Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study investigated the effects of dipyridamole in isolated porcine ciliary arteries (diameter 200-250 microns). Isolated porcine ciliary arteries were suspended in myograph chambers filled with modified Krebs-Ringer solution (37 degrees C; 95% O2/5% CO2) for isometric tension recording. Dipyridamole induced concentration-dependent relaxations of porcine ciliary arteries with endothelium precontracted with thromboxane analogue U-46619 (10(-6)M), KCl (50 mM), or endothelin-1 (10(-8)M). Removal of the endothelium of the ciliary vessels and preincubation of the arteries with L-NAME (10(-5)M), or indomethacin (10(-5)M), or the combination of the two drugs significantly reduced the relaxation to dipyridamole (p = 0.002-0.03). Similar vascular responses could be observed in a time-dependent analysis of the effect of a single concentration dipyridamole (10(-4)M). The stimulator of cAMP forskolin also caused relaxations. Endothelin-1 (10(-12)-10(-7)M) and U-46619 (10(-10)-10(-6)M) induced potent contractions of porcine ciliary arteries. Preincubation with dipyridamole (10(-5)M) reduced contractions to endothelin-1 as compared to control (p < 0.004), while contractions to U-46619 were only slightly affected under these conditions (n.s.). These findings demonstrate that dipyridamole is a vasodilator in porcine ciliary arteries. Endothelial nitric oxide and prostacyclin contribute importantly to the effects of dipyridamole. Further studies are required to show whether these properties of dipyridamole may also occur in vivo and offer clinical use in patients with ocular vasospasms and other ophthalmic vascular dysfunctions.
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PMID:Effect of dipyridamole on vascular responses of porcine ciliary arteries. 867 Jul 38

The pulmonary vasodilator action of an S-nitrosothiol, S-nitroso acetylpenicillamine (SNAP), was investigated in the rat pulmonary vasculature. The influence of its nitric oxide donator property was studied by comparison with the effect of acetylpenicillamine (AP), SNAP minus the nitroso group, and the blockade of nitric oxide release by the L-arginine analogue, L-NAME. In the isolated rat lung perfused with autologous blood at a constant flow rate (IPL), changes in pulmonary artery pressure (Ppa) reflect changes in pulmonary vascular resistance. Dose-response relationships to both SNAP and AP (0.1, 1, 10 and 100 micrograms) were established both during normoxic ventilation (air + 5% CO2; low Ppa) and when Ppa was raised by alveolar hypoxic vasoconstriction (2% O2 + 5% CO2). SNAP caused small dose-dependent fall in normoxic Ppa (mean +/- S.D. 17.4 +/- 3.0 mm Hg). In 11 rat IPL % fall of Ppa was 1, 3 and 4% for 1, 10 and 100 micrograms, respectively (p < 0.01). This fall was more obvious when Ppa was raised by hypoxia (mean Ppa rise (HPV) 11.5 +/- 3.8 mm Hg); there was a 22, 55 and 79% fall in HPV for 1, 10 and 100 micrograms in 11 rat IPL. The dilatation after 10 micrograms SNAP was not consistently affected by 100 micrograms L-NAME (% fall in HPV pre L-NAME 45 +/- 22% vs 42 +/- 23% post L-NAME). AP had no significant effect on Ppa, causing only small falls in Ppa, equivalent to solvent (saline). There was occasionally a small rise in Ppa with 10 and 100 micrograms AP. Thus, the dilator action of SNAP is most likely due to its NO donator property, and is not consistently affected by blockade of endogenous NO release.
