Activation of human D3 dopamine receptor inhibits P/Q-type calcium channels and secretory activity in AtT-20 cells.
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The D3 dopamine receptor is postulated to play an important role in the regulation of neurotransmitter secretion at both pre- and postsynaptic terminals. However, this hypothesis and the underlying mechanisms remain untested because of the lack of D3-selective ligands, paucity of appropriate model secretory systems, and the weak and inconsistent coupling of D3 receptors to classical signal transduction pathways. The absence of ligands that selectively discriminate between D3 and D2 receptors in vivo precludes the study of D3 receptor function in the brain and necessitates the use of heterologous expression systems. In this report we demonstrate that activation of the human D3 dopamine receptor expressed in the AtT-20 neuroendocrine cell line causes robust inhibition of P/Q-type calcium channels via pertussis toxin-sensitive G-proteins. In addition, using the vesicle trafficking dye FM1-43, we show that D3 receptor activation significantly inhibits spontaneous secretory activity in these cells. Our results not only support the hypothesis that the D3 receptor can regulate secretory activity but also provide insight into the underlying signaling mechanisms. We propose a functional model in which the D3 receptor tightly regulates neurotransmitter release at a synapse by only allowing the propagation of spikes above a certain frequency or burst-duration threshold. (+info)
L-type Ca2+ channels and K+ channels specifically modulate the frequency and amplitude of spontaneous Ca2+ oscillations and have distinct roles in prolactin release in GH3 cells.
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GH3 cells showed spontaneous rhythmic oscillations in intracellular calcium concentration ([Ca2+]i) and spontaneous prolactin release. The L-type Ca2+ channel inhibitor nimodipine reduced the frequency of Ca2+ oscillations at lower concentrations (100nM-1 microM), whereas at higher concentrations (10 microM), it completely abolished them. Ca2+ oscillations persisted following exposure to thapsigargin, indicating that inositol 1,4,5-trisphosphate-sensitive intracellular Ca2+ stores were not required for spontaneous activity. The K+ channel inhibitors Ba2+, Cs+, and tetraethylammonium (TEA) had distinct effects on different K+ currents, as well as on Ca2+ oscillations and prolactin release. Cs+ inhibited the inward rectifier K+ current (KIR) and increased the frequency of Ca2+ oscillations. TEA inhibited outward K+ currents activated at voltages above -40 mV (grouped within the category of Ca2+ and voltage-activated currents, KCa,V) and increased the amplitude of Ca2+ oscillations. Ba2+ inhibited both KIR and KCa,V and increased both the amplitude and the frequency of Ca2+ oscillations. Prolactin release was increased by Ba2+ and Cs+ but not by TEA. These results indicate that L-type Ca2+ channels and KIR channels modulate the frequency of Ca2+ oscillations and prolactin release, whereas TEA-sensitive KCa,V channels modulate the amplitude of Ca2+ oscillations without altering prolactin release. Differential regulation of these channels can produce frequency or amplitude modulation of calcium signaling that stimulates specific pituitary cell functions. (+info)
Effect of saponins of Panax notoginseng on synaptosomal 45Ca uptake.
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AIM: To explore the calcium uptake antagonism of saponins of Panax notoginseng (PNS). METHODS: Synaptosomes were prepared from rat cerebral cortex by using differential Ficoll gradients. The effects of PNS on synaptosomal 45Ca uptake were measured in vitro or after acute treatment. RESULTS: PNS 50-800 mg.L-1 produced a concentration-rated inhibition of Ca2+ uptake [IC50 = 111 (46-176) mg.L-1]. Both initial and maximal uptake were inhibited. Similar effect was obtained after acute PNS treatment with 200 mg.kg-1 i.p. The blocking effect of PNS was reversed by calcium in media. CONCLUSION: PNS is a calcium channel blocker in neurons. (+info)
The effect and management of delayed vasospasm after aneurysmal subarachnoid hemorrhage.
