Neurotoxicity of an MPTP analogue, 2'CH3-MPTP, on monoaminergic systems in the mouse brain.
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Biomedical subjects
X L Chen
Publications and source records attributed to X L Chen.
Nitrovasodilators relax arterial smooth muscle by decreasing [Ca2+]i and uncoupling stress from myosin phosphorylation.
Elevations in guanosine 3',5'-cyclic monophosphate concentration ([cGMP]) are proposed to induce arterial smooth muscle relaxation by either 1) decreasing myoplasmic [Ca2+] ([Ca2+]i), 2) decreasing the [Ca2+]i sensitivity of phosphorylation, or 3) uncoupling force from myosin phosphorylation. We evaluated the importance of each of these mechanisms by measuring changes in [cGMP], aequorin- and fura-2-estimated [Ca2+]i, myosin light chain phosphorylation, and stress in histamine-stimulated swine carotid arteries. In tissues submaximally stimulated with 3 microM histamine, nitroprusside (NP) induced a proportional decrease in myoplasmic [Ca2+] and myosin phosphorylation, suggesting that the relaxation was at least partially induced by decreases in [Ca2+]i without a change in the [Ca2+]i sensitivity of phosphorylation. In tissues maximally stimulated with 10 microM histamine, NP and nitroglycerin produced significant relaxations that were not associated with significant sustained reductions in [Ca2+]i or myosin phosphorylation. With both submaximal and maximal histamine stimulation, nitrovasodilators produced more substantial relaxation than that expected from the nitrovasodilator-induced reduction in myosin phosphorylation. These results suggest that nitrovasodilators relax histamine-stimulated swine arterial smooth muscle by at least two mechanisms: 1) reducing [Ca2+]i, an effect observed in submaximally stimulated tissues, and 2) uncoupling of stress from myosin phosphorylation.
Animals↗
Cyclic nucleotide-dependent regulation of Mn2+ influx, [Ca2+]i, and arterial smooth muscle relaxation.
Elevations in cyclic nucleotide levels can decrease myoplasmic [Ca2+] ([Ca2+]i) and thereby induce arterial smooth muscle relaxation. We evaluated whether cyclic nucleotide-induced reductions in [Ca2+]i are caused by 1) decreased Ca2+ influx or 2) increased Ca2+ sequestration or efflux. Swine carotid medial tissues were loaded with fura-2, and Ca2+ influx was estimated from the quenching rate of 360-nm fluorescence after addition of extracellular Mn2+. Histamine stimulation or high KCl depolarization increased Mn2+ influx, [Ca2+]i, and contractile force. The Ca2+ channel blocker diltiazem attenuated histamine- or KCl-induced increases in Mn2+ influx, [Ca2+]i, and force. Addition of forskolin (which increases cAMP) or nitroglycerin (which increases cGMP) attenuated histamine-induced increases in Mn2+ influx, [Ca2+]i, and force. Addition of forskolin or nitroglycerin also relaxed KCl depolarized tissues; however, Mn2+ influx and [Ca2+]i remained high. These results suggest that Mn(2+)-induced quenching of 360-nm fluorescence is an estimate of Ca2+ influx in the intact swine carotid artery. These results also suggest that cyclic nucleotides can relax swine arterial smooth muscle by at least two mechanisms: 1) reduction of [Ca2+]i primarily induced by decreases in Ca2+ influx and 2) uncoupling force from [Ca2+]i without changing Ca2+ influx or [Ca2+]i.
Animals↗
Na(+)-Ca2+ exchange, myoplasmic Ca2+ concentration, and contraction of arterial smooth muscle.
