Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dimalonic acid C60 (10(-5) M), a new fullerene derivative, produced an augmentation of phenylephrine-induced tone and reduced both the acetylcholine-induced maximum relaxation and the amplitude of substance P (10(-8) M)-induced relaxation in endothelium-containing thoracic aorta of rabbit; the acetylcholine- and substance P-induced relaxation was restored in the presence of superoxide dismutase (250 U/ml). Dimalonic acid C60 (10(-5) M) did not influence the phenylephrine-induced contractile response in the absence of endothelium, but the acetylcholine-induced relaxation was eliminated by removal of the endothelium. Superoxide anion generation, using hypoxanthine (1 mM)/xanthine oxidase (16 mU/ml), reduced the acetylcholine-induced relaxation and produced an augmentation of phenylephrine-induced tone in endothelium-containing strips; these effects were negated by the addition of superoxide dismutase (250 U/ml). A nitric oxide-generating agent, S-nitroso-N-acetylpenicillamine, caused relaxation of aorta without endothelium in a concentration-dependent manner, and the concentration-response curve was shifted to the right in the presence of dimalonic acid C60. This inhibitory effect of dimalonic acid C60 was also masked in the presence of superoxide dismutase. Sodium nitroprusside-induced relaxation was not affected by either dimalonic acid C60 or superoxide dismutase. These observations suggest that dimalonic acid C60 inhibits endothelium (nitric oxide)-dependent agonist-induced relaxation through the production of superoxide.
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PMID:Inhibitory effects of a fullerene derivative, dimalonic acid C60, on nitric oxide-induced relaxation of rabbit aorta. 920 May 57

The relationship between airway mucosal permeability and airway hyperresponsiveness was examined with tachykinins, their selective antagonists, and superoxide dismutase in male Hartley guinea pigs. In animals with ozone-induced airway inflammation, airway hyperresponsiveness and mucosal permeability increased concurrently but there was a time lag before the increase in airway vascular permeability. To study the role of tachykinins in the increases in mucosal permeability and in hyperresponsiveness, we used a neurokinin-receptor antagonist, CP-96345, and a neurokinin-2 receptor antagonist, SR-48968. CP-96345 had no significant effect, but SR-48968 reduced the increase in airway mucosal permeability; their effects on airway hyperresponsiveness were the opposite of their effects on airway permeability. Tachykinins themselves, both substance P and neurokinin A, significantly increased airway mucosal permeability. Superoxide dismutase, a scavenger enzyme of superoxide, reduced the ozone-induced airway hyperresponsiveness. These data suggest that the factors causing airway hyperresponsiveness differ from those that influence mucosal permeability, but it is possible that these pathophysiologic conditions are caused by the same substances or processes.
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PMID:[Airway hyperresponsiveness and airway mucosal permeability]. 921 82

In isolated canine middle cerebral arteries contracted with prostaglandin F2 alpha, transmural electrical stimulation (TES), nicotine, and substance P produced relaxations. Transmural electrical stimulation- and nicotine-induced endothelium-independent responses are mediated by nitric oxide (NO) liberated from perivascular nerve, whereas substance P-induced relaxations are mediated by endothelium-derived NO. These responses were attenuated by replacement of 95% O2 and 5% CO2 gas (about 550 mm Hg of partial O2 pressure) with 95% N2 and 5% CO2 gas (about 40 mm Hg); inhibition of the response to TES was stabilized 30 minutes later. Reoxygenation partially reversed the response. Relaxations caused by exogenous NO were not influenced by hypoxia. Inhibition by hypoxia of the response to TES was not affected by superoxide dismutase. However, the inhibitory effect was prevented by amiloride and dimethyl-amiloride, Na(+)-H+ exchange inhibitors, or acidosis caused by the addition of HCl. The inhibition by hypoxia was reversed by amiloride. It is concluded that depression by hypoxia of the response mediated by endogenous NO is associated with impaired membrane function caused by restoration of normal intracellular pH by Na(+)-H+ exchanger.
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PMID:Hypoxia-induced inhibition of the response to nitroxidergic nerve stimulation in canine cerebral arteries. 927 Apr 98