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PMID:Vasodilator action of the S-nitrosothiol, SNAP, in rat isolated perfused lung. 878 95

1. We investigated whether contractile responses evoked by 5-HT1D receptor agonists were influenced by the endothelium (E) and nitric oxide (NO) in the rabbit isolated saphenous vein. 2. Saphenous vein rings were set up for isometric tension recording in oxygenated (5% CO2 in O2) Krebs solution (pH 7.4) containing (10(-6) M): idazoxan (1), indomethacin (10), ketanserin (0.1), prazosin (10), and N(omega) nitro-L-arginine methyl ester (L-NAME; 0 or 10), a NO synthase inhibitor. In some experiments, the E was removed mechanically. 3. 5-Hydroxytryptamine (5-HT), 5-carboxamidotryptamine (5-CT) and sumatriptan (Sum) contracted rabbit saphenous vein rings in the potency order (pD2 range) of 5-CT(7.2-7.6) > 5-HT(6.2-7.1) > Sum(5.0-5.8), irrespective of the presence or absence of the E or L-NAME (n = 9-37 per group) indicating that the potencies of the 3 agonists were not significantly affected by either the E or L-NAME. 4. Efficacy, as assessed by the maximal contractile response (Emax), was significantly greater for Sum compared to 5-HT and 5-CT with intact E irrespective of the presence (77 +/- 3, 62 +/- 3, and 50 +/- 3 mN respectively; P < 0.05 Sum versus 5-HT and 5-CT) or absence (26 +/- 3, 14 +/- 4, and 13 +/- 2 mN respectively; P < 0.05 Sum versus 5-HT and 5-CT) of L-NAME. In E-denuded rings, the Emax values were all higher than in E-intact rings and did not differ between the 3 agonists (36 +/- 4, 37 +/- 4, and 36 +/- 5 mN for Sum, 5-HT and 5-CT, respectively; P > 0.5 between the 3 agonists) indicating that an endothelium-derived relaxing factor (EDRF) counteracted the constrictor activities of the 5-HT1D receptor agonists and raising the possibility that a component of the Sum-induced contractile responses was E-dependent. Without E, the presence of L-NAME did not significantly affect the Emax values of the 3 agonists (41 +/- 4, 41 +/- 5, and 41 +/- 4 mN for Sum, 5-HT, and 5-CT respectively; P > 0.5 between the 3 agonists) indicating that the NO synthase inhibited was of endothelial origin. 5. Potentiation of the Emax of the 3 agonists by L-NAME was significantly albeit partially reversed by L-arginine (10(-2) M) indicating that NO synthase was indeed inhibited by L-NAME. Furthermore, in the presence of E, potentiation of Emax of the 3 agonists by L-NAME was mimicked by methylene blue (10(-5) M) providing further evidence that NO was involved in the attenuation by the E of the contractile responses induced by the 5-HT1D receptor agonists. 6. In the presence of an intact E and L-NAME, contractile responses elicited by 5-HT and Sum were competitively antagonized by the non-selective 5-HT1D receptor antagonist, methiothepin (pA2: 9.4 and 8.8; slopes: 0.66 and 0.81, respectively) and the highly selective 5-HT1D receptor antagonist, GR 127935 (pA2: 9.0 in each case; slopes: 1.04 and 0.93, respectively) indicating that contractions were mediated through activation of a single population of 5-HT1D receptors. Contractile responses elicited by 5-CT were also competitively antagonized by methiothepin and GR 127935, but non parallel rightward shifts of the concentration-response curves were observed suggestive of the involvement of additional but as yet unidentified receptors in mediating the 5-CT-induced responses. 7. In conclusion, the efficacy, but not the potency, of 5-HT, 5-CT and Sum in evoking 5-HT1D receptor-mediated contractile responses are subject to a substantial inhibitory influence of the E and of an EDRF (probably NO).