Na(+)-Ca2+ exchange is proposed to be an important regulator of myoplasmic intracellular Ca2+ concentration ([Ca2+]i) and contraction in vascular smooth muscle. We investigated the role of Na(+)-Ca2+ exchange in regulating [Ca2+]i in swine carotid arterial tissues that were loaded with aequorin to allow simultaneous measurement of [Ca2+]i and force. Reversal of Na(+)-Ca2+ exchange, by reduction of extracellular Na+ concentration ([Na+]o) to 1.2 mM, induced a large increase in aequorin-estimated [Ca2+]i and a low [Ca2+]i sensitivity. The contraction induced by 1.2 mM [Na+]o was partially caused by depolarization and opening of L-type Ca2+ channels because 10 microM diltiazem partially attenuated the 1.2 mM [Na+]o-induced increases in [Ca2+]i. High dose ouabain (10 microM), a putative endogenous Na+,K(+)-ATPase inhibitor, increased both [Ca2+]i and force. However, the increases in [Ca2+]i and force were mostly blocked by 10 microM phentolamine, suggesting the predominant effect of ouabain was to increase norepinephrine release from nerve terminals. In the presence of 10 microM phentolamine, 10 microM ouabain slightly accentuated 1 microM histamine-induced increases in [Ca2+]i and force. The ouabain dose necessary to induce contraction in the absence of phentolamine was significantly less than the ouabain dose necessary to accentuate histamine-induced contractions in the presence of phentolamine. These results suggest that Na(+)-Ca2+ exchange exists in swine arterial smooth muscle. These data also suggest that ouabain (which should increase [Na+]i and inhibit Na(+)-Ca2+ exchange) primarily enhances contractile function in the swine carotid artery by releasing catecholamines from nerve terminals; direct action of Na+,K(+)-ATPase inhibitors on smooth muscle appears to occur only with very high doses.
Animals↗
Tumour-associated antigens of mammary carcinomas recognized by human monoclonal antibody 1G12.
We have reported the production of human monoclonal antibodies (mAb), by the fusion of lymph node lymphocytes from a primary carcinoma patient with murine myeloma cells. Seven heterohybridomas showed reactivity with class III antigens, and five hybridomas (1G12, 2D4, 4H5, 5D10 and 3B10) were reactive with class II antigens. One of these human mAbs (1G12) was intensively studied and results are presented here. 1G12 reacted strongly and specifically with five mammary carcinoma cell lines and showed no cross-reactivity with seven normal fibroblast cells. It continuously produced human mAbs (IgM) at a rate of 4.5-12.5 micrograms/ml over a period of 2 years. Human mAb 1G12 (IgM) was purified by either a combination of anion-exchange chromatography (ABx) and gel filtration (Superose 6) or affinity chromatography (agarose). Immunohistological analysis of frozen tissue sections was performed with biotinylated 1G12. All mammary carcinomas analysed (n = 26) were positive, while the connective tissue of 36 different patients was completely negative with 1G12. In normal breast, endometrium and intestine only a weak or moderate staining of the epithelial cells was observed. Normal oesophagus, small bowel, cervix, uterus, lung and skin were completely negative. Partly purified tumour antigen recognized by 1G12 had a molecular mass of 1-2 MDa and showed strong binding with Ulex europaeus lectin I and Bauhina purpurea agglutinin, indicative for the glucoprotein nature of antigens. These results show that human mAb 1G12 may be useful for the analysis of tumour-associated antigen of mammary carcinoma patients. In further studies the therapeutic and diagnostic application of 1G12 should be analysed in more detail.
Animals↗
Anticancer gelatin microspheres with multiple functions.
Biodegradable, hydrophilic gelatin microspheres (GM) with an average diameter of 70 microns were prepared by cross-linking gelatin with glutaraldehyde for hepatic intra-arterial infusion. An anticancer agent, mitomycin C (MMC), together with a radioisotope, 131I, were bound to the GM for chemotherapy and local internal radiotherapy. The 131I-labelled MMC-GM (131I-MMC-GM) could accumulate in the specific site and embolize the hepatic arteries after the hepatic intra-arterial infusion, while it caused various effects to the liver cells. The 131I-MMC-GM remained within the hepatic arteries for at least one month. In vitro release of drugs from the GM was also quantified using a dynamic dialysis method.
Animals↗
Characterization of the depressor effect of intrathecal endothelin in anesthetized rats.
Intrathecal administration of 1-100 pmol endothelin-1 in urethan-anesthetized rats elicited a dose-dependent decrease in arterial pressure and a modest bradycardia. The depressor response was associated with a sustained hindquarters vasodilation and a modest transient mesenteric vasoconstriction, indicating disparate effects on regional vascular resistance. In contrast, renal sympathetic nerve activity was unaffected except at the highest dose of endothelin-1 (100 pmol). The depressor effect of intrathecal endothelin is unlikely to be due to spinal ischemia produced by vasoconstriction, since a much greater dose of endothelin was needed to produce an increase in spinal vascular resistance compared with the dose necessary to produce hindquarters vasodilation and the depressor effect. Unlike intravenous administration, intrathecal endothelin-1 and endothelin-3 produced indistinguishable effects on arterial pressure, heart rate, renal sympathetic nerve activity, spinal blood flow, and spinal vascular resistance, suggesting that the spinal neuronal endothelin receptors may be less selective than those in the blood vessels. The centrally mediated depressor effect and the selective regional hemodynamic actions of intrathecal endothelin suggest a role of spinal endothelin in regulating cardiovascular function.
