Dynamic changes in dopaminergic neurotransmission induced by a low concentration of bisphenol-A in neurones and astrocytes.

One of the most common chemicals that behaves as an endocrine disruptor is the compound 4,4'-isopronylidenediphenol, called bisphenol-A (BPA). We previously reported that prenatal and postnatal exposure to BPA potentiated central dopaminergic neurotransmission, resulting in supersensitivity to psychostimulant-induced pharmacological actions. Many recent findings have supported the idea that astrocytes, which are a subpopulation of glial cells, play a critical role in neuronal transmission in the central nervous system. The present study aimed to investigate the role of neurone-astrocyte communication in the enhancement of dopaminergic neurotransmission induced by BPA. We found that treatment of mouse purified astrocytes and neurone/glia cocultures with BPA in vitro caused the activation of astrocytes, as detected by a stellate morphology and an increase in levels of glial fibrillary acidic protein. A low concentration of BPA significantly enhanced the Ca2+ responses to dopamine in both neurones and astrocytes. Furthermore, a high concentration of BPA markedly induced the activation of caspase-3, which is a marker of neuronal apoptotic cell death in mouse midbrain neurone/glia cocultures. By contrast, treatment with 17beta-oestradiol (E2) had no such effects. Prenatal and neonatal exposure to BPA led to an enhancement of the dopamine-dependent rewarding effect induced by morphine. These findings provide evidence that BPA alters dopamine responsiveness in neurones and astrocytes and that, at least in part, it may contribute to potentiate the development of psychological dependence on drugs of abuse.

Effects of oral theophylline on sick sinus syndrome.

OBJECTIVES: We sought to determine the effect of theophylline on cardiac pauses in sick sinus syndrome. BACKGROUND: Sick sinus syndrome, a relatively benign condition, is usually treated with pacemaker implantation without any proved effectiveness. Thus, an appropriate pharmacologic therapy would be useful. METHODS: Theophylline (200 to 400 mg/day for 1 month) was initially administered orally to 17 patients with sick sinus syndrome, which is manifested by sinus pauses of > 2.5 s. Eleven of the 17 patients subsequently received theophylline for an additional 8 to 37 months. Twenty-four-hour Holter recordings were obtained before treatment, at the end of 1 month of treatment and then at 6-month intervals. RESULTS: Theophylline decreased the frequency of sinus pauses from 256 +/- 230 to 23 +/- 62 pauses per 24 h and decreased the duration of the longest pauses from 4.7 +/- 1.8 to 2.2 +/- 0.97 s after 1 month of treatment. Subjective symptoms associated with cardiac pauses disappeared in 16 of 17 patients. Ventricular premature beats increased in frequency but did not last longer than two beats. Three patients experienced adverse effects. Nine of the 11 patients receiving long-term treatment had a good outcome, but 2 patients required a pacemaker because of the reappearance of long sinus pauses. CONCLUSIONS: The results suggest that oral theophylline may be beneficial for the treatment of patients with sick sinus syndrome.

Up-regulation of the G(q/11alpha) protein and protein kinase C during the development of sensitization to morphine-induced hyperlocomotion.

It has been recognized that protein kinase C (PKC) pathway is involved in the synaptic plasticity. The present study was then designed to examine the changes in G(q/11alpha) and G(betagamma) subunits and PKC activity on sensitization to the morphine-induced hyperlocomotion. Repeated subcutaneous administration of morphine every 72 h produced sensitization to the morphine-induced hyperlocomotion. In morphine-sensitized mice, the protein level of G(q/11alpha) subunit in the limbic forebrain including the nucleus accumbens, but not in the lower midbrain containing the ventral tegmental area, was markedly increased, whereas the levels of G(betagamma) subunit were not altered in either areas. Under these conditions, the levels of membrane-bound phosphorylated-PKC in the limbic forebrain was clearly up-regulated by intermittent morphine treatment. We also found the lack of changes in the level of the regulator of G protein signaling 4, which is a specific G(q/11alpha)-dependent GTPase activating protein, in the limbic forebrain obtained from morphine-sensitized mice. These results indicate that the up-regulation of membrane-bound PKC following intermittent morphine treatment results from the increase in levels of G(q/11alpha) protein. In order to investigate the direct involvement of PKC in the morphine-induced hyperlocomotion, the locomotion induced by acute morphine treatment in the presence or absence of a PKC inhibitor was measured. A specific PKC inhibitor Ro-32-0432 given intracerebroventricularly caused a dose-dependent inhibition of morphine-induced hyperlocomotion. These findings suggest that the up-regulation of G(q/11alpha)-dependent PKC activity in membranes of the limbic forebrain is implicated in the development of sensitization to morphine-induced hyperlocomotion in mice.

