UMLS:C0406810 - FACTA Search

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Query: UMLS:C0406810 (NAME)
13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Na(+)-Ca(2+) exchanger is a protein present in the cell membrane of many cell types. In heart it plays important roles in Ca homeostasis and ionic current generation. Recently, it has been reported that the beta-adrenergic agonist isoprenaline (ISO) can increase directly Na(+)-Ca(2+) exchanger activity in guinea-pig ventricular myocytes. Adenosine (ADO) exerts anti-adrenergic properties that make it effective against some arrhythmias and the aim of the present study was to determine whether or not ADO can antagonize the direct modulatory effect of ISO on the exchanger.Whole-cell patch clamp measurements of Na(+)-Ca(2+) exchanger current (I(NaCa)) were made from guinea-pig ventricular myocytes, with major interfering currents inhibited. I(NaCa) was measured at 378 degrees C as current sensitive to external nickel (Ni(2+), 10 mM) during an applied descending voltage ramp. ISO (1 microM) significantly increased both inward and outward I(NaCa). This effect was abolished in the presence of ADO (200 microM). ADO alone did not significantly alter the amplitude of I(NaCa). The effect of ADO on the response of I(NaCa) to ISO was mimicked by the A(1)ADO receptor agonist N(6)-cyclopentyladenosine (CPA, 10 microM), whereas the effect of ADO on the response of I(NaCa) to ISO was inhibited by the A(1)ADO receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX, 2 microM). These data suggest that the A(1)ADO receptor mediated the response. The anti-adrenergic effects on I(NaCa) of ADO were not affected by the protein kinase C (PKC) inhibitor, chelerythrine (CLT, 1 microM), nor by the nitric oxide (NO) synthase inhibitor, N (G)-nitro-L-arginine methyl ester((L)-NAME, 0.5 mM). Moreover, in the presence of PKC activator phorbol 12-myristate 13-acetate (PMA, 1 microM) or exogenous NO donor sodium nitroprusside (SNP, 100 microM), ISO preserved its stimulatory effect on I(NaCa). However, prior incubation of myocytes with pertussis toxin (PTX, 5 microg ml(-1) did prevent the effect of ADO. The anti-adrenergic effect of ADO on I(NaCa) was mimicked by externally applied carbachol (CCh, 10 microM), a muscarinic receptor agonist. We conclude that ADO antagonized the effect of beta-adrenergic stimulation of I(NaCa) by directly activating inhibitory G-protein (G(i))-linked A(1) receptors in guinea-pig ventricular myocytes. These findings may suggest a novel mechanism by which adenosine exerts some of its antiarrhythmic effects.
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PMID:Anti-adrenergic effect of adenosine on Na(+)-Ca(2+) exchange current recorded from guinea-pig ventricular myocytes. 1129 91

