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At least 19 recordsLinked to original sources
PubMed1997

Effects of lobeline and dimethylphenylpiperazinium iodide (DMPP) on N-methyl-D-aspartate (NMDA)-evoked acetylcholine release in vitro: evidence for a lack of involvement of classical neuronal nicotinic acetylcholine receptors.

Biochemical, behavioral and electrophysiological evidence suggests interactions between pathways containing neuronal nicotinic acetylcholine receptors (NAChRs) and excitatory amino acid receptors. Recently, protective effects of nicotine against N-methyl-D-aspartate (NMDA)-induced toxicity in primary cortical cultures were reported. To address possible interactions between NAChR and NMDA receptor containing pathways, several NAChR agonists were evaluated for their effects on NMDA-evoked [3H]acetylcholine ([3H]ACh) release from slices of rat striatum. Nicotine, cytisine and epibatidine had no effect on NMDA-evoked release or basal release of [3H]ACh over a wide range of concentrations. Lobeline and dimethylphenylpiperazinium iodide (DMPP), however, decreased basal [3H]ACh release and attenuated NMDA-evoked [3H]ACh release with EC50 values of 35 and 155 microM, respectively. The NAChR antagonists, dihydro-beta-erythroidine (DH beta E) and d-tubocurarine had no effect on NMDA-evoked [3H]ACh release, whereas mecamylamine attenuated the NMDA-evoked [3H]ACh evoked release with an EC50 value of 144 microM. Methyllycaconitine (MLA), a highly selective and potent antagonist of the alpha-bungarotoxin-sensitive alpha 7 NAChR subtype, also had no effect on NMDA-evoked [3H]ACh release at concentrations upto 10 microM. The inhibitory effects of DMPP and lobeline on NMDA-evoked [3H[ACh release were relatively insensitive to mecamylamine, d-tubocurarine, MLA and DH beta E. In addition, DMPP or lobeline-induced attenuation of basal [3H]ACh release was insensitive to blockade by sulpiride, a dopamine (D2) receptor antagonist. In contrast to their effects on NMDA-evoked striatal [3H]ACh release, both DMPP and lobeline increased basal release of striatal [3H]DA and hippocampal [3H]norepinephrine ([3H]NE) and did not attenuate NMDA-evoked release of these two transmitters. Instead, DMPP and lobeline appeared to have an additive effect on both NMDA-evoked hippocampal [3H]NE release and striatal [3H]DA release. These pharmacological results suggest that the inhibitory effects on lobeline and DMPP on striatal [3H]ACh release are independent of their interactions with classical NAChRs or the NMDA receptor complex itself.

Acetylcholine↗
PubMed1993

Nicotinic receptor-mediated release of noradrenaline in the human neuroblastoma SH-SY5Y.

Dimethylphenylpiperazinium iodide (a nicotinic agonist) evokes noradrenaline release from human neuroblastoma SH-SY5Y cells that have been pretreated with 12-O-tetradecanoylphorbol 13-acetate for 8 min. This effect of dimethylphenylpiperazinium iodide was inhibited by 1 microM mecamylamine but not by 1 microM atropine, which suggests that SH-SY5Y cells express nicotinic receptors coupled to the release of noradrenaline. Dimethylphenylpiperazinium iodide-evoked release was enhanced by 5 microM Bay K 8644 (an L-type calcium agonist) and inhibited by 1 microM nifedipine. Dimethylphenylpiperazinium iodide depolarised SH-SY5Y cells and enhanced the level of intracellular calcium in cells loaded with fura 2. The effects of dimethylphenylpiperazinium iodide on noradrenaline release, depolarisation, and intracellular calcium levels were all inhibited by 1 microM desmethylimipramine. The results of this study show that nicotinic receptors in SH-SY5Y cells stimulate noradrenaline release by activation of L-type calcium channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1982

Nicotinic-like effects and tissue disposition of isopropylamine.