Prenatal and neonatal exposure to bisphenol-A enhances the central dopamine D1 receptor-mediated action in mice: enhancement of the methamphetamine-induced abuse state.

Bisphenol-A (BPA), one of the most common environmental endocrine disrupters, has been extensively evaluated for toxicity in a variety of tests in rodents, including developmental and reproductive toxicity, and carcinogenicity. However, little is known about its action on the CNS. In this report, we show that prenatal and neonatal exposure to BPA in mice leads to the enhancement of the dopamine D1 receptor-dependent rewarding effect induced by a psychostimulant methamphetamine. Furthermore, this treatment with BPA markedly enhanced hyperlocomotion and its sensitization induced by methamphetamine, which reflects extensive abuse associated with sociological and psychiatric problems. We also demonstrated that chronic exposure to BPA produced an up-regulation of dopamine D1 receptor function to activate G-protein in the mouse limbic forebrain, which is thought to be a critical site for the expression of rewarding effects by abuse drugs. Additionally, chronic BPA exposure produced a significant increase in levels of the dopamine D1 receptor mRNA in the whole brain. In contrast, no change in protein levels of methamphetamine-targeted proteins, dopamine transporter or the type 2 vesicle monoamine transporter in the brain was observed by prenatal and neonatal exposure to BPA. The present data provide the first evidence that prenatal and neonatal exposure to BPA can potentiate the central dopamine D1 receptor-dependent neurotransmission, resulting in supersensitivity of methamphetamine-induced pharmacological actions related to psychological dependence on psychostimulants.

Effects of nipradilol on venous hemodynamics: evaluation with a Doppler blood flow method.

Nipradilol is a newly synthesized beta-blocker which has a propranolol-like structure and contains a nitrate moiety. To examine the effect of nipradilol on venous blood flow, a single oral dose of nipradilol (6 mg) and propranolol (20 mg) was administered in the same 15 normal volunteers on separate days. Peak flow velocities, flow velocity integrals, and the diameter of the right brachiocephalic vein were measured before and 2 h after drug administration using Doppler echocardiography. These two beta-blockers significantly decreased systolic blood pressure to the same extent as they did heart rate. Nipradilol dilated the venous diameter by 8% and decreased peak flow velocity by 8% during systole and 9% during diastole. The flow velocity integral in one cardiac cycle also decreased significantly by 14%. Propranolol, however, failed to modify these parameters. These results suggest that nipradilol decreased venous return through its nitroglycerin-like direct vasodilating action.

[A case of an idiopathic enlargement of the right atrium, lacking in prominent right atrium contour and mimicking left pericardial defect on the chest X ray].

A 47-year-old man was admitted for evaluation of heart murmur in 1982. On admission, two-dimensional echocardiogram showed a giant right atrium with mild tricuspid regurgitation, but a chest X ray showed no prominent right atrium contour. Echocardiographic finding at various postures and chest X ray with artificial pneumothorax indicated little likelihood of left pericardial defect. An angiocardiogram and computed tomography showed the dilated right atrium with clockwise rotation. There was no indication of right atrial overload. Therefore, we made the diagnosis of an idiopathic enlargement of the right atrium. For about 10 years after discharge, we have followed up this patient. He has received no treatment and has been asymptomatic. On the other hand, echocardiography shows that the right atrium has gradually enlarged. Electrocardiogram has clearly revealed only a tall and slender peaked P wave in chest leads for the last 5 years. This may indicate not only an increasing load on the right atrium but also that the enlarged atrium is getting closer to the walls of the chest. We report this case of an idiopathic enlargement of the right atrium lacking in prominent right atrium contour, and mimicking left pericardial defect on chest X ray.