To investigate the long-term influence of insulin resistance and hyperinsulinemia on vascular reactivity, both muscarinic and alpha2-receptor-mediated relaxations and the contribution of nitric oxide to these mechanisms were studied in the fructose-fed rat. Male Sprague-Dawley rats were fed either fructose-rich chow (FFR, n = 6) or normal chow (CNT, n = 6) for 40 weeks. Systolic blood pressure was measured by tail-cuff method. A 3-mm segment of mesenteric artery was excised, cannulated and pressurized, pretreated with prazosin (10(-6) mol/L) and propranolol (3 x 10(-6) mol/L), then precontracted with serotonin (10(-6) mol/L). Endothelium dependent relaxation was induced by addition of acetylcholine (10(-9) to 10(-4) mol/L), or a selective alpha2-agonist B-HT 920 (10(-9) to 10(-5) mol/L), with or without the nitric oxide synthase inhibitor L-NAME (10(-4) mol/L). Systolic blood pressure was significantly higher in FFR at the early period; however, there was no difference at the end of 40 weeks compared to CNT. Fasting plasma insulin was much higher in FFR than in CNT (110+/-62 v 41+/-11 microU/mL, P < .05), whereas plasma glucose was not different. Maximum relaxation to acetylcholine was attained at 10(-6) mol/L in FFR but at 3 x 10(-7) mol/L in CNT. The degree of maximum relaxation attained with acetylcholine was similar in FFR and CNT (89+/-9 and 94+/-4% of precontraction), although attenuated (P < .01) by the addition of L-NAME only in FFR (to 34+/-22%, P < .05) but not in CNT (to 82+/-25%). The half-maximal relaxation dose of acetylcholine was greater in FFR (P < .01) compared with CNT and was significantly increased (P < .05) by L-NAME in both groups. B-HT 920 at 10(-5) mol/L induced a greater relaxation in CNT (36+/-10% of serotonin constriction) than in FFR (19+/-14%, P < .05). These responses were significantly blunted by L-NAME. Thus, muscarinic receptor-mediated vascular relaxation is less sensitive and more nitric oxide dependent in FFR versus CNT. Alpha2-adrenergic-mediated relaxation, predominantly mediated by nitric oxide, is also impaired in FFR. It is possible that prolonged insulin resistance and hyperinsulinemia in FFR could alter endothelial-dependent vasodilatory mechanisms, thereby contributing to the increase in blood pressure seen in this model.
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PMID:Long-term fructose feeding impairs vascular relaxation in rat mesenteric arteries. 1149 99

The effects of the Brazilian herbal medicine Catuama and each of its plant constituents (Paullinia cupana, Trichilia catigua, Zingiber officinalis and Ptychopetalum olacoides) were investigated on rabbit corpus cavernosum (RbCC) using a bioassay cascade. Catuama caused short-lived and dose-dependent relaxations (11% +/- 7%, 26% +/- 5% and 82% +/- 9%, at doses of 1, 3 and 10 mg, respectively). Neither the nitric oxide synthesis inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME; 10 microM) nor the soluble guanylate cyclase inhibitor ODQ (10 microM) significantly affected the Catuama-induced relaxations. Similarly, the selective ATP-dependent K(+) channel (K(ATP)) blocker glibenclamide (10 microM), the muscarinic receptor antagonist atropine (1 microM) and the voltage-dependent Na(+) channel blocker tetrodotoxin (1 microM) all failed to affect significantly the Catuama-induced relaxations. These results indicate that the relaxations induced by Catuama involve neither nitric oxide release nor K(ATP) channel activation. The extracts of P. cupana, Z. officinalis and P. olacoides caused short-lived and dose-dependent RbCC relaxations, whereas T. catigua evoked long-lasting relaxations which were occasionally preceded by a brief contractile effect. The extract of P. cupana was the most active in relaxing RbCC strips. The relaxations induced by all extracts were not significantly affected by L-NAME (10 microM). The infusion of ODQ (10 microM) had no significant effect on the P. cupana- and Z. officinalis-induced relaxations but reduced by >50% (p < 0.05) those evoked by P. olacoides and T. catigua. Incubations of RbCC with Catuama(10 mg/mL for 0.25 to 5 min) caused increases of cAMP levels (143% increase at 5 min of incubation). Incubations of RbCC with P. cupana extract (1 mg/mL) increased the cAMP levels by 200% whereas higher doses (10 and 100 mg/mL) caused smaller increases in the nucleotide levels (150% and 89%, respectively). The extracts of Z. officinalis and P. olacoides (same doses) caused smaller increases of the cAMP levels compared with the P. cupana extract, whereas T. catigua (1-100 mg) did not increase the levels of this nucleotide above the basal values. Our results show that of the four extracts assayed, P. cupana was the most effective, indicating that it is the main extract responsible for the relaxing effect of Catuama on rabbit cavernosal tissue.
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PMID:The relaxation of isolated rabbit corpus cavernosum by the herbal medicine Catuama and its constituents. 1150 34