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Delayed cerebral vasospasm after aneurysm rupture is one of the major complications of subarachnoid hemorrhage. The purpose of this review was to determine the true incidence of vasospasm. All literature on cerebral aneurysms from 1960 onwards was reviewed, and the figures extracted from publications that mentioned vasospasm. Angiographic vasospasm, where patients were studied at the time of peak incidence, was reported in about two thirds of cases. Symptomatic vasospasm or delayed ischemia affects about one third. Untreated, nearly a third of those with ischemic deficits die and a similar proportion are left permanently disabled. Variations of Triple-H (hypervolemia, hypertension, hemodilution) therapy, used early after hemorrhage for prophylaxis of vasospasm, are associated with a decrease of nearly half in the incidence of delayed ischemia. When used as therapy outcome also appears better, with a reduction particularly in the death rate. Calcium antagonists have been widely used, especially nimodipine. In several controlled trials the incidence of delayed ischemia was significantly reduced. More importantly, the overall outcome of all subarachnoid hemorrhage patients was better with nimodipine prophylaxis. The 21-aminosteroid tirilazad mesylate has been the subject of several trials. In one the overall outcome of all patients was improved, but the effect was essentially in males only. Further studies with larger doses in females are being analyzed. (+info)
Effects of dl-3-n-butylphthalide on regional cerebral blood flow in right middle cerebral artery occlusion rats.
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AIM: To study the effect of dl-3-n-butylphthalide (NBP) on regional cerebral blood flow (rCBF) in forcal cerebral ischemia rats. METHODS: In chloral hydrate-anesthetized rat, the proximal portion of right middle cerebral artery (RMCA) was occluded, and H2 needle electrode was implanted in right striatum. rCBF was monitored in striatum using hydrogen clearance method. RESULTS: Ten min after RMCA occlusion (RMCAO), NBP (5, 10, 20 mg.kg-1 i.p.) markedly increased rCBF to striatum (P < 0.01). When NBP was given i.p. 40 min after RMCAO, the increasing effect on rCBF was also observed (P < 0.05). However, when NBP was injected i.p. 60 min after RMCAO, the increasing effect of NBP on rCBF was not found. In NBP-pretreated (i.p. 40 min before RMCAO) group, rCBF in striatum measured at different time points of 30, 60, 90, 120, 150, and 180 min after RMCAO were increased by 97%, 107%, 136%, 211%, 173%, and 317%, respectively, compared with the percentages of vehicle group. The potency of the effect of Nim (0.5 mg.kg-1 i.p.) was similar to that of NBP (10 mg.kg-1 i.p.). CONCLUSION: NBP pre-treatment or post-treatment markedly enhanced the rCBF to striatum in RMCAO rats. (+info)
Inhibitory effects of nimodipine on platelet aggregation and thrombosis.
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AIM: To study the inhibitory effects of nimodipine (Nim) on rat platelet aggregation and arterial thrombosis in vivo. METHODS: The aggregation rate of platelets induced by ADP and inhibition rate of Nim were measured by the change of light transmission. Effect of Nim on arterial occlusion time was measured by electric stimulation. Effect of Nim on the contents of 6-keto-PGF1 alpha and TXB2 in serum was measured by radioimmunoassay. RESULTS: Nim 4.5, 9, 18, and 36 mg.kg-1.d-1 ig for 4 d restrained the platelet aggregation. The IC50 (95% confidence limits) was 26 (9-44) mg.kg-1. Nim 4.5, 9, and 18 mg.kg-1.d-1 ig for 4 d markedly prolonged the time of thrombotic occlusion in carotid artery induced by electric stimulation. Nim 9 and 18 mg.kg-1.d-1 improved the imbalance of 6-keto-PGF1 alpha/TXB2 in serum after thrombosis. CONCLUSION: Nim was a potent inhibitor of platelet aggregation, which was partially concerned with the improved balance of 6-keto-PGF1 alpha/TXB2. (+info)
Nimodipine and perfusion changes after stroke.