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PMID:Influence of the endothelium and nitric oxide on the contractile responses evoked by 5-HT1D receptor agonists in the rabbit isolated saphenous vein. 887 54

Laser Doppler flowmetry was used to further investigate the role of nitric oxide (NO) in CO2-induced cerebrocortical hyperemia in rats. A second objective was to elucidate the source(s) of the NO involved in the response to hypercapnia. We used the L-arginine analogue N omega-nitro-L-arginine methyl ester (L-NAME) to inhibit NO synthase (NOS) and 7-nitroindazole (7-NI) to selectively inhibit brain or nonendothelial NOS. Rats were anesthetized with a single dose of intraperitoneal (IP) pentobarbital (65 mg/kg) for surgery; 60-90 min later they were ventilated with 1.0% halothane in 30% O2 for 1 h to achieve a steady state. The animals were assigned to one of five groups. A control group (n = 9) was infused with 1 mL of saline. The second group (n = 10) received 20 mg/kg of L-NAME intravenously (IV). A third group (n = 9) also received L-NAME; in addition, cerebrocortical laser Doppler flow (LDF) and mean arterial pressure (MAP) were restored to baseline using the NO donor sodium nitroprusside (SNP). In a fourth group (n = 9), MAP was increased to the level usually seen after L-NAME with an infusion of phenylephrine (0.5-5 micrograms.kg-1.min-1). A fifth group (n = 11) received 7-NI at 40 mg/kg IP. The hypercapnic response of LDF was tested in all groups by adding 5% CO2 to the inspired gas at 30-45 min posttreatment; all changes in LDF were significant. In the control group, hypercapnia induced a 70% +/- 24% increase in LDF. In the L-NAME-treated group, the response was decreased to 36% +/- 22% at a posttreatment LDF that was 25% +/- 13% lower than the pre-L-NAME level. In the group where baseline LDF and MAP were restored with SNP, the CO2 response was 56% +/- 15% (not significant versus control). In the group in which MAP was increased with phenylephrine, the response to hypercapnia was 48% +/- 22% at a posttreatment LDF unchanged from pretreatment. These data suggest that increased vascular tone or the absence of basal NO after NOS inhibition influenced the vasodilator response to hypercapnia. In the 7-NI-treated group the response to hypercapnia was 38% +/- 3%, significantly attenuated at a posttreatment flow only 14% +/- 7% lower than pre-7-NI. We conclude that 1) endothelial NO does not mediate the response to hypercapnia but may have a permissive role in the response and 2) that brain NO may have an important role in response to hypercapnia.
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PMID:The role of nitric oxide in the cerebrovascular response to hypercapnia. 902 30

1. The aims of this study were to compare in the rat isolated perfused lung preparation, the antagonist effects of iloprost, a stable analogue of prostacyclin, and prostaglandin E1 (PGE1) on the hypoxic pulmonary pressure response, and to investigate the possible involvement of KATP and KCa channels and of EDRF (NO) in the effects. In addition, iloprost and PGE1 effects were compared to those of adenosine and forskolin. 2. Isolated lungs from male Wistar rats (260-320 g) were ventilated with 21% O2 + 5% CO2 + 74% N2 (normoxia) or 5% CO2 + 95% N2 (hypoxia) and perfused with a salt solution supplemented with ficoll. Glibenclamide (1 microM), charybdotoxin (0.1 microM), NG-nitro-L-arginine methyl ester (L-NAME, 100 microM) were used to block KATP, KCa channels and NO synthesis, respectively. 3. Iloprost, PGE1, adenosine and forskolin caused relaxation during the hypoxic pressure response. The order of potency was: iloprost > PGE1 = forskolin > adenosine. EC50 values were 1.91 +/- 0.52 10(-9) M, 3.31 +/- 0.58 10(-7) M, 3.24 +/- 0.78 10(-7) M and 7.70 +/- 1.68 10(-5) M, respectively. Glibenclamide, charybdotoxin and L-NAME inhibited partially the relaxant effects of iloprost and forskolin but not those of PGE1. 4. It is concluded that in the rat isolated lung preparation, iloprost and forskolin but not PGE1 dilate pulmonary vessels partly through KATP channels, KCa and nitric oxide release. Furthermore our results suggest that the role of cycli AMP in these effects is not unequivocal.
