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)

1. We have used the isolated, buffer-perfused, mesenteric arterial bed of the rat (preconstricted with methoxamine or 60 mM K+) to characterize nitric oxide (NO)-independent vasorelaxation which is thought to be mediated by the endothelium-derived hyperpolarizing factor (EDHF). 2. The muscarinic agonists carbachol, acetylcholine (ACh) and methacholine caused dose-related relaxations in preconstricted preparations with ED50 values of 0.18 +/- 0.04 nmol (n = 8), 0.05 +/- 0.02 nmol (n = 6) and 0.26 +/- 0.16 nmol (n = 5), respectively. In the same preparations NG-nitro-L-arginine methyl ester (1-NAME, 100 microM) significantly (P < 0.05) decreased the potency of all the agents (ED50 values in the presence of L-NAME: carbachol, 0.66 +/- 0.11 nmol; ACh, 0.28 +/- 0.10 nmol; methacholine, 1.97 +/- 1.01 nmol). The maximal relaxation to ACh was also significantly (P < 0.05) reduced (from 85.3 +/- 0.9 to 73.2 +/- 3.7%) in the presence of L-NAME. The vasorelaxant effects of carbachol were not significantly altered by the cyclo-oxygenase inhibitor indomethacin (10 microM; n = 4). 3. The K+ channel blocker, tetraethylammonium (TEA, 10 mM) also significantly (P < 0.001) reduced both the potency of carbachol (ED50 = 1.97 +/- 0.14 nmol in presence of TEA) and the maximum relaxation (Rmax = 74.6 +/- 3.2% in presence of TEA, P < 0.05, n = 3). When TEA was added in the presence of L-NAME (n = 4), there was a further significant (P < 0.001) decrease in the potency of carbachol (ED50 = 22.4 +/- 13.5 nmol) relative to that in the presence of L-NAME alone, and Rmax was also significantly (P < 0.05) reduced (74.6 +/- 4.2%). The ATP-sensitive K+ channel inhibitor, glibenclamide (10 microM), had no effect on carbachol-induced relaxation (n = 9). 4. High extracellular K+ (60 mM) significantly (P < 0.01) reduced the potency of carbachol (n = 5) by 5 fold (ED50: control, 0.16 +/- 0.04 nmol; high K+, 0.88 +/- 0.25 nmol) and the Rmax was also significantly (P < 0.01) reduced (control, 83.4 +/- 2.7%; high K+, 40.3 +/- 9.2%). The residual vasorelaxation to carbachol in the presence of high K+ was abolished by L-NAME (100 microM; n = 5). In preparations preconstricted with high K+, the potency of sodium nitroprusside was not significantly different from that in preparations precontracted with methoxamine, though the maximal response was reduced (62.4 +/- 3.4% high K+, n = 7; 83.1 +/- 3.1% control, n = 7). 5. In the presence of the cytochrome P450 inhibitor, clotrimazole (1 microM, n = 5 and 10 microM, n = 4), the dose-response curve to carbachol was significantly shifted to the right 2 fold (P < 0.05) and 4 fold (P < 0.001) respectively, an effect which was further enhanced in the presence of L-NAME. Rmax was significantly (P < 0.01) reduced by the presence of 10 microM clotrimazole alone, being 86.9 +/- 2.5% in its absence and 61.8 +/- 7.8% in its presence (n = 6). 6. In the presence of the cell permeable analogue of cyclic GMP, 8-bromo cyclic GMP (6 microM), the inhibitory effects of L-NAME on carbachol-induced relaxation were substantially enhanced (ED50: L-NAME alone, 0.52 +/- 0.11 nmol, n = 5; L-NAME + 8-bromo cyclic GMP, 1.42 +/- 0.28 nmol, n = 7, Rmax: L-NAME alone, 82.2 +/- 2.4%; L-NAME + 8-bromo cyclic GMP, 59.1 +/- 1.8%. P < 0.001). These results suggest that the magnitude of the NO-independent component of vasorelaxation is reduced when functional cyclic GMP levels are maintained, suggesting that basal NO (via cyclic GMP) may modulate EDHF activity and, therefore, on loss of basal NO production the EDHF component of endothelium-dependent relaxations becomes functionally greater. 7. The present investigation demonstrates that muscaranic receptor-induced vasorelaxation in the rat mesenteric arterial bed is mediated by both NO-dependent and independent mechanisms. The L-NAME-insensitive mechanism, most probably occurs via activation of a K+ conductance and shows the characteristics of EDHF-mediated responses. Finally, the results demonstrate that EDHF activity may become upregulated on inhibition of NO production and this may compensate for the loss of NO.
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PMID:Characterization and modulation of EDHF-mediated relaxations in the rat isolated superior mesenteric arterial bed. 911 62

