Electroconvulsive therapy (ECT) is used to treat drug-resistant depressive disorders. The results of studies on the mechanism underlying the effectiveness of ECT on depression are still controversial. ECT stimulus is usually larger than the threshold of induction of seizures and activation of whole-brain is believed to be necessary to produce therapeutic effects. A single ECT session induces alterations of the electroencephalogram (EEG) including initial epileptic discharges, then slow waves, and finally flattened EEG. Repeated ECT results in an increasing number of slower waves in the EEG for as long as a month. ECT-induced changes in various neurotransmitter systems have also been reported. Serotonin (5-hydroxytryptamine, 5-HT) is one of the most important neurotransmitters involved in depressive illness, and ECT alters several 5-HT-receptor subtypes in the central nervous system. 5-HT_1A receptors in post-synaptic neurons are sensitized by repeated ECT, but those in pre-synaptic neurons (auto-receptors) are not changed. In addition, our electrophysiological studies have shown that ECT increases sensitivity to 5-HT of 5-HT₃ receptors in the hippocampus, resulting in an increase in release of neurotransmitters such as glutamate and γ-aminobutyric acid. In contrast, ECT decreases the auto-receptor functions in noradrenergic and dopaminergic neurons in the locus coeruleus and substantia nigra, respectively, resulting in an increase in release of noradrenaline and dopamine. In conclusion, 5-HT_1A-receptor sensitization may be important for explaining the effectiveness of ECT, as this change induces a decrease in the number of 5-HT_2A receptors that are elevated in depressive patients. Facilitation of neurotransmitter releases due to 5-HT₃-receptor sensitization by ECT may also play an important role in effective treatment of depressive patients refractory to therapeutic drugs.

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Recent progress in electrophysiological and microscopic techniques have enabled us to estimate exocytotic and pre-exocytotic events in the secretory machinery in single pancreatic beta-cells. We have been studying mechanisms involved in the regulation of insulin granule movement, which supplies release-ready granules, by direct visualization of granule traffic in living beta-cells and found the movement to be regulated by a mechanism different from that controlling exocytosis. From the obtained findings together with those from electrophysiological approaches, a new understanding of the role of the crucial second messenger Ca²⁺, and other second messengers, as well as resultant protein phosphorylation has been generated. The aim of this review is to describe a synergistic network for the control of insulin release by second messengers and protein kinases.

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The aim of this study was to investigate the therapeutic effectiveness of lacidipine in stroke-prone spontaneously hypertensive rat (SHRSP) with cerebrovascular lesions in comparison with nicardipine. SHRSP were fed 1% saline as drinking water. After the onset of stroke, saline was replaced with water and each drug was administered orally once a day for 3 weeks. In the drug-untreated group, recurrence of stroke was repeated, deterioration and amelioration of neurological deficits (ND) were repeated, and histological examination and measurement of regional blood flow (rBF) using nonradioactive colored microspheres performed at the end of treatment revealed severe damages and significantly decreased rBF in brain and kidney, respectively. In kidney, not only lacidipine (1 mg/kg) but also nicardipine (30 mg/kg) decreased vascular lesions and ameliorated low-rBF significantly. Both drugs also inhibited the recurrence of stroke completely even at a low dose that did not ameliorate severe hypertension. Neuronal damages and ND in each lacidipine-treated group were ameliorated significantly, whereas those in each nicardipine-treated group were slightly improved. Lacidipine at 1 mg/kg alone ameliorated the cerebral low-rBF significantly even at 24 hr after administration. These results suggest that a long-lasting improvement of low-rBF after stroke may be useful in the treatment of SHRSP with cerebrovascular lesions.

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Tamsulosin, a selective α_1A-adrenoceptor antagonist, and terazosin, a non-selective one, are effective for the treatment of urinary disturbance due to benign prostatic hypertrophy. In the present study, their α₁-adrenoceptor-blocking effects on blood vessels, which may cause orthostatic hypotension, were investigated in 10 healthy males. After the subjects took orally 0.2 mg of tamsulosin, 1 mg of terazosin or a lactate capsule as the control in a randomized cross-over fashion, their finger tip vasoconstrictor response to cold stimulation and vasoconstrictor response of the dorsal hand vein to increasing doses of phenylephrine were examined. The finger tip vasoconstrictor response was significantly reduced and the infusion rate of phenylephrine producing a half-maximal constriction was significantly increased by terazosin, but tamsulosin had no significant effect on these parameters. These data suggest that the usual dose of tamsulosin exerts little α₁-adrenoceptor-blocking activity on blood vessels, and orthostatic episodes might be mild, if any, during the treatment with tamsulosin.