Pharmacological studies using the Doppler technique revealed that pregnancy decreases the systemic blood pressure and enhances uterine blood velocity in rats. The reactivity of the uterine artery to alpha-adrenoceptor and muscarinic receptor agonists was higher than that of systemic arteries. Sodium nitroprusside increased uterine arterial blood velocity slightly during gestation and markedly in non-pregnant rats. N(G)-L-Arginine methyl ester (L-NAME) decreased the uterine blood velocity mainly in gravid animals. The effect of diclofenac on uterine blood velocity was also more pronounced during pregnancy. The actions of sodium nitroprusside, L-NAME and diclofenac on systemic blood pressure were similar in pregnant and virgin rats. Altogether, these results indicate that pregnancy enhances nitric oxide (NO) and vasodilatory prostanoid production in the uterine vascular muscle which becomes less sensitive to exogenous NO. The uterine vasodilated status appears to be determined by conjugated actions of endothelial NO and vasodilator prostanoids of which the synthesis and the effects are weakly modified in systemic arteries during gestation.
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PMID:In vivo regulation of vasomotricity by nitric oxide and prostanoids during gestation. 1155 67

Within the central nervous system, acetylcholine (ACh) functions as a state-dependent modulator at a range of sites, but its signaling mechanisms are yet unclear. Cholinergic projections from the brain stem and basal forebrain innervate the suprachiasmatic nucleus (SCN), the master circadian clock in mammals, and cholinergic stimuli adjust clock timing. Cholinergic effects on clock state require muscarinic receptor-mediated activation of guanylyl cyclase and cGMP synthesis, although the effect is indirect. Here we evaluate the roles of carbon monoxide (CO) and nitric oxide (NO), major activators of cGMP synthesis. Both heme oxygenase 2 (HO-2) and neuronal nitric oxide synthase (nNOS), enzymes that synthesize CO and NO, respectively, are expressed in rat SCN, with HO-2 localized to the central core of the SCN, whereas nNOS is a punctate plexus. Hemin, an activator of HO-2, but not the NO donor, SNAP, mimicked cholinergic effects on circadian timing. Selective inhibitors of HO fully blocked cholinergic clock resetting, whereas NOS inhibition partially attenuated this effect. Hemoglobin, an extracellular scavenger of both NO and CO, blocked cholinergic stimulation of cGMP synthesis, whereas l-NAME, a specific inhibitor of NOS, had no effect on cholinergic stimulation of cGMP, but decreased the cGMP basal level. We conclude that basal NO production generates cGMP tone that primes the clock for cholinergic signaling, whereas HO/CO transmit muscarinic receptor activation to the cGMP-signaling pathway that modulates clock state. In light of the recently reported inhibitory interaction between HO-2/CO and amyloid-beta, a marker of Alzheimer's disease (AD), we speculate that HO-2/CO signaling may be a defective component of cholinergic neurotransmission in the pathophysiology of AD, whose manifestations include disintegration of circadian timing.
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PMID:Carbon monoxide and nitric oxide: interacting messengers in muscarinic signaling to the brain's circadian clock. 1157 81

Pyridostigmine bromide (PB) is a reversible cholinesterase inhibitor used for treatment of myasthenia gravis and for prophylactic protection against organophosphate nerve agent. We previously showed PB can induce apoptotic death in rat brain following systemic treatment. To study mechanisms by which PB induces brain cell death, cultured rat cerebellar granule cells were used. Cytotoxicity was determined after exposure to PB (10-1000 microM) for 24 h; a high concentration of PB (>500 microM) significantly increased lactate dehydrogenase release, which was reduced by pretreatment with the antioxidant, N-t-butyl-alpha-phenyl-nitrone (PBN). Apoptosis, as determined by TUNEL staining, was concentration dependent (10-250 microM) after a 24-h exposure and cytotoxicity was confirmed by gel electrophoresis of DNA, release of cytochrome c from mitochondria, elevation of caspase activity, and electron microscopy. The oxidant-sensitive fluorescent dye 2',7'-dichlorofluorescin diacetate was used to detect reactive oxidative species (ROS) generation. Pretreatment with PBN, superoxide dismutase, catalase, or the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) blocked PB-induced ROS generation and apoptotic cell death. Pretreatment with atropine or MK-801 blocked ROS generation and the subsequent neurotoxicity, showing that both muscarinic and NMDA receptors mediate the response. DNA extracted from PB-treated cells revealed oligonucleosomal fragmentation on gel electrophoresis and antioxidants attenuated the DNA fragmentation, providing further evidence for a link of ROS generation and apoptosis. These results indicate that muscarinic receptor-mediated ROS generation is an initiating factor in PB-induced apoptotic cell death and activation of the NMDA glutamate receptor is directly linked to the response.
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PMID:Reactive oxygen species mediate pyridostigmine-induced neuronal apoptosis: involvement of muscarinic and NMDA receptors. 1170 96