Transmural electrical field stimulation (EFS, 4-32 Hz) produced a biphasic contractile response consisting of a rapid and transient contraction (first phase) followed by a slow contraction (second phase) in ring preparations of guinea pig portal veins. Both contractions were enhanced by the nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 30 microM). In the presence of L-NAME, tetrodotoxin (1 microM) and guanethidine (3 microM) inhibited both contractions and phentolamine (10 microM), and reserpine treatment abolished the first-phase contraction without affecting the second-phase contraction. These results suggest that the first-phase contraction is caused by norepinephrine released from the perivascular nerves. In the presence of phentolamine and L-NAME, the second-phase contraction was inhibited by the nonselective P2-purinoceptor antagonist suramin (30-300 microM) and the P(2Y)-purinoceptor antagonist reactive blue 2 (RB2; 10-100 microM). alpha,beta-Methylene-adenosine triphosphate (alpha,beta-mATP; 3-30 microM), which desensitizes P(2X)-purinoceptors, and the P(2X)-purinoceptor antagonist 4,4'-diisothiocyanatostilbene-2,2'-disulphonate (DIDS; 1-10 microM) had a little effect. Exogenous ATP (0.1-3 mM) and UTP (0.1-3 mM) in the presence of L-NAME produced contractions in a concentration-dependent manner. The ATP-induced contraction was enhanced by suramin, RB2, and DIDS but unaltered by alpha,beta-mATP. The UTP-induced contraction was inhibited by suramin and RB2 but unaltered by alpha,beta-mATP and DIDS. These results indicate that in the guinea pig portal vein, the classic P(2X)-purinoceptors do not contribute to the nonadrenergic component of sympathetic neurotransmission. Furthermore, the pharmacology of the nonadrenergic component of neurotransmission resembles that of vasoconstrictor responses to exogenous UTP rather than to ATP.
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PMID:Nonadrenergic contractile response of guinea pig portal vein to electrical field stimulation mimics response to UTP but not to ATP. 912 74

1. We have investigated the mechanism by which L-arginine stimulates membrane depolarization, an increase of intracellular calcium ([Ca2+]i) and insulin secretion in pancreatic beta-cells. 2. L-Arginine failed to affect beta-cell metabolism, as monitored by NAD(P)H autofluorescence. 3. L-Arginine produced a dose-dependent increase in [Ca2+]i, which was dependent on membrane depolarization and extracellular calcium. 4. The cationic amino acids L-ornithine, L-lysine, L-homoarginine (which is not metabolized) and NG-monomethyl-L-arginine (L-NMMA, a nitric oxide synthase inhibitor) produced [Ca2+]i responses similar to that produced by L-arginine. The neutral nitric oxide synthase inhibitors NG-nitro-L-arginine (L-NNA) and N omega-monomethyl-L-arginine (L-NAME) also increased [Ca2+]i. D-Arginine was ineffective. 5. L-Arginine did not affect whole-cell Ca2+ currents or ATP-sensitive K+ currents, but produced an inward current that was carried by the amino acid. 6. The reverse transcriptase-polymerase chain reaction demonstrated the presence of messenger RNA for the murine cationic amino acid transporters mCAT2A and mCAT2B within the beta-cell. 7. L-Arginine did not affect beta-cell exocytosis as assayed by changes in cell capacitance. 8. Our data suggest that L-arginine elevates [Ca2+]i and stimulates insulin secretion as a consequence of its electrogenic transport into the beta-cell. This uptake is mediated by the mCAT2A transporter.
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PMID:Electrogenic arginine transport mediates stimulus-secretion coupling in mouse pancreatic beta-cells. 913 Jan 59