Anesthesia↗
Gangliosides prevent MPTP toxicity in mice--an immunocytochemical study.
The role of gangliosides in preventing neuronal degeneration was examined in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse parkinsonian model. Intraventricular injections of a ganglioside mixture prior to MPTP treatment reduced MPTP's toxicity on tyrosine hydroxylase-positive neurons in the substantia nigra. This raises the interesting possibility that early ganglioside administration may be beneficial in the treatment of neurodegenerative disorders.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Neuropeptides in hypertension: role of neuropeptide Y and calcitonin gene related peptide.
1. The effect of neuropeptide Y (NPY) on cardiovascular function at three levels of the noradrenergic axis where the peptide is known to co-exist with noradrenaline (NA) and or adrenaline (A) was studied in normotensive Sprague-Dawley (SD), Wistar-Kyoto (WKY) or spontaneously hypertensive rats (SHR). 2. In the perfused mesenteric arterial bed, NPY and the structurally similar peptide intestinal polypeptide (PYY) decreased the periarterial nerve stimulation induced release of NA and potentiated the increase in perfusion pressure to nerve stimulation or exogenously applied agonists (e.g. angiotensin, vasopressin, phenylephrine). In contrast to NPY and PYY, C-terminal NPY fragments inhibited NA release and produced a parallel decrease in perfusion pressure thus supporting the concept of Y1 (post) and Y2 (pre) NPY receptors. 3. In the mesenteric artery of SHR the prejunctional inhibitory effect of NPY was attenuated while the postjunctional response was enhanced. 4. Following intrathecal (Int) injection of NPY, there was a decrease in blood pressure, total peripheral resistance (predominantly by a decrease in mesenteric vascular resistance) and renal nerve activity. The depressor effect of Int NPY was attenuated in the SHR. 5. Unilateral injections of NPY into the posterior hypothalamic nucleus increased blood pressure, hindquarter and renal vascular resistance and renal nerve activity. The pressor effect was enhanced in the SHR. 6. Periarterial nerve stimulation of the perfused mesenteric artery produced a frequency dependent vasodilation in beds pretreated with guanethidine and precontracted with methoxamine.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Presynaptic peptide receptors and hypertension.
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Adrenergic beta-Antagonists↗
In vitro effects of neuropeptide Y at the vascular neuroeffector junction.
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Animals↗
Hemodynamic and sympathetic effects of spinal administration of neuropeptide Y in rats.
Intrathecal administration of 4 nmol/kg neuropeptide Y in Dial-urethane-anesthetized rats elicited decreases in arterial pressure, renal sympathetic nerve activity, and a slight decrease in heart rate. The depressor response was associated with a sustained hindquarters and mesenteric vasodilation resulting in a decrease in total peripheral resistance. Intrathecal NPY also resulted in a decrease in renal sympathetic nerve activity. There was a positive correlation between the percent changes in arterial pressure and renal sympathetic nerve activity. With the use of renal nerve activity and heart rate as indexes, NPY resulted in a decrease in baroreflex sensitivity. The depressor effect of intrathecal NPY did not appear to be due to spinal vasoconstriction and ischemia, since spinal microvascular resistance was decreased slightly. We conclude that the intrathecal administration of NPY produces an inhibition of sympathetic nerve activity, resulting in a decrease in total peripheral resistance and arterial pressure.
Animals↗
[Biphasic effects of caffeine on tension in isolated aorta of rat].
The dual effects of caffeine on the tension were observed in rat thoracic aorta. When the preparation was exposed to Tyrode's solution containing caffeine of 1, 5 and 10 mmol/L, the tension increased. In 1-2 min it slowly decreased to a level lower than the pre-caffeine tension. After norepinephrine (1 mumol/L) was added, caffeine produced a greater inhibitory effect and the contraction phase disappeared. The dual effects of caffeine were not affected by the vascular endothelium. In the Tyrode's solution containing NiCl2 2 mmol/L, the first addition of caffeine (10 mmol/L) or norepinephrine (0.1 mumol/L) caused a contraction. The one caused by norepinephrine was greater. A second addition of caffeine did not cause a contraction, but addition of norepinephrine at this time caused a small contraction. After the washout of norepinephrine which had caused a greater contraction, the addition of caffeine (10 mmol/L) did not cause a contraction. These results indicate that norepinephrine completely depletes caffeine-sensitive Ca2 stores but caffeine only partially depletes norepinephrine-sensitive Ca2+ stores.