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We investigated the efficacy of histidine on potassium-depolarization induced hydroxyl radical (·OH) generation in the extracellular fluid of rat myocardium by a flexibly mounted microdialysis technique (O system). After the rat was anesthetized, a microdialysis probe was implanted in the left ventricular myocardium, and then sodium salicylate in Ringer’s solution (0.5 nmol/μl per minute) was infused to detect the generation of ·OH as reflected by the nonenzymatic formation of 2, 3-dihydroxybenzoic acid (DHBA). Infusion of KCl (70 mM) clearly produced an increase in ·OH formation. However, when KCl in the presence of a high concentration of histidine (25 mM) was infused through the microdialysis probe, KCl failed to increase the 2, 3-DHBA formation. To examine the effect of histidine on ischemia-reperfusion of the myocardium, the heart was subjected to myocardial ischemia for 15 min by occlusion of the left anterior descending coronary artery (LAD). When the heart was reperfused, a marked elevation of the levels of 2, 3-DHBA was observed in the heart dialysate. However, when corresponding experiments were performed with histidine (25 mM)-pretreated animals, histidine prevented the ischemia-reperfusion induced ·OH formation trapped as 2, 3-DHBA. These results indicate that histidine may protect against K⁺-depolarization-evoked ·OH generation in rat myocardium.

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Intrarenal infusion of 4-pentenoic acid is known to lower renal cortical ATP content and cause a reduction in glomerular filtration rate (GFR). The alteration in nucleotide metabolism might augment the production of adenosine, thereby eliciting the fall in GFR. This study was conducted to examine whether 4-pentenoic acid stimulates renal production of adenosine, and if so, to examine the role of adenosine A1 receptor in the reduction of GFR by 4-pentenoic acid. With infusion of 4-pentenoic acid (1 μmol·kg^-1·min^-1) into the renal artery of anesthetized dogs, GFR gradually decreased and reached minimum at 60 min with values ranging from 33.9±2.2 to 20.2±2.8 ml/min. Neither renal blood flow nor mean arterial pressure was affected, but tubular reabsorption of water and sodium was significantly attenuated. Renal venous plasma concentration and urinary excretion of adenosine rose markedly (20-fold) without any change in arterial concentration, suggesting that renal adenosine production was augmented by 4-pentenoic acid. However, KW-3902 (8-(noradamantan-3-yl)-1, 3-dipropylxanthine), a selective antagonist of the adenosine A1 receptor, did not affect the action of 4-pentenoic acid on GFR or renal handling of water and sodium. It is concluded that 4-pentenoic acid markedly increases renal adenosine production, but adenosine A1 receptor is not involved in the 4-pentenoic acid-induced nephrotoxicity.

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Lafutidine is a new type antiulcer agent with antisecretory and gastroprotective activities. We investigated the effect of lafutidine on indomethacin-induced antral ulcer in refed rats. Subcutaneous indomethacin injection resulted in the formation of gastric antral ulcer. Lafutidine (1 - 10 mg/kg, p.o.) reduced the area of ulcer in a dose-dependent manner when administered immediately after the indomethacin injection. Capsaicin at 3 mg/kg, p.o. and 16, 16-dimethyl prostaglandin E₂ at 3 μg/kg, p.o. also reduced the ulcer area. Chemical deafferentation of capsaicin-sensitive neurons or N^G-nitro-L-arginine treatment aggravated the ulcer formation and abolished the preventive effect of lafutidine and capsaicin. After the induction of gastric ulcer, lafutidine given twice daily for 2.5 days reduced the area of ulcer in a dose-dependent manner with a significant effect at 10 mg/kg, p.o., as compared with that of the control group. In chemically-deafferentated rats, lafutidine did not show any healing effect. Cimetidine (30 mg/kg, p.o.) and famotidine (1 mg/kg, p.o.) had no significant effect on indomethacin-induced antral ulcer. These results may suggest that lafutidine, unlike cimetidine and famotidine, can prevent the indomethacininduced antral ulcer formation and accelerate the healing of the ulcer in refed rats through mechanisms involving the capsaicin-sensitive afferent neurons and nitric oxide.

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Alkylamines inhibit NADPH oxidase both in intact neutrophils and in a cell-free system. The aim of this study was to examine the mechanism underlying this inhibitory effect. Among alkylamines with different chain lengths, the C12 compound (laurylamine) showed the greatest inhibitory effect on the cell-free NADPH oxidase activity induced by arachidonic acid (AA) in the presence of GTPγS. The inhibition was overcome by further addition of AA, and it was observed irrespective of whether laurylamine was added before or after the enzyme activation by AA. When added prior to the enzyme activation, laurylamine blocked translocation to the membrane of all three cytosolic components (p47-phox, p67-phox and rac) in a cell-free translocation assay. When added after the activation, laurylamine released only rac from the membrane. Laurylamine did not inhibit the reduction of cytochrome c by xanthine oxidase, suggesting that it does not have superoxide-scavenging activity. These results indicate that laurylamine inhibits both the activation process of NADPH oxidase and the activated enzyme itself by blocking the assembly of the oxidase components.