1. The flavoprotein binder diphenyleneiodonium (DPI) is a potent, irreversible inhibitor of nitric oxide synthase (NOS), but produces only a transient pressor response following systemic administration to animals, despite evidence of persistent NOS inhibition. To characterize further the effects of DPI on vascular tone, isometric tension was recorded from rat isolated aortic rings mounted between steel wires in an organ bath. 2. The NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 1 mM) initiated an additional contraction of prostaglandin F2 alpha-preconstricted rings with endothelium which was sustained throughout the period of L-NAME exposure (+234 +/- 39% at 15 min). In contrast, addition of DPI (5 microM) to rings with endothelium produced a transient initial contraction (+111 +/- 27% at 2 min) followed by a more sustained relaxation (-27 +/- 19% at 15 min, P < 0.001 vs L-NAME). 3. The contraction to DPI was also observed in rings without endothelium, was abolished by L-NAME pretreatment, and was unaffected by the alpha-adrenoreceptor inhibitor prazosin. Relaxation in response to DPI was not inhibited by endothelium removal or by pretreatment with either L-NAME or with the ATP-sensitive potassium channel blocker glibenclamide. 4. The endothelium-independent relaxation to DPI was inhibited at 23 degrees C and its time course was delayed by pretreatment with the guanylate cyclase inhibitor methylene blue. 5. Thus, in addition to a transient initial contraction due to NOS inhibition, DPI produces an endothelium-independent, temperature-dependent relaxation which appears in part due to activation of guanylate cyclase. This relaxant effect of DPI may explain the transient nature of its pressor effect in vivo despite sustained NOS inhibition.
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PMID:Endothelium-independent relaxation of aortic rings by the nitric oxide synthase inhibitor diphenyleneiodonium. 913 92

Blood flow and its distribution must be appropriately regulated to ensure that perfusion is matched to local tissue demands. We investigated the role of ATP in triggering a conducted alteration in arteriolar diameter in the Saran-covered cheek pouch retractor muscle of anesthetized hamsters (n = 60). Vascular responses were observed using in vivo video microscopy upstream from the site of micropressure application of ATP (10(-8)-10(-4) M) either into the lumen or just outside the wall of first- and second-order arterioles. The role of nitric oxide (NO) in the vascular responses to ATP was determined by inhibiting NO synthase activity with N(omega)-nitro-L-arginine methyl ester (L-NAME) with and without coadministration of an excess of L-arginine. Intraluminal application of ATP led to a concentration-dependent vasodilation, which was conducted upstream along the arteriole. The dilatory response was blocked by systemic pretreatment with L-NAME and was maintained in the presence of an excess of L-arginine. In contrast, ATP introduced extraluminally resulted in a conducted vasoconstrictor response that was enhanced by pretreatment with L-NAME. The dilator response to intraluminal ATP, in the context of ATP release from erythrocytes under conditions associated with decreased supply relative to demand, supports a role for the erythrocyte in communicating local tissue needs to the vasculature, enabling the appropriate matching of oxygen supply to demand.
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PMID:Arteriolar responses to extracellular ATP in striated muscle. 913 75

