l-DOPA induces concentration-dependent facilitation and inhibition of presynaptic acetylcholine release in the guinea-pig submucous plexus

Neurotransmitter- or neuromodulator-like actions ofl-DOPA were investigated with intracellular recordings from submucous plexus neurons of the guinea-pig caecum.l-DOPA at 30 nM augmented the amplitude of fast EPSPs, but did not affect depolarizations elicited by puff application of acetylcholine (ACh). The augmenting effect ofl-DOPA on the fast EPSPs was counteracted byl-DOPA methyl ester. The fast EPSPs were depressed by 10 μMl-DOPA, but transiently augmented after rinsing the drug.l-DOPA methyl ester did not affect the inhibitory action ofl-DOPA on the fast EPSPs, but antagonized the potentiation following the inhibition. The depolarization elicited by exogenously applied. ACh was inhibited by 10 μMl-DOPA. Intracellular Ca²⁺ concentrations ([Ca²⁺]_i) of the neuronal soma were measured with fura-2 microfluorophotometry. The transient increase in the [Ca²⁺]_i evoked by the somatic action potential (Δ[Ca²⁺]_AP) was facilitated by 30 nMl-DOPA, but decreased by the drug at 10 μM. It is concluded thatl-DOPA at low concentrations enhances the Δ[Ca²⁺]_AP, increasing the neurotransmitter release, but at high dose diminishes the Δ[Ca²⁺]_AP, inhibiting the neurotransmission.     

Periodic oscillation of intracranial pressure in ventricular dilation: a preliminary report

Artificial pressure waves (PWs) were generated by manual inflation of a balloon in the trigonum of the lateral ventricle in seven adult mongrel dogs with normal cerebrospinal fluid (CSF) circulation. In 14 of 16 series of continuous appearances of artificial PWs, local shifts of the brain were successfully monitored using small strain-gauge sensors at the periventricular structures in these animals. Of the 14 series, 13 showed displacements of the periventricular structures, suggesting ventricular dilation. These results did not always correlate with macroscopic findings. They are thought to be due largely to periventricular oedemas and, in part, non-uniform dilations of the ventricles during PWs. We conclude that a water hammer formed by reflection of an increased pulse pressure of PWs at the site of CSF absorption causes a shift of CSF from the ventricle to the periventricular structures through the wall of the ventricle. This phenomenon appears amplified in patients with impaired CSF absorption. Thus, PWs have a pathological role in the progress of ventricular dilation in patients with normal pressure hydrocephalus.     

L-dopa facilitates the release of endogenous norepinephrine and dopamine via presynaptic beta 1- and beta 2-adrenoceptors under essentially complete inhibition of L-aromatic amino acid decarboxylase in rat hypothalamic slices

In rat hypothalamic slices, L-aromatic amino acid decarboxylase (AADC) was assayed, and the actions of L-DOPA on impulse (2 Hz)-evoked norepinephrine (NE) and dopamine (DA) release were studied under inhibition of AADC. Slices were incubated with L-DOPA, and DA and NE produced by conversion of the precursor were analyzed by high performance liquid chromatography with electrochemical detection (HPLC-ECD). In the slices, the Km and Vmax of AADC were 131 microM and 122 pmol/min/mg protein, respectively. NSD-1015, an AADC inhibitor, caused a noncompetitive type of inhibition, and the K1 value was 0.086 microM. In the presence of 20 microM NSD-1015, which was expected to cause 99.6% inhibition of AADC, L-DOPA (0.01-100 nM) concentration-dependently facilitated the release of NE from the superfused slices, and the L-DOPA (10 nM)-induced facilitation was antagonized by 100 nM ICI 89,406 and 100 nM ICI 118,551, a selective beta 1- and beta 2-adrenoceptor antagonist, respectively. This action of L-DOPA was not modified by 30 microM tropolone, an inhibitor of catechol-O-methyl-transferase. L-DOPA at 0.01-1 nM similarly facilitated the release of DA. A quantitative analysis revealed that the L-DOPA-induced increase in NE and DA release was much higher by a factor of 3 to 4 orders than was the amount of DA and NE converted from L-DOPA. These results add further support to the hypothesis that L-DOPA itself acts as a neuroactive substance in the rat central nervous system.     

