinary Dopamine Excretion in Young Patients with Essential Hypertension

The evidence that some older patients with essential hypertension have low urinary dopamine excretion has brought into question the levels of urinary dopamine and plasma dopa, the major source of urinary dopamine, in young patients with essential hypertension. Twenty-four-hour urine sodium, creatinine, dopamine and noradrenaline and plasma dopa were evaluated in 48 patients with essential hypertension aged 18 to 27 years and 25 normotensive subjects. In comparison with age-matched normotensive subjects, the hypertensive patients had higher urinary dopamine (1920 +/- 80 vs 1520 +/- 130 nmol/day, p < 0.01) and noradrenaline (216 +/- 11 vs 179 +/- 12 nmol/day, p < 0.05) excretion. There was a significant correlation between urinary dopamine and noradrenaline excretion. There was no difference in plasma dopa levels between normotensive and hypertensive subjects. These results suggest that the elevated conversion of dopa to dopamine in the kidney is leading to increased urinary dopamine excretion in young patients with essential hypertension.

Angiotensin converting enzyme insertion/deletion polymorphism is associated with plasma antigen levels of plasminogen activator inhibitor-1 in healthy Japanese population

Plasminogen activator inhibitor-1 (PAI-1) has a central role in the regulation of the fibrinolytic enzyme system. An elevated plasma PAI-1 level is associated with thrombotic disorders. In vitro and in vivo studies indicate that the renin-angiotensin system is involved in the regulation of PAI-1. A 287-bp insertion/deletion (I/D) polymorphism in the gene-encoding angiotensin converting enzyme (ACE) is associated with cardiovascular disorders. We evaluated the association between the ACE I/D polymorphism and plasma PAI-1 antigen levels in 110 healthy Japanese male subjects. Subjects with the D-allele of the gene-encoding ACE had higher levels of PAI-1 (26.3 +/- 14.7 ng/ml, mean +/- standard deviation) compared with those without (21.0 +/- 12.0; P = 0.0491). A multiple linear regression model with independent variables (age, body-mass index, total cholesterol level, triglyceride level, ACE I/D genotype, and PAI-1 genotype due to a single guanine I/D polymorphism in the PAI-1 gene) demonstrated that the triglyceride level (P = 0.0059) and ACE I/D genotype (P = 0.0372) were independent predictors of plasma PAI-1 antigen levels in a subset of the subjects without diabetes mellitus that were not taking lipid-lowering drugs. These findings suggest that the ACE I/D polymorphism is a genetic factor for the regulation of plasma PAI-1 antigen levels in the healthy Japanese population.

Effect of L-dopa in Young Patients with Hypertension:

The effects of L-dopa on blood pressure, heart rate, plasma renin activity, norepinephrine, epinephrine and prolactin were studied in a randomized single-blind trial in 36 patients with essential hypertension. In response to L-dopa, 250 mg administered orally, the blood pressure decreased significantly as compared with the results of placebo treatment. The heart rate and plasma norepinephrine and epinephrine were unchanged. The plasma renin activity and prolactin decreased as a result of L-dopa administration. The administration of a peripheral DA2 dopamine receptor blocker, domperidone (20 mg, orally) prevented the L-dopa-induced reduction in plasma prolactin but failed to block the fall in blood pressure and plasma renin activity. These results suggest that the blood pressure-lowering effect of L-dopa may be mediated through multiple sites involving D1 dopamine receptors, the central nervous system, and the renin-angiotensin system.

Plasma prolactin, renin and catecholamines in young normotensive and borderline hypertensive subjects.

It has been reported that patients with essential hypertension have high plasma prolactin levels and suggested that reduced central dopaminergic activity may be a factor in the pathogenesis of essential hypertension. This study examines the influence of posture on plasma prolactin, plasma catecholamines, plasma renin activity, blood pressure and heart rate in 24 patients with borderline hypertension (age 19 +/- 1 years) and 20 normotensive subjects matched for age and body mass index. Supine plasma prolactin levels were similar in both groups [borderline hypertension, 11.3 +/- 0.7 ng/ml; normotensive, 10.7 +/- 0.8 ng/ml (mean +/- s.e.m.)] and no increase in plasma prolactin was observed after 10 min standing in both groups. Normotensive and borderline hypertensive subjects had similar values for supine and upright plasma renin activity and plasma norepinephrine. There were no significant correlations between supine plasma prolactin and supine blood pressure, supine plasma renin activity or plasma norepinephrine when data from both normotensive and borderline hypertensive subjects were combined. These results may provide indirect evidence against the occurrence of reduced central dopaminergic activity in borderline hypertension.

Effect of the angiotensin converting enzyme inhibitor, captopril (SQ14,225), on orthostatic sodium and water retention in patients with idiopathic edema.

Captopril (SQ14,225), an orally administered angiotensin converting enzyme inhibitor, was given to 8 patients with idiopathic edema, in order to study the role of the renin-angiotensin-aldosterone system in orthostatic sodium and water retention. Compared to 5 normal subjects, patients with idiopathic edema showed significantly greater reduction in water and sodium excretion, and greater increment in plasma aldosterone and plasma renin activity, in the upright posture. Captopril significantly restored water and sodium excretion, attenuated the increment in plasma aldosterone, and enhanced the rise in plasma renin activity in patients with idiopathic edema. The effects of captopril on these variables were not remarkable in normal subjects. These results suggest that an enhanced response of the renin-angiotensin-aldosterone system to standing plays an important role in the pathophysiology of idiopathic edema.

EFFECT OF A CALCIUM ENTRY BLOCKER ON BLOOD PRESSURE, PLASMA RENIN ACTIVITY, ALDOSTERONE AND CATECHOLAMINES IN NORMOTENSIVE SUBJECTS

The effects of the calcium entry blocker nifedipine on blood pressure, heart rate, plasma renin activity, aldosterone, noradrenaline and adrenaline were studied in 23 normotensive subjects in the supine and upright positions. Nifedipine, 10 mg administered sublingually, lowered mean blood pressure and increased heart rate, plasma noradrenaline and renin activity without increasing plasma aldosterone in the supine position. The increase in plasma aldosterone in response to upright posture was inhibited by nifedipine, whereas the rise in plasma noradrenaline was augmented. These results suggest that intracellular calcium is important as a regulator of aldosterone secretion as well as of vascular tone in normotensive subjects.

Effect of Captopril on Plasma Prolactin in Patients with Essential Hypertension

The effects of the angiotensin-converting enzyme inhibitor captopril on blood pressure, heart rate, plasma prolactin, and renin activity were examined in a single-blind, placebo-controlled trial on 30 patients with essential hypertension (15 given drug, 15 placebo). Captopril, 25 mg administered orally, reduced the blood pressure and increased the plasma renin activity. Captopril decreased mean plasma prolactin from 17.5±1.4 ng/mL to 9.1±1.0 ng/mL (p<0.001). Significant correlation was found between captopril-induced change from control values of plasma prolactin (Δplasma prolactin) vs Δplasma renin activity (r = -0.688, p<0.001). These results suggest that acute administration of captopril was accompanied by a reduction in plasma prolactin and that this reduction may be of clinical significance during therapy of hypertension.