1. The aim of the present study was to assess interactions between nitric oxide (NO) and prostacyclin (PGI2) during endothelium-dependent relaxations evoked by bradykinin, calcium ionophore (A23187) and acetylcholine in canine isolated pulmonary artery. 2. Relaxations to low concentrations of bradykinin and A23187 were abolished by combined inhibition of NO-synthase (by N omega-nitro-L-arginine methyl ester L-NAME, 30 microM) and cyclo-oxygenase (indomethacin, 10 microM), suggesting mediation by NO and PGI2. The individual contributions of NO and PGI2 to the dilator responses were quantified by use of areas above the separate indomethacin-insensitive and L-NAME-insensitive components of the concentration-effect curves, respectively. Individually, NO and PGI2 accounted for only 53 +/- 5% and 16 +/- 9% of total bradykinin-induced relaxation, and 46 +/- 10% and 20 +/- 9% of total A23187-induced relaxation, suggesting that NO and PGI2 acted synergistically to cause endothelium-dependent relaxation. 3. Relaxation to low concentrations of acetylcholine was abolished by L-NAME but not affected by indomethacin, suggesting the response was mediated solely by NO with no interaction from PGI2. 4. Glibenclamide (1 microM), an inhibitor of ATP-sensitive potassium (K+ATP) channels, inhibited responses to bradykinin or A23187 but did not affect relaxations evoked by acetylcholine. Glibenclamide did not affect endothelium-independent relaxations to PGI2 or the NO-donor, 3-morpholinosydnonimine (SIN-1). 5. With bradykinin, glibenclamide attenuated total relaxation by 49 +/- 8%, but did not alter the individual NO and PGI2-mediated components of the response. Glibenclamide abolished the synergistic interaction between endothelium-derived NO and PGI2. 6. At high concentrations, bradykinin, A23187 or acetylcholine caused endothelium-dependent relaxation that was insensitive to L-NAME + indomethacin. With bradykinin or A23187, this component of relaxation was inhibited by glibenclamide, whereas with acetylcholine, glibenclamide had no effect. 7. The synergistic interaction between endothelium-derived NO and PGI2 in canine pulmonary artery is mediated by activation of K+ATP channels, presumably by an endothelium-derived hyperopolarizing factor (EDHF). The pattern of endothelial dilator mediators and the presence of this synergistic interaction is dependent on the nature of the endothelial stimulus.
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PMID:Synergistic interaction between endothelium-derived NO and prostacyclin in pulmonary artery: potential role for K+ATP channels. 915 37

1. The mechanism of the sustained acetylcholine-induced endothelium-dependent hyperpolarization (EDH) in intact rat small mesenteric arteries prestimulated with noradrenaline (10(-6) M) was investigated by means of the single microelectrode voltage-clamp method. 2. The vascular smooth muscle cells (VSMCs) in this preparation are poorly or even not coupled for the reasons that: (1) the mean input resistance Rlnp of the clamped vascular smooth muscle increases from 120 M omega under control conditions to 440 M omega after application of K+ channel blocking drugs, (2) the voltage relaxation after injection of hyperpolarizing currents has a monoexponential time course and is linearly dependent on Rlnp, and (3) voltage steps induced by current-clamp steps are not transferred to locations in the vascular musculature 120 microns apart from the current injecting microelectrode. 3. Sustained (> 5 min) application of ACh (10(-5) M) hyperpolarized the VSMCs by induction of a hyperpolarizing current. This effect was completely blocked by the inhibitor of the nitric oxide (NO) synthase L-NAME (10(-3) M) but not by the inhibitor of the soluble guanylate cyclase (sGCl) Methylene Blue (MB, 10(-4) M). 4. Application of the NO donor sodium nitroprusside (SNP, 10(-6) M) for more than 5 min mimicked the induction of the endothelium-dependent hyperpolarizing current in vessels with destroyed endothelium. The reversal potential of this current is dependent on the extracellular K+ concentration. The effect of SNP could also not be blocked by MB. 5. The blockers of ATP-dependent and Ca(2+)-dependent K+ channels, glibenclamide (Glb, 10(-5) M) and charybdotoxin (CTX, 5 x 10(-8) M), respectively, blocked a hyperpolarizing current in the VSMCs similar to the ACh- or SNP-induced current. 6. The isolated application of either Glb or CTX did not block the activation of the hyperpolarizing current by SNP. Only the combined administration of Glb and CTX blocked the SNP-induced current completely. 7. Our results suggest that in rat small mesenteric artery, ACh hyperpolarizes the VSMCs tonically by activating both ATP- and Ca(2+)-dependent K+ currents, only via release of NO from the endothelium without need for activation of the sGCl.
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PMID:Acetylcholine-induced K+ currents in smooth muscle cells of intact rat small arteries. 916 80