Animals↗
[Relation between vegetative nervous activities and coronary spasm].
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Autonomic Nervous System↗
[Effects of extracellular sodium concentration on the sodium-pump activity in Purkinje fibres of sheep].
Intracellular sodium activity (aiNa), extracellular potassium activity (aok) and resting membrane potential (Vm) were measured in sheep cardiac Purkinje fibres exposured intermittently to calcium-free solution containing different concentrations of low sodium. In Ca-free low sodium solution, aiNa decreased, the rates and amplitudes of aiNa changes were related to [Na]o linearly. The linear correlation between the stable values of aiNa (aiNa(S)) at 6th minute of aiNa decrease and [Na]o meant that the amplified active Na+ extrusion and pump current resulting from decreased [Na]o, kept finally Na+ gradient across the membrane relatively stable. Hence, it was proposed that it was the Na+ gradient across the membrane but not the internal Na+ that regulated the sodium pump activity. The membrane hyperpolarization which was incident with the increase of active Na+ extrusion was caused mainly by the amplified pump current and embellished by the intercellular K+ depletion and accumulation simultaneously, which was suggested by the mutual relation of time courses of changes in aiNa, Vm, aok during the exposure of the fibre to 1.3Na Ca-free solution.
Animals↗
[Effects of Apocynum hendersonii (Hook. f.) Woodson on cardiac electric and mechanical activity].
Calcium antagonist-like effect of Apocynum hendersonii on myocardiac preparations was observed in the present experiments. The action potential duration and contractility were decreased. Automatic or exciting activity in partially depolarized fibers was considerably inhibited or concealed. Observation in vivo showed that pacemaking in SA node and conducting in AV node area were inhibited.
Action Potentials↗
[Ethanol for hepatic arterial embolization (experimental study)].
In this experiment, 27 dogs underwent hepatic arterial embolization (HAE) with 99% ethanol in 10 (group A), 75% ethanol in 10 (group B) and 60% ethanol in 7 (group C). By the laparotomy, catheter was inserted into hepatic artery and ethanol at dose of 0.3 ml/kg was injected within 20 seconds. Arterial angiography was taken before and after HAE. The dogs were sacrificed in 1, 2, 4, 8 weeks. Liver specimens were examined grossly and microscopically. Both A and B group showed satisfactory results of embolization, but 99% ethanol caused severe damage to hepatocytes, perisinusoidal area and bile ducts. Eight of 10 dogs died of hepatic failure and infection within two weeks. 75% ethanol mainly occluded the smaller arterial branches. Hepatocellular and biliary tract lesions were slight and reversible. All the animals survived normally except two. Group C had some mild and limited liver damage and scattering thrombosis which might result from intima lesion. This article also discusses the clinical availability of ethanol HAE.
Animals↗
Cardiovascular effects and modulation of noradrenergic neurotransmission following central and peripheral administration of neuropeptide Y.
Experiments have been conducted to evaluate the effect of neuropeptide Y (NPY) administered at three distinct levels of the nervous system: 1) the posterior hypothalamic nucleus, 2) the spinal cord, and 3) the vascular noradrenergic neuroeffector junction. It was observed that NPY produced varying cardiovascular effects at these three distinct sites of the nervous system. Microinjections into the posterior hypothalamic nucleus resulted in an increase in blood pressure, which was reduced by prior microinjection of a muscarinic or H1-histamine antagonist but not an H2-histamine antagonist. In addition to the involvement of histaminergic and cholinergic pathways, the pressor effect of NPY appears to result from an increase in sympathetic outflow. NPY was also seen to decrease the potassium-induced release of norepinephrine (NE) from slices obtained from the posterior hypothalamic nucleus. In contrast to what was observed in the hypothalamus, the intrathecal injection of NPY at a level of T4 or T10 in anesthetized or T10 in unanesthetized rats resulted in a depressor effect as well as a decrease in heart rate. Both an alpha 2- and beta-adrenoceptor antagonist reduced the NPY effect. The depressor effect of intrathecal NPY was attenuated in rats pretreated with reserpine as well as in Spontaneously Hypertensive rats (SHR). These data suggest that the effects of NPY are closely associated with sympathetic preganglionic neurons in the spinal cord. At the vascular noradrenergic neuroeffector junction, NPY decreased the nerve stimulation-induced release of NE while potentiating the contractile response. Moreover, NPY potentiated the increase in perfusion pressure of the perfused mesenteric arterial bed in response to angiotensin, vasopressin, or phenylephrine.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