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Effects of K⁺ channel modulators, cromakalim and E4031 [1-[2-(6-methyl-2-pyridyl)-ethyl]-4-(4-methylsulfonylaminobenzoyl) piperidine], on the relationship between the action potential duration (APD) and Ca²⁺ transients were examined in single myocytes isolated from guinea pig cardiac left ventricle. Application of cromakalim decreased APD at 90% repolarization (APD₉₀) and Ca²⁺ transient elicited at 0.5 Hz (IC₅₀s=0.6 and 3 μM, respectively). Application of 0.3 μM E4031 increased these parameters by 110% and 45%, respectively. Under voltage-clamp, the relation between the duration of depolarization to 0 mV and Ca²⁺ transients could be described by the sum of two exponential components; the time constants were approximately 5 and 280 msec, respectively. The first component was abolished by 10 μM ryanodine, suggesting the involvement of Ca²⁺-induced Ca²⁺ release (CICR). Neither cromakalim nor E4031 directly affected Ca²⁺ current and Ca²⁺ transients under voltage clamp. When APD was changed by K⁺ channel modulators, the relation between APD₉₀ and Ca²⁺-transients was almost similar to that obtained by changing the depolarization duration under voltage-clamp. CICR was changed significantly only when APD₉₀ was markedly shortened by cromakalim. The extensively prolonged AP and Ca²⁺ transient in the presence of E4031 were reduced by an addition of cromakalim. It is concluded that these two K⁺ channel modulators can significantly alter the AP-induced Ca²⁺ transient mainly by changing APD, which regulates both Ca²⁺ influx and extrusion.

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The effect of immobilization, gentle handling and decapitation on the level of plasma histamine in Wistar rats was investigated. Mast cell deficient (Ws/Ws) rats were used to characterize the source of elevated histamine in plasma by stress, and the effect of nedocromil, a mast cell stabilizer, on histamine release was assessed in these models in vivo. The plasma histamine concentration of freely moving rats was 93.0±2.3 pmol/ml. Gentle handling produced a transient increase in plasma histamine level by 1.9-fold, whereas immobilization resulted in a longer-lasting elevation by 2.6-fold compared to that in the freely moving rats. Decapitation increased the plasma histamine level by 10- to 16-fold compared with that in the freely moving rats. No increase in plasma histamine was found in Ws/Ws rats exposed to stress. Nedocromil inhibited the increase in plasma histamine level induced by stress in a dose-dependent manner. These findings suggest that stress induces histamine release from mast cells in Wistar rats and the extent of this histamine release increases with the severity of stress. Nedocromil proved to be a good pharmacological tool to inhibit stress-induced release of mediators from mast cells.

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A new portable-type laser blood flowmeter was recently developed for measuring the blood flow in vessels. The sensitivity and specificity of the laser flowmeter was assessed in comparison with the well-established electromagnetic flowmeter using a canine isolated, blood-perfused ventricular tissue preparation. The laser flowmeter can record the phasic pattern of the coronary blood flow like the electromagnetic flowmeter. The extent of the changes after intracoronary administration of ACh and angiotensin II as well as coronary occlusion was almost identical between these two methods. These results suggest that the new laser flowmeter may possess potential utilities in both basic experimental and clinical practices.

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The cardiovascular effects of a new class I antiarrhythmic drug, bisaramil, were examined using canine isolated, blood-perfused heart preparations. Bisaramil exerted negative chronotropic, inotropic and dromotropic effects as well as coronary vasodilator action, which are qualitatively the same as those of classical class I drugs. The selectivity of bisaramil for the intraventricular conduction vs the other cardiac variables was compared with that of disopyramide and flecainide. Bisaramil was the most selective for intraventricular conduction, while it was the least selective for ventricular muscle contraction. We conclude that bisaramil may become a useful antiarrhythmic drug with less cardiac adverse effects.

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We investigated the dose-response effects of phenylephrine and antagonistic effects of prazosin on axial movement of the rat incisor and arterial blood pressure. Phenylephrine caused a temporal extrusive tooth movement and an increase in blood pressure at all doses. With increasing phenylephrine doses, the maximum extrusive tooth movement and maximum increase in blood pressure were enhanced. The maximum extrusive tooth movement and increase in blood pressure induced by phenylephrine were markedly suppressed after pretreatment with prazosin. These results suggested that extrusive tooth movement is closely related to the rise in blood pressure due to stimulation of vascular α₁-receptors.

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