The isolated perfused rat mesenteric bed releases endothelium-derived hyperpolarizing factor (EDHF) in response to acetylcholine (ACh) or histamine. I propose that EDHF released in the mesenteric vascular bed is a cytochrome P450 (CYP)-linked, arachidonate metabolite. In the presence of nitro-L-arginine methyl ester (L-NAME) and indomethacin, injections of ACh (0.001 to 10 nmol) or histamine (0.1 to 1,000 nmol) elicited transient, dose-dependent dilation of cirazoline (an alpha1-adrenoceptor selective agonist) preconstricted mesenteric beds. The L-NAME-resistant responses to ACh or histamine were insensitive to tetrodotoxin (1 micromol/L), thus negating its neuronal origin, but were profoundly attenuated by a K+ channel inhibitor tetrabutylammonium (0.5 mmol/L). 7-Ethoxyresorufin (a selective and competitive blocker of CYP 1A isozyme) blunted ACh and histamine mediated EDHF responses but did not alter vasodilation initiated through K+ channel activation by either cromakalim or NS-1619, or through the nitric oxide-cGMP pathway (sodium nitroprusside). Clotrimazole, an imidazole that inhibits CYP by binding to the heme moiety, attenuated ACh, histamine, and cromakalim but not sodium nitroprusside-mediated vasodilator responses. Other CYP isozyme selective inhibitors, such as metyrapone (CYP 2B), 7-pentoxyresorufin (CYP 2B1), sulfaphenazole (CYP 2C/3A), and 17-octadecynoic acid (4A-linked omega-hydroxylase inhibitor), did not alter ACh or histamine-induced EDHF response. The EDHF-mediated dilations initiated by ACh and histamine, as well as K(ATP) activation by cromakalim, were blocked by mepacrine, a nonselective phospholipase A2 inhibitor. Mepacrine did not alter K(Ca) activation by compound NS-1619. I conclude that 1) the isolated perfused rat mesenteric prearteriolar bed releases in response to ACh and histamine, an EDHF that causes vasodilation through K+ channel activation; 2) the EDHF is most likely a CYP-derived arachidonate product; 3) CYP 1A is well suited as the isozyme responsible for EDHF production in this vascular bed; and 4) PLA2 appears to mediate the release of the precursor arachidonic acid.
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PMID:Endothelium-derived hyperpolarizing factor: characterization as a cytochrome P450 1A-linked metabolite of arachidonic acid in perfused rat mesenteric prearteriolar bed. 923 31