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BACKGROUND AND PURPOSE: Meta-analysis of previous trials of oral nimodipine in acute stroke has suggested a benefit when commenced within 12 hours of onset. We sought to study the effect of oral nimodipine on reperfusion after acute stroke and the relation between reperfusion and outcome. METHODS: Fifty patients with acute middle cerebral artery territory cortical infarction were blindly randomized within 12 hours of onset to either oral nimodipine (30 mg every 6 hours) or placebo. Treatment was continued for 2 weeks. Cerebral blood flow was assessed with the use of 99mTc-hexamethylpropyleneamine oxime single-photon emission CT before therapy, 24 hours later, and at 3 months. Hypoperfusion was measured by a validated volumetric technique. Neurological impairment and functional outcome were assessed with the Canadian Neurological Scale and Barthel Index, respectively. Tissue loss was measured with CT at 3 months. Four patients were excluded from analysis for technical reasons. RESULTS: Twenty-three patients received nimodipine, and 23 received placebo. In the nimodipine group, there was early reperfusion that was not maintained at outcome (P=0.01). In the placebo group, mean infarct hypoperfusion volumes showed no overall change. Nonnutritional reperfusion in nimodipine-treated patients was associated with adverse neurological (P=0.05) and functional outcome (P=0.06). There was, however, no difference in clinical outcome between the 2 groups. CONCLUSIONS: Oral nimodipine administered within 12 hours enhanced acute reperfusion, but this was largely nonnutritional. Larger studies using a shorter treatment delay are required to evaluate the clinical efficacy of nimodipine in acute ischemic stroke. (+info)
Studies on maitotoxin-induced intracellular Ca(2+) elevation in chinese hamster ovary cells stably transfected with cDNAs encoding for L-type Ca(2+) channel subunits.
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The aim of the present study was to characterize the role played by different L-type Ca(2+) channel subunits in [Ca(2+)](i) increase induced by maitotoxin (MTX). In the presence of 5 mM extracellular K(+), MTX (0.01-0.5 ng/ml) induced a significant concentration-dependent increase in Fura-2-monitored [Ca(2+)](i) in single Chinese hamster ovary (CHO) cells expressing the alpha(1c) (CHOCalpha9 cells) or the alpha(1c)beta(3)alpha(2)delta (CHOCalpha9beta3alpha2/delta4 cells) subunits of voltage-gated Ca(2+) channels (VGCCs), whereas the effect was much reduced in wild-type CHO cells lacking VGCCs. In addition, MTX effect on CHOCalpha9, CHOCalpha9beta3alpha2/delta4, and GH(3) cells (0.01-0.1 ng/ml) was inhibited by the selective L-type Ca(2+) channel entry-blocker nimodipine (10 microM); a nimodipine-insensitive component was still present, particularly at high (>1 ng/ml) toxin concentrations. In CHOCalpha9beta3alpha2/delta4 cells, depolarizing concentrations of extracellular K(+) (55 mM) reinforced the [Ca(2+)](i) increase induced by MTX (0.1 ng/ml), and this effect was prevented by nimodipine (10 microM). Finally, patch-clamp experiments in CHOCalpha9beta3alpha2/delta4 cells showed that low MTX concentrations (0.03 ng/ml) induced the occurrence of an inward current at -60 mV, which was completely prevented by Cd(2+) (100 microM) and by nimodipine (10 microM), whereas the same dihydropyridine concentration (10 microM) failed to prevent the electrophysiological effects of a higher toxin concentration (3 ng/ml). In conclusion, the results of the present study showed that MTX-induced [Ca(2+)](i) elevation involves two components: 1) an action on L-type VGCCs at the pore-forming alpha(1c) subunit level, which is responsible for the greatest rise of [Ca(2+)](i); and 2) a VGCC-independent mechanism that is present both in excitable and in nonexcitable cells and is responsible for a lower elevation of [Ca(2+)](i). (+info)