Previous studies in our laboratory have demonstrated that the acute sympathomimetic effects of isopropylamine are due to stimulation of autonomic ganglia. The present studies were designed to determine whether isopropylamine produced ganglionic blockade after its initial stimulation of autonomic ganglia. Infusion of isopropylamine (2.5 mg/kg/min) produced an initial increase in arterial pressure and heart rate which was followed by a prolonged hypotension and bradycardia; lower doses produced only a hypotensive response. After infusion of isopropylamine, the positive chronotropic responses to preganglionic cardioaccelerator nerve stimulation were significantly reduced, whereas the responses to postganglionic nerve stimulation were essentially unchanged. Similarly, the negative chronotropic responses to peripheral vagal stimulation were significantly reduced after isopropylamine administration. Moreover, isopropylamine reduced the cardiovascular responses to i.v. injections of the ganglion nicotinic stimulant, dimethylphenylpiperazinium iodide. Studies on the disposition of isopropylamine indicated that there was significant cumulation of isopropylamine in all tissues as compared to plasma. When the relationship between plasma isopropylamine and the decreases in mean arterial pressure was examined, a significant positive correlation (r = 0.87) was found. These results indicate that isopropylamine has both ganglion stimulating and blocking properties and is similar in its action to the classical nicotinic ganglion stimulant drugs such as dimethylphenylpiperazinium iodide and tetramethylammonium.

Animals↗
PubMed1980

Influence of clonidine on experimental hypertension induced by cholinergic stimulation.

Hypertension may be induced by pharmacologic activation of central cholinergic receptors either indirectly, through the injection i.v. of physostigmine, or directly, through the injection of i.v. of arecholine in anesthetized rats. Activation of peripheral preganglionic cholinergic receptors with dimethylphenylpiperazinium iodide (DMPP) also produced a hypertensive response. Pretreatment with various doses of clonidine caused inhibition of the pressor response to central cholinergic stimulation but was without effect on the response to ganglionic cholinergic stimulation.

Animals↗
PubMed1998

Characterization of levamisole binding sites in Trichinella spiralis.

Characterization of the levamisole receptor was performed with total extracts of Trichinella spiralis muscle larvae using binding assays with tritiated levamisole ([3H]LEV, 291 GBq/mmol). We detected a specific [3H]LEV binding activity with a dissociation constant (Kd) of 4.76 microM and a receptor density (Bmax) of 2.14 pmol/mg of protein. In inhibition studies, only dimethylphenylpiperazinium iodide (DMPP) and hexamethonium were found to be competitive inhibitors of the [3H]LEV binding with an inhibition constant (Ki) of 31.04 and 4.43 microM, respectively, whereas d-tubocurarine and alpha-bungarotoxine had no effect on [3H]LEV binding activity, and procaine and atropine potentiated the [3H]LEV-receptor binding. All these data support the idea that levamisole acts as a cholinergic agonist in T. spiralis.

Animals↗
PubMed1983

Release of dopamine and 5-hydroxytryptamine from rat striatal slices following activation of nicotinic cholinergic receptors.

1. The administration of the nicotinic cholinergic agonists dimethylphenylpiperazinium iodide (DMPP) or nicotine caused a concentration dependent release of [3H] dopamine, [3H]5-hydroxytryptamine as well as endogenous dopamine and 5-hydroxytryptamine from superfused slices of rat striatum. 2. Release of both labelled and non-labelled transmitter was antagonized by the nicotinic antagonist, hexamethonium but not the muscarinic antagonist, atropine. 3. The present study provides additional evidence that nicotinic-cholinergic receptors are present in the mammalian central nervous system. 4. Activation of these nicotinic-cholinergic receptors in the striatum results in the release of both dopamine and 5-hydroxytryptamine.

Animals↗
PubMed1988

Augmentation of cardiac reflexes in the cat by the calcium antagonist verapamil.

The effect of intravenous and intrapericardial administration of verapamil on cardiac reflexes was studied in chloralose-anesthetized cats. Cardiac reflexes were induced by either intrapericardial application of serotonin (80 micrograms/kg) and dimethylphenylpiperazinium iodide (DMPP) (20 micrograms/kg) or by occlusion of the ascending aorta for 30 s. Intrapericardial application of verapamil (3 and 6 micrograms/kg) did not change the epicardial chemoreflexes, whereas intravenous administration of verapamil in the normal clinical dose enhanced the cardiac reflexes induced by chemical or mechanical stimulation. These results indicate that verapamil does not act directly on the vagal afferent nerve fibers in the epicardium of the heart. We suggest that the augmentation of cardiac reflexes by verapamil might be caused by an action of verapamil on the sinoaortic baroreflex or baroreceptors.

Animals↗
PubMed1993

Inhibition of neuronal nicotinic acetylcholine receptors by imipramine and desipramine.