Gastric motility in patients with recurrent gastric ulcers.

The existence of abnormal gastric motility in gastric ulcer disease remains controversial. The aim of this study was to characterize gastric motility in patients with recurrent gastric ulcers. Studies were performed in 10 control subjects and in 24 patients with recurrent active gastric ulcer disease as diagnosed by gastrointestinal endoscopy. Gastric motility was evaluated by cutaneous electrogastrography (EGG) and by gastric semi-liquid meal emptying. The EGG was recorded before and after ingestion of a test meal containing 20 mg/kg of acetaminophen. Patients with a dominant EGG frequency of greater than 0.06 Hz were defined as tachygastria, while those with a frequency of less than 0.04 Hz were defined as bradygastria. A transient frequency decrease, called postprandial dip (PD), was identified visually. The degree of gastric emptying was determined from the serum acetaminophen concentration 45 minutes after the meal. Control subjects showed no irregularity in their dominant EGG frequency in tither fasting or postprandial states. PD was observed in 8 control subjects. In patients presenting with active gastric ulcers, abnormal patterns in the dominant EGG frequency (either as tachygastria or bradygastria) were observed in 14 of the 24 patients when fasting and in 15 of them in the postprandial state. After successful treatment, the number of patients with abnormal patterns in their dominant EGG frequency remained unchanged, while PD was observed in 11 patients. No significant difference was observed in the EGG power ratio as a result of successful treatment. Gastric emptying was significantly delayed compared with controls in both the active and healed stages. These findings suggest that abnormal gastric motility, including gastric electrical abnormalities and delayed gastric emptying, plays an important role in the pathophysiology of recurrent gastric ulcers.     

Autoradiographic studies using L-[(14)C]DOPA and L-DOPA reveal regional Na(+)-dependent uptake of the neurotransmitter candidate L-DOPA in the CNS

We previously proposed that L-3,4-dihydroxyphenylalanine (L-DOPA) is a neurotransmitter in the CNS. Receptor and transporter molecules for L-DOPA, however, have not been determined. In the present study, in order to localize the uptake sites of L-DOPA in the CNS, we performed autoradiographic uptake studies using L-[14C]DOPA and L-[3H]DOPA in the uptake study on rat brain slice preparations, and further analyzed the properties of L-DOPA uptake. Image analysis of the L-[14C]DOPA autoradiogram showed a unique heterogeneous distribution of uptake sites in the brain. The intensity was relatively high in the cerebral cortex, the hypothalamus, the cerebellum and the hippocampus, while the density was moderate or even low in the striatum and the substantia nigra. L-DOPA and phenylalanine, but not dopamine (10mM) were able to almost completely inhibit the uptake of L-[14C]DOPA to basal levels. Microautoradiographic studies using L-[3H]DOPA revealed accumulation of dense grains in the median eminence, the supraoptic nucleus of the hypothalamus, the cerebral cortex (layer I) and the hippocampus. In the cerebellum, grains formed in clusters surrounding the Purkinje cells. This grain accumulation was concluded to be in Bergmann glial cells, since the morphological pattern of grain accumulation was similar to that of the immunoreactivity of the glutamate aspartate transporter, a marker protein for Bergmann glial cells. In the hippocampus, the grain density significantly decreased under Na(+)-free conditions. In addition, grain density also decreased in the absence of Cl(-). In contrast, grains in the choroid plexus and the ependymal cell layer, were not affected by the absence of Na(+). These findings indicated that the uptake of L-DOPA occurs via various types of large neutral amino acid transport mechanisms. It appears that neuronal and/or glial cells, which take up L-DOPA in a Na(+)-dependent manner, exist in the CNS. Our finding further supports the concept that L-DOPA itself may act as a neurotransmitter or neuromodulator.     