Assessment of regional early diastolic function using cine magnetic resonance imaging in patients with hypertrophic cardiomyopathy.

In patients with hypertrophic cardiomyopathy (HCM), we conducted cine magnetic resonance imaging (MRI) studies in which our objectives were to quantify the regional early diastolic function of the left ventricle and to evaluate the relationship between regional diastolic function and hypertrophy. Short-axis images of the left ventricle were recorded by cine MRI in 8 control patients and 24 patients with HCM. The images were then divided into 10 blocks to evaluate regional early diastolic function. The regional wall-thickness-time curve, the radius-time curve, and their first-derivative curves were computed for each of the 10 blocks. There was no difference between the time-to-peak-radius-increasing ratio and the time-to-peak-wall-thickness-thinning ratio in the 10 blocks in the control patients. These 2 parameters in the patients with HCM were significantly longer than those in the control patients. There was also a significant linear correlation between the time-to-peak-wall-thickness-thinning ratio and regional wall thickness. Cine MRI was useful for evaluating regional early diastolic function, which is apparently related to regional hypertrophy, in patients with HCM.

Intravenous injection of adenosine triphosphate for assessing sinus node dysfunction in patients with sick sinus syndrome.

The clinical value of rapid intravenous injection of adenosine triphosphate (ATP, Adephos Kowa # L3, CAS 56-65-5) for assessing sinus node function was examined in 5 patients with sick sinus syndrome (SSS) and 6 normal controls. All patients with SSS showed cardiac pauses longer than 3 s on a 24-h Holter ECG monitoring. First, after prophylactic insertion of a temporary pacemaker in the right ventricle, overdrive suppression test was conducted using the standard technique, and sinus node recovery time (SNRT) was observed to evaluate the sinus node function. Then, 10 min later, 10 mg of ATP was rapidly injected intravenously, and body surface and intracavitary ECG were continuously recorded until the basal state was regained. The rapid injection of ATP resulted in a slight inhibition of sinus node automaticity in normal subjects, but marked inhibition was in patients with SSS associated with suppression of AV conduction. The longest post ATP atrial cycle (AA interval in the intracavitary ECG showed a close inverse relationship with SNRT corrected for basal sinus length (CSNRT), according to the following formula: longest AA interval (ms) = 3.32 x CSRT (ms) +254.4 (r = 0.91, p < 0.001). The results suggest that rapid intravenous injection is a useful tool for the diagnosis of SSS.

Effects of inosine on adenosine-induced coronary vasodilation in the open chest dog.

The effects of inosine (CAS 58-63-9) on adenosine-induced coronary vasodilation were studied in open-chest dogs. Inosine and hypoxanthine were infused into the coronary artery at a rate to obtain respective calculated coronary plasma concentrations of 10(-5) mol/l, and the dose-coronary flow response of adenosine was recorded with and without inosine or hypoxanthine infusion. When the maximum coronary dilation was obtained, 10 ml of 2 x 10(-3) mol/l 8-phenyltheophylline (8-PT) solution was injected into the femoral vein. Additionally, adenosine deaminase activity was measured in vitro in the presence of various concentrations of either inosine or hypoxanthine. It was found that inosine, but not hypoxanthine, intensified the coronary vasodilatory effect of adenosine, which was abolished by 8-PT injection: EC50 of adenosine was reduced from 10(-5.43) mol/l to 10(-5.90) mol/l by inosine. Inosine and hypoxanthine did not affect adenosine deaminase activity at concentrations of 10(-4) mol/l or less. These findings indicate that inosine intensifies the coronary vasoactivity of adenosine, independent of inhibition of adenosine deaminase activity.