The actions of two structurally related tricyclic antidepressants on neuronal nicotinic acetylcholine receptors were investigated in human neuroblastoma (SY-SY5Y) cells, using whole-cell patch-clamp recordings. Both desipramine and imipramine reversibly inhibited inward currents evoked by application of the nicotinic receptor agonist dimethylphenylpiperazinium iodide (30-300 microM) with IC50 values of 0.17 microM and 1.0 microM respectively (holding potential -70 mV). The degree of current inhibition caused by either tricyclic compound was unaffected by agonist concentration (30-300 microM). The effects of desipramine were voltage-independent over the range -40 mV to -100 mV, and inhibition caused by imipramine only increased very slightly with membrane hyperpolarization over the same range. These results indicate that tricyclic antidepressants can inhibit neuronal nicotinic acetylcholine receptors by mechanisms which are distinct from their actions at non-neuronal nicotinic acetylcholine receptors.

Desipramine↗
PubMed2002

Muscularis mucosae contraction evokes colonic secretion via prostaglandin synthesis and nerve stimulation.

This in vitro study tested the hypothesis that muscularis mucosae contractile activity contributes to rabbit colonic mucosal function by mechanisms other than simple mechanical deformation of the epithelium. Experiments were performed by using a technique that allows simultaneous recording of muscle activity and transmucosal potential difference, a measure of epithelial ion transport. ATP, bradykinin, histamine, PGE(2), PGF(1alpha), and PGF(2alpha) elicited muscularis mucosae contractions that were resistant to atropine and TTX. Only ATP-induced contractions were indomethacin sensitive, and only those to dimethylphenylpiperazinium iodide (DMPP) were reduced by atropine. All agonist-evoked increases in transmucosal potential difference were atropine resistant, and, with the exception of those to PGE(2), PGF(2alpha), and VIP, they were also TTX sensitive. Mucosal responses to ATP, bradykinin, and histamine were indomethacin sensitive, whereas those to DMPP, the prostaglandins, and VIP were not. When cyclooxygenase activity or the mucosal innervation was compromised, even maximal muscularis mucosae contractions did not produce large secretory responses. It is concluded that contraction-related prostaglandin synthesis and noncholinergic secretomotor neuron stimulation represent the physiological transduction mechanism through which muscularis mucosae motor activity is translated into mucosal secretion.

Adenosine Triphosphate↗
PubMed1997

Renal sympathetic nerve activity and the weight of the remaining kidney in unilateral nephrectomized rats.

To examine compensatory response of the kidney to reduction in renal mass, acute and chronic effects of unilateral nephrectomy on renal sympathetic nerve activity (RNA) and weight of the remaining kidney were analyzed in rats. Under acute nephrectomy, RNA decreased significantly due to ligation of the renal vessels, ureter and nerves. With acute unilateral renal denervation, basal mean RNA (MRNA) did not change but the reflex inhibition of RNA due to ligation disappeared. Chronic effects of nephrectomy were analyzed at 3, 7, 14 and 28 days after surgery. At 3, 7, 14 and 28 days after nephrectomy, MRNA were about two times larger than the values obtained in sham operation group (p < 0.01). Changes in arterial pressure and heart rate were not significant after unilateral nephrectomy. When the maximal MRNA due to dimethylphenylpiperazinium iodide (DMPP) administration was set as 100%, relative basal MRNA at 3, 7, 14 and 28 days were estimated in sham and nephrectomy groups. Also, relative basal MRNA increased about two times in nephrectomy group. After unilateral nephrectomy, the remaining kidney weight per unit body weight increased significantly by 18-35%. These findings indicate that the RNA in the remaining kidney was reflexly inhibited by the activation of afferent input due to ligation of renal vessels, ureter and nerves under acute nephrectomy. Under chronic unilateral nephrectomy, basal MRNA and the weight of the remaining kidney were increased significantly. The RNA per unit of kidney weight in unilateral nephrectomized rats was increased at 3 and 7 days and then it was relatively constant at 14 and 28 days.

Action Potentials↗
PubMed1992

Nicotinic acetylcholine receptors in human neuroblastoma (SH-SY5Y) cells.

Whole-cell patch-clamp recordings were used to investigate nicotinic acetylcholine receptors (nAChRs) in the human neuroblastoma cell line, SH-SY5Y. Acetylcholine, nicotine and the neuronal nAChR agonist dimethylphenylpiperazinium iodide (DMPP), but not muscarine, all evoked inward currents in the cells (voltage-clamped at -60 mV). DMPP's actions were concentration- and voltage-dependent, and were antagonised by the neuronal nAChR antagonist mecamylamine (1-3 microM). Atropine was ineffective at 0.1 microM, but at 1 microM caused significant reductions in current amplitudes. Pre-incubation of cells with 2 microM alpha-cobratoxin had no effect on the actions of DMPP, and inward currents could also be induced when extracellular NaCl was replaced with CaCl2. DMPP also reversibly depolarized SH-SY5Y cells. These findings clearly identify nAChRs in SH-SY5Y cells, and provide two possible mechanisms by which receptor activation may lead to noradrenaline release, namely by triggering Ca2+ influx through the nAChR itself or by opening voltage-gated Ca2+ channels.