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PMID:Role of potassium channels and nitric oxide in the effects of iloprost and prostaglandin E1 on hypoxic vasoconstriction in the isolated perfused lung of the rat. 903 43

Airway epithelial cells and vascular endothelial cells modulate the tone of the underlying smooth muscle by releasing relaxing factors such as prostanoids and nitric oxide (NO). In the present study, we investigated whether the relaxant effect of ketamine depends on any of the epithelium-derived relaxing factors. Tracheae of female guinea pigs were cut spirally into strips (15 x 3 mm) and mounted in water-jacketed organ baths filled with Krebs-bicarbonate buffer aerated with a mixture of 95% O2 and 5% CO2 at 37 degrees C. Changes in the tension of the strips were measured isometrically with a force displacement transducer and recorded with a polygraph. In the first set of experiments, we examined the effect of ketamine on the concentration-response curves for histamine and carbachol in strips in which the epithelium was kept intact and in strips with denuded epithelium. In the second and third set of experiments, we studied the effect of indomethacin, a cyclooxygenase inhibitor, and N-omega-nitro-L-arginine methylester(L-NAME), a NO synthase inhibitor, on the relaxant activity of ketamine on tracheal strips contracted by histamine or carbachol. The following results were obtained: 1. Mechanical denudation of the tracheal epithelium shifted the concentration-response curve for histamine to the left (the 50% effective concentration [EC50] value of histamine decreased from 3.5 +/- 0.02 x 10(-6) M in the intact strips to 0.98 +/- 0.01 x 10(-6) M in denuded strips, P < 0.001). However, removal of the tracheal epithelium did not change the response to carbachol (the EC50 for carbachol was 1.1 +/- 0.02 x 10(-7) M in intact strips versus 0.88 +/- 0.01 x 10(-7) M after epithelial removal, P > 0.05). 2. Ketamine shifted to the right the concentration-response curves for histamine and carbachol in both intact and denuded tracheae. 3. Indomethacin did not alter the relaxant effect of ketamine on the tracheae contracted by either histamine (the concentration that inhibits 50% [IC50] of ketamine = 1.5 +/- 0.01 x 10(-3) M in control strips and 1.3 +/- 0.04 x 10(-3) M in strips pretreated with indomethacin, P > 0.05) or carbachol (the IC50 of ketamine was 2.5 +/- 0.02 x 10(-4) M in control strips and 2.4 +/- 0.01 x 10(-4) M in strips pretreated with indomethacin, P > 0.05). 4. L-NAME did not influence the relaxant effect of ketamine on tracheae contracted by either histamine (the IC50 of ketamine = 1.6 +/- 0.05 x 10(-3) M in control strips and 1.6 +/- 0.05 x 10(-3) M in strips pretreated with L-NAME, P > 0.05) or carbachol (the IC50 of ketamine = 2.6 +/- 0.04 x 10(-4) M in control strips and 2.3 +/- 0.01 x 10(-4) M in trips pretreated with L-NAME, P > 0.05). These results indicate that neither the mechanical removal of the tracheal epithelium nor the blockade of the release of potent mediators from tracheal epithelial cells influence the relaxant effect of ketamine on guinea pig tracheal strips contracted by histamine or carbachol. We conclude that ketamine relaxes the airway smooth muscle by an epithelium-independent mechanism.
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PMID:The relaxant effect of ketamine on guinea pig airway smooth muscle is epithelium-independent. 905 17

Nitric oxide (NO) is an inhibitory nonadrenergic, noncholinergic (NANC) neurotransmitter in the rat gastric fundus and is released upon electrical or pharmacological stimulation of the inhibitory NANC neurons. In this study, it was attempted to measure the release of NO from the rat gastric fundus upon electrical stimulation or administration of nicotine directly via an electrochemical probe (ISO-NO). The system was evaluated by adding exogenous NO. Addition of exogenous NO induced concentration-dependent relaxation of the rat gastric fundus and an increase in the ISO-NO probe baseline current. The concentration of NO detected by the ISO-NO probe was lower than the concentration of NO administered. When no tissue was present, higher concentrations of NO were detected than in the presence of a tissue. In the absence of 95% O2/5% CO2 the concentration of NO detected was highest. Electrical stimulation induced relaxations of the rat gastric fundus which were reduced by NG-nitro-L-arginine methylester (L-NAME). An increase in the ISO-NO probe baseline current was also observed, but this was duc to nonspecific effects as the response also occurred without a tissue present and was not sensitive to L-NAME. Nicotine induced relaxations, which were reduced by L-NAME, but the ISO-NO probe baseline current remained unaltered, even in the presence of L-arginine plus superoxide dismutase. It can be concluded that it is not possible to detect directly the NO release from the rat gastric fundus upon electrical or pharmacological stimulation of the NANC neurons with the ISO-NO probe.