Cardiovascular effects in rats of alpha1 and alpha2 adrenergic agents injected into the nucleus tractus solitarii

Summary The cardiovascular effects of selective alpha₁ and alpha₂ agonists and antagonists injected into the nucleus tractus solitarii (NTS) were studied in urethane-anesthetized rats. Methoxamine (0.3–3 g) injected bilaterally into the NTS caused a dose-dependent increase in blood pressure and heart rate. Phenylephrine (6 g) and an imidazolidine derivative St 587 (3 g) similarly injected also produced an increase in blood pressure, whereas a-methylnoradrenaline and an azepine derivative B-HT 920 (1 and 3 g) caused a decrease in blood pressure and heart rate. The pressor response to methoxamine (1 g) was markedly inhibited by prazosin (0.3 pg) injected into the same sites or hexamethionum (25 mg/kg, i. v.). Prazosin (0.3 g) alone injected bilaterally into the NTS did not affect the blood pressure, while yohimbine (0.1 g) similarly injected increased the pressure. These results suggest that in the rat NTS there exist alpha₁ adrenoceptors responsible for an increase in arterial pressure. The NTS alpha2 adrenoceptors seem to be involved in the tonic regulation of arterial pressure. Send offprint requests to T. Kubo at the above address     

Diagnostic implications of elevated levels of smooth-muscle myosin heavy-chain protein in acute aortic dissection. The smooth muscle myosin heavy chain study

BACKGROUND: A rapid 30-minute assay of circulating smooth-muscle myosin heavy-chain protein has been developed as a biochemical diagnostic tool for aortic dissection. OBJECTIVE: To determine the sensitivity and specificity of this assay. DESIGN: Cross-sectional study. SETTING: 8 major cardiovascular centers in Japan. PATIENTS: 95 patients with acute aortic dissection, 48 patients with acute myocardial infarction, and 131 healthy volunteers. MEASUREMENTS: Levels of circulating smooth-muscle myosin heavy-chain protein. RESULTS: Patients with acute aortic dissection who presented within 3 hours after onset had elevated levels of circulating smooth-muscle myosin heavy-chain protein. In these patients, the assay had a sensitivity of 90.9%, a specificity of 98% compared with healthy volunteers, and a specificity of 83% compared with patients who had acute myocardial infarction; the clinical decision limit was 2.5 microgram/L. All patients with proximal lesions had elevated levels of smooth-muscle myosin heavy-chain protein, and only patients with distal lesions had decreased levels (<2.5 microgram/L). CONCLUSIONS: Levels of smooth-muscle myosin heavy-chain protein can be used to diagnose aortic dissection soon after symptom onset. The assay had the greatest diagnostic value in patients with proximal lesions.     

新型冠状病毒肺炎疫情期间发热门诊开展药学服务模式探索

目的结合新型冠状病毒肺炎(简称新冠肺炎)疫情防控特点,探讨医院发热门诊开展药学服务的工作模式。方法回顾整理新冠肺炎疫情防控期间发热门诊的药学服务工作,针对薄弱环节进行持续改进。结果与结论医院发热门诊在疫情防控第一时间实施电子处方,采取岗前培训、医师诊疗系统药学信息服务支持、推进发热门诊实时互动审方、探索通过互联网平台实现患者离院后药学服务延伸等有力措施,推动发热门诊药学服务工作的深入开展,保障了发热门诊患者用药安全性和有效性。随着"互联网+诊疗"模式的迅速兴起,"互联网+药学服务"平台亟待建立。     

Slowly progressive insulin-dependent diabetes in a patient with primary biliary cirrhosis with portal hypertension-type progression

A 73-year-old woman had previously been diagnosed with CREST syndrome, PBC and diabetes. Hepatic fibrosis was not evident, in spite of the transudative ascites and active esophageal varices. ACA were positive, whereas AMA and anti-gp210 antibodies were negative. She showed low urinary excretion of C-peptide and was weakly positive for anti-GAD antibody. She was diagnosed with a form of PBC that progresses via portal hypertension rather than liver failure and with SPIDDM. Her HLA type did not contain risk allele for IDDM or PBC. SPIDDM should be considered when patients with PBC with portal hypertension-type progression develop diabetes.