Early afterdepolarization abolished by potassium channel opener in a patient with idiopathic long QT syndrome.

We describe a 17-year-old boy with idiopathic long QT syndrome and repeated syncopal episodes. Early afterdepolarization (EAD) in the monophasic action potential (MAP) was demonstrated in the posterior septum of the left ventricle. Injection of the potassium channel opener nicorandil decreased EAD and shortened MAP duration. The syncopal episodes due to ventricular fibrillation disappeared after administration of the potassium channel opener.

Relationship between pressure-rate product and myocardial oxygen consumption of normal and hypertrophic right ventricles in open-chest dogs.

There are few reports on the relationship between right ventricular performance and its myocardial oxygen consumption (RVMVO2). The present study was conducted to investigate the relationship between RVMVO2 and the mechanical performance of normal and hypertrophic right ventricles in open-chest dogs. Right ventricular hypertrophy (RVH) was induced by producing chronic right ventricular pressure overload by banding the pulmonary arteries of 8 puppies for 6 months. The experiment was performed under basal conditions and after increasing the RVMVO2 in the eight dogs with RVH as well as in 20 normal dogs. The RVMVO2 showed significant positive relationships with right coronary (RCA) flow, right ventricular systolic pressure, and right ventricular pressure-rate product (PRP) in both the normal right ventricle and RVH hearts. However, the slope between the PRP and RVMVO2 was significantly steeper in the normal right ventricle (RV) than in the hypertrophic RV. When the PRP was normalized for the thickness of the right ventricular free wall, the slope of the two regression lines merged into a single line of fit. These results suggest that the pressure-rate product can be used to predict myocardial oxygen demand not only in the normal RV but also in well-compensated, hypertrophic RV. Isoproterenol induced smaller increases in cardiac output in the dogs with RVH than in those with normal RV. It also appears that the cardiac output of the hypertrophic RV is less sensitive to beta-adrenoceptor stimulation than that of the normal RV.

Apical hypertrophy associated with rapid T wave inversion on the electrocardiogram.

A 53-year-old man who had no chest pain and no family history of heart disease demonstrated a rapid T wave change on an electrocardiogram, from a positive T wave to a giant negative T wave, within 1 year. Echocardiography showed no left ventricular hypertrophy before or after the T wave change. Cine-magnetic resonance imaging revealed focal apical hypertrophy after the appearance of the giant negative T wave. Although T wave inversions sometimes develop within a short period in patients with hypertrophic cardiomyopathy, they are rare in a patient without hypertension or chest pain.

Morning increase in hemodynamic response to exercise in patients with angina pectoris.

The present study was conducted to determine whether or not there is diurnal variation in the hemodynamic responses to stimuli that increase myocardial oxygen demand, and the effects of such variation on electrocardiograms (ECG). Fifteen patients with angina pectoris, 17 patients with old myocardial infarction, and 8 healthy controls were examined in this study. Graded exercise stress testing was conducted in the supine position, once in the morning and once in the afternoon, using a bicycle ergometer. A standard 12-lead ECG was recorded before, immediately after, and 3, 5, and 10 min after the end of the exercise. The exercise ECG and blood pressure changes were compared among the groups and, within each group, the results after morning and afternoon exercise were compared. Hemodynamic responses, including heart rate, blood pressure, and the pressure-rate product, showed greater increases in the morning than in the afternoon in angina patients and controls, in association with greater depression of the electrocardiographic ST-segment. In contrast, patients with old myocardial infarction exhibited no difference in hemodynamic responses or the ST-pattern from morning to afternoon. The results suggest that diurnal variation of hemodynamic responses to increased oxygen demand may explain, at least partly, why myocardial ischemia of effort angina is more severe in the morning than in the afternoon.