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PMID:Evaluation of an electrochemical microprobe for direct NO measurement in the rat gastric fundus. 917 85

1. The pulmonary vasculature is constantly exposed to oxygen and reactive oxygen species such as nitric oxide (NO) and superoxide anions which can combine at a near diffusion limited rate, to form the powerful, oxidant, peroxynitrite (ONOO-). When formed in large amounts, ONOO- is thought to contribute to tissue injury and vascular dysfunction seen in diseases such as the acute respiratory distress syndrome (ARDS) and septic shock. Recent studies have shown that ONOO- can cause vasodilatation and at higher concentrations can activate poly (adenosine 5'-diphosphoribose) synthase (PARS) leading to consumption of nicotinamide adenine dinucleotide (NAD+) and adenosine 5'-triphosphate (ATP). As the lung represents a prime site for ONOO- formation, we characterized its effects on pulmonary vascular tone and on endothelial function. In addition, we have assessed the role of PARS in producing the vasoactive properties of ONOO- on pulmonary artery rings. 2. Isolated pulmonary artery rings from rats were mounted in organ baths containing warmed and gassed (95% O2: 5% CO2) Krebs buffer. Force was measured with isometric force transducers. After equilibration, ONOO- (10 nM-100 microM) was added in a cumulative manner. In separate experiments designed to assess any vasodilator properties of ONOO-, tissues were pre-contracted with the thromboxane mimetic U46619 (1 microM). Once a stable base-line was achieved, ONOO- was added in a cumulative fashion. ONOO- had no significant effect on resting pulmonary artery tone but caused concentration-dependent relaxations of pre-contracted vessels in the range 1 microM to 100 microM. In some experiments the effects of freshly prepared ONOO- solutions were compared with those allowed to decay at 4 degrees C for 2 days. 3. In some experiments either vehicle or ONOO- (1, 10 or 100 microM) was added for 15 min before U46619 (1 microM). Concentration-response curves to the endothelium-dependent vasodilator, acetylcholine (10 nM-100 microM) were then constructed. In these experiments, ONOO- (1 microM or 10 microM) had no effect on the actions of acetylcholine. However, at the highest concentration tested (100 microM), ONOO- increased acetylcholine-induced relaxations. 4. The vasodilator actions of ONOO- were unaffected by the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 100 microM) or by removal of superoxide anions with superoxide dismutase (SOD) (30 units ml-1). However, the relaxations induced by ONOO- were significantly inhibited by the PARS inhibitor, 3-aminobenzamide (10 microM). In contrast to its effects on ONOO-, 3-aminobenzamide had no effect on the relaxation caused by acetylcholine or sodium nitrite, but actually increased that induced by sodium nitroprusside. 5. These data show that ONOO- causes vasodilatation of rat pulmonary arteries, probably via activation of PARS. Moreover, at concentrations where relaxation was achieved, ONOO- did not affect the ability of pulmonary artery rings to relax to acetylcholine. We propose that ONOO-, but not endothelially derived NO, activates PARS resulting in the rapid depletion of ATP and a consequent reduction in contraction as well as other active processes of vascular smooth muscle. The finding that 3-aminobenzamide inhibited the actions of ONOO- but not acetylcholine, suggests that NO and ONOO- cause relaxation by independent mechanisms. It has been suggested that ONOO- is responsible for the vascular hyporesponsiveness to constrictor agents seen in experimental sepsis. This observation together with our current finding, that 3-aminobenzamide inhibits the relaxation induced by ONOO- but not by acetylcholine, suggests that inhibitors of PARS may reduce the persistent hypotension seen in sepsis without affecting the actions of endothelium-derived NO. Thus, the use of PARS inhibitors may represent a novel therapeutic approach to the treatment of septic shock.