Acetylcholine↗
PubMed1993

Inhibition of the nicotinic acetylcholine receptor by barbiturates and by procaine: do they act at different sites?

1. The effects of three barbiturates and the local anesthetic procaine on the ion channel function of mouse nicotinic acetylcholine receptor (nAChR) muscle subtype expressed in Xenopus laevis oocytes were examined by whole-cell voltage-clamp technique. 2. A concentration-response curve for the specific nicotinic agonist dimethylphenylpiperazinium iodide (DMPP) was first determined. This agonist produced increasing whole-cell currents up to a concentration of 100 microM (EC50 = 13 microM), then decreased responses at higher concentrations. 3. The barbiturates (amobarbital, secobarbital, pentobarbital) and procaine produced reversible inhibition of DMPP-induced currents at clinically used concentrations. The two classes of drugs differed in the voltage dependence of the inhibition: procaine-induced inhibition was increased at more negative transmembrane holding potentials (-90 vs. -45 mV); whereas amobarbital-induced inhibition did not vary at different transmembrane potentials. 4. Mutant forms of the nAChR, containing single amino acid changes in the M2 regions of alpha and beta subunits, showed increased sensitivity to procaine but no change in sensitivity to amobarbital-induced inhibition. 5. These electrophysiologic studies provide further evidence that barbiturates and local anesthetics produce inhibition of the nAChR at different sites.

Allosteric Site↗
PubMed1973

The detection of differential beta-adrenoceptor blockade in the cat.

1. Tachycardia and bronchodilatation were produced by intravenous dimethylphenylpiperazinium iodide (DMPP) in the spinal or pithed cat. Responses other than those involving beta-adrenoceptors were minimized by appropriate blocking agents.2. With intact adrenals, both the tachycardia and bronchodilatation with 10 mug/kg DMPP were equal to those with 1 mug/kg adrenaline.3. After adrenalectomy, tachycardia with 100 mug/kg DMPP was equal to that with 1.5 mug/kg adrenaline, but the bronchodilatation was equal to that with only 0.3 mug/kg. This difference may reflect the relative activity of the sympathetic supply to the organs.4. After adrenalectomy, propranolol was 3 times as effective against bronchodilatation due to DMPP as against tachycardia. Practolol was inactive against bronchodilatation.5. With intact adrenals, propranolol reduced both tachycardia and bronchodilatation due to DMPP equally. Propranolol also antagonized equally both effects of adrenaline in the pithed cat after adrenalectomy.6. In the spinal cat, propranolol caused bradycardia and bronchoconstriction that persisted after adrenalectomy or pithing. It was reduced by pempidine and guanethidine and is attributed to spontaneous adrenergic neuronal activity.7. The Appendix describes a device for cycle-by-cycle spirometry and correction for zero drift of a micromanometer, used in this study for the continuous recording of bronchial resistance.

Adrenalectomy↗
PubMed1989

Effects of nicotinic agonists and antagonists on N-methyl-D-aspartate-induced 3H-norepinephrine release and 3H-(1-[1-(2-thienyl)cyclohexyl]-piperidine) binding in rat hippocampus.

The nicotinic agonists dimethylphenylpiperazinium iodide (DMPP) and carbachol (CARB) as well as (-)nicotine [-)NIC) were tested alone and in combination with N-methyl-D-aspartate (NMDA) for their abilities to enhance the efflux of 3H-norepinephrine (NE) from slices of rat hippocampus. CARB and (-)NIC produced small, transient increases in NE efflux, while DMPP produced larger, longlasting increases. Inasmuch as the nicotinic antagonists mecamylamine (MECA) and hexamethonium (C6) did not consistently inhibit the increases in NE efflux produced by these agonists, the role of a nicotinic receptor in mediating these responses is uncertain. CARB and DMPP enhanced the ability of NMDA to stimulate NE release, while (-)NIC did not. MECA, but not C6, was found to selectively antagonize NMDA-stimulated NE release that did not appear to involve a nicotinic receptor. Binding studies indicated that MECA and the related nicotinic antagonist pempidine produced an inhibition of NMDA-stimulated NE release by an action at the PCP receptor that is known to be linked to the NMDA receptor-ionophore complex. These data suggest that the actions of these ganglionic blocking agents on excitatory responses in the hippocampus involve inhibition of excitatory amino acid as well as nicotinic receptors.