This study was designed to characterise the muscarinic receptor subtype responsible for acetylcholine-mediated in vitro pulmonary artery relaxation in rats and the importance of the presence of neostigmine (an anti-cholinesterase) during receptor characterisation. Cumulative administration of acetylcholine elicited concentration-dependent relaxation of phenylephrine (1 microM) precontracted preparations. Inclusion of neostigmine (10 microM) caused a parallel leftward shift with an increase of the pD(2) value (7.09 vs. 6.43) of the concentration-response curve of acetylcholine. The magnitude of maximum relaxation, however, was not affected. Using a range of conventional muscarinic receptor antagonists (atropine, pirenzepine, methoctramine, p-FHHSiD and tropicamide) and the highly selective Green Mamba muscarinic toxins (MT-3 and MT-7), it was found that muscarinic M(3) receptors are probably responsible for endothelium-dependent relaxation of the pulmonary artery upon acetylcholine challenge. Preincubation with N(G)-nitro-L-arginine methyl ester (L-NAME, 20 microM, a nitric oxide synthase inhibitor), but not N(G)-nitro-D-arginine methyl ester (D-NAME, 20 microM), abolished acetylcholine-elicited relaxation. Moreover, 6-anilino-5,8-quinolinedione (LY 83583, 1 microM) and methylene blue (1 microM) (both are guanylate cyclase inhibitors) markedly attenuated acetylcholine-elicited relaxation. However, the presence of indomethacin (3 microM, a cyclo-oxygenase inhibitor), (-)-perillic acid (30 microM, a p21(ras) blocker), 2-[2'-amino-3'-methoxy-phenyl]-oxana-phthalen-4-one (PD 98059) (10 microM, a p42/p44 mitogen-activated protein kinase inhibitor), 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB 203580) (1 microM, a p38 mitogen-activated protein kinase blocker), wortmannin (500 nM, a phosphatidylinositol-3 kinase inhibitor) and genistein (10 microM, a tyrosine kinase blocker) failed to alter acetylcholine-provoked pulmonary arterial relaxation. These results suggest that acetylcholine caused pulmonary arterial relaxation through the activation of muscarinic M(3) receptors in the endothelium. Moreover, the p21(ras)/mitogen-activated protein kinase pathway seems to play no role in mediating acetylcholine-elicited relaxation.
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PMID:Role of mitogen-activated protein kinase pathway in acetylcholine-mediated in vitro relaxation of rat pulmonary artery. 1175 66

Muscarinic receptors play an important role in secretory and vasodilator responses in rat salivary glands. Nitric oxide synthase (NOS) activity was found coupled to muscarinic receptor activation as well as to nitric oxide-mediated amylase secretion elicited by carbachol. Parotid glands presented a predominant M(3) and a minor muscarinic M(1) acetylcholine receptor population, though carbachol stimulated NOS activity only through muscarinic M(3) receptors as revealed in the presence of 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) and pirenzepine. Amylase secretion induced by carbachol appeared to be partly mediated by nitric oxide and nitric oxide-induced signaling since N-nitro-L-arginine methyl ester (L-NAME) inhibited the effect as well as did methylene blue. A negative regulation of NOS by protein kinase C activation in the presence of a high concentration of carbachol was seen in parotid glands and this inhibition was paralleled by amylase secretion.
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PMID:Activation of nitric oxide synthase through muscarinic receptors in rat parotid gland. 1193 89