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PMID:Characterization of the vasodilator properties of peroxynitrite on rat pulmonary artery: role of poly (adenosine 5'-diphosphoribose) synthase. 917 90

The roles of nitric oxide, adenosine and cortical arousal in the response to 7.5% CO2 inhalation were investigated by measuring cerebral blood flow bilaterally in the rat somatosensory cortices with laser-Doppler flow probes. Administration of N(omega)-nitro-L-arginine methyl ester (L-NAME; 20 mg/kg, i.v.) significantly attenuated the response to hypercapnia (mean decrease of 47%). This effect was partially reversed by a subsequent administration of L-arginine. Caffeine (10 mg/kg, i.v.) also significantly reduced hypercapnic responses (mean decrease of 44%). Caffeine administration was also associated with a tendency for animals to exhibit electrocorticographic signs of arousal; often associated with a reduction in the attenuation of the flow response to CO2 inhalation. 8-(3-Chlorostyryl) caffeine (CSC, 1.0 mg/kg), a selective antagonist at adenosine A2a striatal receptors failed to attenuate CO2-evoked responses, whereas CGS 15943, a less selective A2a receptor antagonist, significantly reduced CO2 responses. These data from the rat suggest (1) that both nitric oxide and adenosine may contribute to pial arteriolar vasodilatation during hypercapnia, and (2) that CO2 inhalation acts as a potent stimulus for cortical arousal, with enhanced neuronal activity contributing to the vascular response. The effects of administration of adenosine antagonists, such as the methylxanthines antagonists caffeine and theophylline, on CBF responses to hypercapnia can potentially be negated by the ability of these agents to facilitate CO2-induced cortical arousal.
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PMID:Hypercapnia-induced increases in cerebral blood flow: roles of adenosine, nitric oxide and cortical arousal. 920 26

The purpose of this study was to determine the involvement of eicosanoids and nitric oxide (NO) in the response to hypoxia in isolated intrapulmonary (third branch) arteries from 10- to 17-day-old piglets. We also compared the response to hypoxia in pulmonary arteries to pulmonary veins, mesenteric arteries and coronary arteries. Hypoxia was generated in vascular rings (under resting force or precontracted with 30 mM KCl) by switching the gas aerating the organ chambers from one composed of 21% O2-5% CO2-balance N2 (pO2 145 +/- 1.27 mm Hg) to a mixture of 5% CO2-balance N2 (pO2 33.87 +/- 0.24 mm Hg). In precontracted rings hypoxia produced a transient vasoconstriction (26 +/- 8% of the precontraction value) reaching a peak in 3-4 min, followed by a relaxation. A similar pattern of response was observed in pulmonary veins, coronary arteries and mesenteric arteries. The contractile phase was not present in endothelium-denuded arteries or after incubation with the NO synthase inhibitor L-NAME (10(-4) M) or the guanylate cyclase inhibitor methylene blue (10(-5) M). No changes in the hypoxia-induced vasoconstriction were observed after preincubation with the NO precursor L-arginine (10(-5) M), the lipoxygenase inhibitor meclofenamate (10(-5) M), the cyclooxygenase inhibitor AA 861 (10(-5) M), or the cytochrome P450 oxidase inhibitor SKF 525A (10(-5) M). These findings demonstrate that the contractile response to hypoxia in the isolated intrapulmonary porcine artery is caused by the loss of the inhibitory effects of endothelium-derived NO on the vascular tone. Eicosanoids do not appear to be involved in this response. Since the response to hypoxia in isolated rings is not specific to pulmonary vessels, any correlation between this response and hypoxic pulmonary vasoconstriction should be avoided.
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PMID:Endothelium-derived nitric oxide-dependent response to hypoxia in piglet intrapulmonary arteries. 931 36


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