Animals↗
PubMed1985

Nicotinic cholinergic agonists inhibit androgen biosynthesis by cultured rat testicular cells.

The actions of cholinomimetics on androgen biosynthesis were investigated using a primary culture of testicular cells derived from adult hypophysectomized rats. Testicular cells were maintained in serum-free medium and treated with hCG and/or drugs on day 8 of culture. Media were collected 2 days later for measurement of steroids and cAMP. Treatment with hCG increased testosterone production 50-fold over control values, whereas treatment with cholinomimetics alone failed to increase androgen production. Concomitant treatment of testicular cells with nicotinic cholinergic agonists (lobeline, nicotine, and dimethylphenylpiperazinium iodide) inhibited hCG-stimulated androgen biosynthesis in a dose-dependent fashion, with IC50 values of 3 X 10(-5), 1.7 X 10(-4), and greater than 10(-3) M, respectively. In contrast, two muscarinic cholinergic agonists, muscarine and bethanechol, failed to inhibit androgen production at concentrations up to 10(-3) M. A ganglionic nicotinic antagonist (hexamethonium), but not a skeletal muscle nicotinic antagonist (decamethonium), partially blocked the actions of lobeline. Lobeline (10-4) M) decreased hCG-stimulated testosterone production (50-75%) throughout the 2-day culture period; however, this inhibition was reversible upon removal of the drug. Lobeline also inhibited hCG-stimulated cAMP accumulation as well as testosterone production induced by cholera toxin (65% inhibition), forskolin (50% inhibition), or (Bu)2cAMP (70% inhibition). Lobeline inhibition of hCG-stimulated testosterone production was accompanied by decreases in medium accumulation of 17 alpha-hydroxypregnenolone (75%), 17 alpha-hydroxyprogesterone (85%), dehydroepiandrosterone (50%), and androstenedione (61%); however, the medium content of pregnenolone and progesterone were unchanged. Additional experiments demonstrated that lobeline suppressed the conversion of exogenous progesterone to testosterone, but did not affect the conversion of exogenous 17 alpha-hydroxyprogesterone to testosterone. These results indicate that nicotinic, but not muscarinic, cholinergic agonists inhibit androgen biosynthesis through selective inhibition of 17 alpha-hydroxylase activity. Thus, endogenous acetylcholine may be involved in the negative regulation of testicular steroidogenesis.

Androgens↗
PubMed1997

Dual effect of DMPP on the resting release of noradrenaline from rat hippocampal slices.

The effect of the nicotinic receptor agonist dimethylphenylpiperazinium iodide (DMPP) on the resting release of [3H]noradrenaline from superfused hippocampal slices was studied in rat. Continuous administration of DMPP at a concentration range of 1-100 microM increased the [3H]noradrenaline release in a dose-dependent manner. The response to DMPP was characterized by an immediate steep increase (peak response) followed by a sudden decline to a lower level that was constant with time (tall response) and still was significantly higher than the spontaneous release. Further analysis revealed that the release of noradrenaline in response to DMPP consists of two components. While nicotinic receptor antagonists (mecamylamine 10 microM, pancuronium 10 microM, pipecuronium 10 microM), the nonselective Ca-antagonist Cd2+ (125 microM) and tetrodotoxin (TTX, 1 microM) completely abolished the peak response (phase I), they had no effect on the tall response (phase II). Ca(2+)-free medium containing 1 mM EGTA also blocked phase I but in contrast with other drugs enhanced phase II. The release during phase I is subject to presynaptic feedback modulation, since the alpha 2-adrenoceptor agonist xylazine (3 microM) inhibited the DMPP-evoked stimulation of [3H]noradrenaline release, that inhibition was antagonized by a selective alpha 2-adrenoceptor antagonist, (+/-)-[7,8-(methylenedioxy)-14-alpha-hydroxyalloberbane hydrochloride [(+/-)-CH-38083] (2 microM). (+/-)-CH-38083 (2 microM) alone significantly enhanced the DMPP-evoked increase of [3H]noradrenaline release. Phase II was not effected by alpha 2-adrenergic drugs. Whereas the noradrenaline uptake blockers despramine (DMI, 1-10 microM), nisoxetine (1-10 microM), and nomifensine (10 microM) inhibited both phases, nomifensine at a concentration of 1 microM selectively blocked only phase II. Our data indicate that DMPP has a dual effect on the hippocampal noradrenaline release: phase I is a transient, nicotinic receptor-mediated exocytotic release, and phase II is a maintained, carrier-mediated process.

Animals↗