To investigate the vascular endothelial dysfunction in the insulin resistance syndrome, muscarinic and alpha2-adrenergic mediated relaxations were studied in the fructose-fed rat. Male Sprague-Dawley rats were fed either fructose-rich chow (FFR, n=14) or normal chow (CNT, n=13) for 8 weeks. Systolic blood pressure (SBP) was measured by the tail-cuff method. A 3 mm segment of mesenteric artery was cannulated and pressurized, pretreated with prazosin (10(-6) mol/l) and propranolol (3x10(-6) mol/l), then pre-contracted with serotonin (10(-6) mol/l). Endothelium-dependent relaxation was induced by addition of acetylcholine (ACh, 10(-9)-10(-4) mol/l) or a selective alpha2-agonist, B-HT 920 (10(-9)-10(-5) mol/l), with or without the nitric oxide (NO) synthase inhibitor, L-NAME (10(-4) mol/l). SBP was significantly elevated in FFR but not in CNT. Plasma triglyceride in FFT (241+/-115 mg/dl) was significantly (p<0.01) higher than in CNT (84+/-34 mg/dl). Insulin and insulin/glucose ratio were higher but not significantly. Plasma glucose was not different between the two groups. In the dose-response curves to ACh, maximum relaxation and ED50 were similar between FFR and CNT. Moreover, L-NAME shifted the dose-response curves similarly to the right in both groups. Dose-response curves to B-HT 920, however, showed less relaxation in FFR than in CNT (p<0.05). B-HT 920-induced relaxations were mostly abolished by L-NAME. It is concluded that endothelial alpha2-adrenergic relaxation, predominantly mediated by NO, is likely more sensitive to the development of insulin resistance than muscarinic receptor relaxation in this 8-weeks FFR model. This early impairment of endothelial alpha2-adrenergic relaxation may contribute to the development of hypertension and insulin resistance in the FFR.
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PMID:Impaired endothelial alpha-2 adrenergic receptor-mediated vascular relaxation in the fructose-fed rat. 1204 35

The acute cardiovascular effects of rotundifolone (ROT), the major constituent (63.5 %) of the essential oil of Mentha x villosa (OEMV), were tested in rats by using a combined (in vivo and in vitro) approach. ROT (1, 5, 10, 20 and 30 mg kg(-1) i. v.) induced a significant and dose-dependent hypotension and bradycardia in non-anaesthetized normotensive rats. The hypotensive effect was significantly attenuated by pre-treatment of the rats with atropine (2 mg kg(-1) i. v.) or L-NAME (20 mg kg(-1) i. v.). Furthermore, the bradycardic effect was abolished by atropine. In isolated rat atrial preparations, ROT (10, 100, 300 and 500 microg ml(-1)) produced concentration-related negative inotropic and chronotropic effects. In isolated intact aortic rings, increasing concentractions of ROT (0.3, 1, 10, 100, 300 and 500 microg ml(-1)) were able to antagonize the contractile effect of phenylephrine (1 microM) (IC50 = 184 +/- 6 microg ml(-1)). The smooth muscle-relaxant activity of ROT was inhibited by either removal of vascular endothelium, atropine (1 microM), L-NAME (100 and 300 microM) or indomethacin (10 microM) (IC50 values = 235 +/- 7, 247 +/- 8, 387 +/- 21, 723 +/- 75 and 573 +/- 38 microg ml(-1), respectively). These results suggest that rotundifolone markedly lowers arterial pressure and heart rate in non-anaesthetized animals. The hypotensive action of rotundifolone can be a consequence of a decrease in heart rate and peripheral vascular resistance, probably due to a non-selective muscarinic receptor stimulation.
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PMID:Muscarinic agonist properties involved in the hypotensive and vasorelaxant responses of rotundifolone in rats. 1222 91

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