1. The aim of this study was to characterize P2 receptors in the arterial vascular bed of human perfused placental cotyledons. Vasoconstrictor responses to bolus injections of purine and pyrimidine nucleotides were tested at basal tone, and vasodilator responses in preparations with tone raised by perfusion with prostaglandin F2alpha (PGF2alpha; 10-50 nM). 2. At basal tone, bolus injections of the P2X-selective agonist alpha,beta-methylene ATP (alpha,beta-meATP; 0.5-500 nmol) elicited dose-dependent vasoconstriction. ATP (0.005-5 micromol) also elicited dose-dependent vasoconstriction, but was less potent than alpha,beta-meATP. Vasoconstriction was also elicited by other nucleotides, but only at the highest dose tested (5 micromol): UTP > CTP = ITP (n = 6). GTP and TTP did not cause vasoconstriction. 3. Constrictor responses to bolus injections of alpha,beta-meATP were resistant to desensitization and were not significantly affected when carried out in the presence of 1 microM alpha,beta-meATP added to the perfusate. However, responses to bolus injections of alpha,beta-meATP were partially blocked by perfusion with 10 microM alpha,beta-meATP. In contrast, responses to ATP and UTP were unaffected by 10 microM alpha,beta-meATP. The P2X receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS; 10 and 100 microM) had no significant effect on vasoconstriction mediated by alpha,beta-meATP and ATP. 4. Removal of the endothelium had no significant effect on constrictor responses to alpha,beta-meATP, ATP and UTP. Inhibition of nitric oxide (NO) synthesis with N(G)-nitro-L-arginine methyl ester (L-NAME; 100 microM) had no significant effect on vasoconstriction to ATP and alpha,beta-meATP. 5. In preparations with tone raised with PGF2alpha (10-50 nM) vasodilatation was elicited by nucleotides with the following order of potency: 2MeSATP = ADP >> ATP > UTP > CTP = GTP = ITP = TTP. pD2 values were: 2MeSATP, 10.03+/-0.26 (n=7); ADP, 9.97+/-0.40 (n=5); ATP, 8.89+/-0.18 (n=7); UTP, 7.79+/-0.35 (n=7). Maximal responses to 2MeSATP and ADP were similar and were approximately 40% greater than maximal responses to ATP and UTP. 6. Vasodilator responses to nucleotides were abolished by L-NAME (100 microM) and by removal of the endothelium. 7. In conclusion, contractile responses mediated by alpha,beta-meATP and ATP in human placental smooth muscle are resistant to desensitization and insensitive to PPADS and, thus, show a dissimilar pharmacological profile to the classic smooth muscle P2X1 receptor. There may be two subtypes of smooth muscle P2 receptor based on differential antagonism of alpha,beta-meATP and ATP with alpha,beta-meATP. A smooth muscle P2 receptor mediates vasoconstriction to UTP, and may indicate a further subtype. Endothelium-dependent, NO-dependent, vasodilatation to 2MeSATP and ADP may be mediated by P2Y1 receptors, while endothelial P2Y2 receptors are likely to mediate NO-dependent relaxation to ATP and UTP.
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PMID:Characterization of P2 receptors for purine and pyrimidine nucleotides in human placental cotyledons. 924 47

The effect of the nitric oxide synthase inhibitor NG-Nitro-L-arginine methyl ester (L-NAME) towards muscarinic receptors was studied in vitro and in vivo. L-NAME displaced the antimuscarinic ligand [3H]quinuclidinyl benzilate ([3H]QNB) from its specific binding sites in rat cerebral cortex and cerebellum homogenates with a more than 10,000 fold lower affinity than atropine, pirenzepine and AFDX 116. Data for L-NAME binding were best fit according to a two-site model (Kd 7.2 nM and 3,000 nM) in the rat cerebellum, whereas in rat cortex a one-site model (Kd 1670 nM) was superior. In anesthetized rats and rabbits L-NAME (7.5-185 mumol/kg) attenuated a hypotensive response to Acetyl beta-methyl-choline (Ac beta-Me Ch)(6.25 nmol/kg) in a dose related fashion, but this effect was negligible as compared to that of atropine (8.8 and 17.7 nmol/kg). Furthermore, the effect of L-NAME was not specifically antimuscarinic since its attenuating effect against ATP- or histamine-induced responses was not statistically different from that of Ac beta-Me Ch. A vagus stimulation induced bradycardia was entirely uninfluenced by L-NAME (37 mumol/kg). In isolated bladder experiments (rabbit) we demonstrated a complete lack of efficacy of L-NAME against Ac beta-Me Ch induced contractions. In the pithed rat preparation L-NAME was ineffective against the MeN-A-343 induced pressor responses. In summary, we demonstrated that the nitric oxide synthase inhibitor L-NAME shows very weak affinity at M1- and M2-receptors in the rat brain in vitro, but appears to have no significant antimuscarinic properties against M1-, M2- and M3-receptor mediated effects in rats and rabbits in vivo.
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PMID:NG-nitro-L-arginine methyl-ester: a muscarinic receptor antagonist? 926 60

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