1. Peroxynitrite (ONOO-) is a cytotoxic species, formed by the reaction between nitric oxide and superoxide free radicals, that may be involved in inflammation. In this study we have investigated the effect of peroxynitrite on plasma extravasation and microvascular blood flow in the dorsal skin and on nociceptive responses in the hind paw of the rat. 2. Male Wistar rats were anaesthetized and their dorsal skin shaved. Plasma extravasation was measured by the extravascular accumulation of 125I-labelled albumin over 0-45 min and 0-240 min. Blood flow was measured by laser-Doppler flowmetry over 0-240 min. Studies in the hind paw were carried out in the conscious rat. Hind paw weight changes were determined by volume displacement and nociception by a mechanical hyperalgesia technique. 3. Intradermal (i.d.) peroxynitrite (100-200 nmol site-1) produced a significant (P < 0.01) dose-dependent increase in plasma extravasation in dorsal skin over 0-45 min which was not increased over 45-240 min. Plasma extravasation was significantly (P < 0.001) decreased in rats pretreated with the anti-inflammatory steroid dexamethasone (1 mg kg-1, i.v.; -180 min), but not modulated by treatment with the hydrogen peroxide deactivator catalase (2200 u site-1), or the superoxide scavenger superoxide dismutase (500 u site-1), effective doses of the tachykinin NK1 antagonist SR140333 (1 nmol site-1), the cyclo-oxygenase inhibitor indomethacin (358 mumol site-1), or combined pretreatment with mepyramine (histamine H1-receptor antagonist; 2.8 nmol site-1) and methysergide (5-HT antagonist; 1.9 nmol site-1). 4. Microvascular blood flow was significantly (P < 0.05) increased 30 and 120 min after i.d. peroxynitrite (100 nmol site-1) in dorsal skin and remained raised until the end of the recording period (240 min). The increase in blood flow was unaffected by dexamethasone (1 mg kg-1, i.v.; -180 min) or indomethacin (10 mg kg-1, s.c.; -30 min). 5. Hind paw volume was significantly (P < 0.001) increased 30 min after intraplantar peroxynitrite (87.5 and 175 nmol paw-1) and remained raised for the duration of the experiment (360 min). By comparison, nociception was not altered by intraplantar peroxynitrite. 6. These data indicate that peroxynitrite can cause an increase in both plasma extravasation and blood flow, suggesting that peroxynitrite could be of biological relevance to microvascular responses. These findings may be of importance in the pathology of inflammatory diseases in which peroxynitrite formation occurs.
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PMID:Effect of peroxynitrite on plasma extravasation, microvascular blood flow and nociception in the rat. 940 73

The effects of nitric oxide (NO) on the spontaneous release of 5-hydroxytryptamine (5-HT) were studied in the in vitro vascularly perfused guinea-pig small intestine. The NO donor SIN-1 concentration-dependently decreased 5-HT release with an EC50 of 1.34 microM, whereas the NO synthase inhibitor N(G)-nitro-L-arginine (100 microM) was without effect. The inhibition by SIN-1 of 5-HT release was enhanced by superoxide dismutase (150 U/ml) and antagonized by the selective inhibitor of soluble guanylyl cyclase, ODQ (1 microM). Tetrodotoxin (1 microM) prevented the inhibition by SIN-1 of 5-HT release, which suggests that the effect of SIN-1 is indirectly mediated via release of an inhibitory neurotransmitter. Substance P could be excluded as inhibitory transmitter because the effect of SIN-1 remained unchanged in the presence of the NK1 receptor antagonist CP 99994 (100 nM). The cyclic GMP analogue, 8-bromo cyclic GMP (300 microM), also decreased basal release of 5-HT, but this decrease was not tetrodotoxin-sensitive. It is concluded that NO inhibits the release of 5-HT from enterochromaffin cells via release of an enteric neurotransmitter. Acetylcholine (via nicotinic receptors) and substance P (via NK1 receptors) are not involved in the NO-mediated inhibition. The inhibition of 5-HT outflow by NO is due to the activation of soluble guanylyl cyclase. 8-Bromo cyclic GMP inhibited 5-HT release by a direct effect on the enterochromaffin cells.
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PMID:Inhibition by nitric oxide and cyclic GMP of 5-hydroxytryptamine release from the vascularly perfused guinea-pig small intestine. 967 48

It is thought that elevated levels of reactive oxygen metabolites contribute to the dysfunction of vascular endothelium in hypertension. We hypothesized that high intravascular pressure itself elicits production of superoxide, which then interferes with nitric oxide (NO)-mediated responses of arterioles. Thus, isolated arterioles (approximately 80 microm in diameter) from gracilis muscle of normotensive Wistar rats were cannulated and exposed to 140 mm Hg perfusion pressure for 30 minutes (in the absence of perfusate flow). After high intravascular pressure treatment, dilations to increases in perfusate flow (0 to 30 microL/min) were significantly reduced (from 39+/-2.2 to 19+/-2.1 microm at 30 microL/min), eliciting an increase in wall shear stress from approximately 20 to approximately 60 dyne/cm2. Nomega-nitro-L-arginine (10(-4) mol/L) did not affect, whereas indomethacin eliminated, flow-induced dilations after pressure treatment. In control, substance P (SP, 10(-9) to 5x10(-8) mol/L), sodium nitroprusside (SNP, 10(-8) to 10(-6) mol/L), and adenosine (ADO, 10(-6) to 5x10(-5) mol/L) elicited dilations (SP: 31.5+/-1.9 microm, SNP: 45.6+/-4 microm, and ADO: 37.2+/-4.1 microm, at maximum concentrations, respectively). After pressure treatment, maximum dilations to SP and SNP were significantly reduced (by 49% and 39%, respectively), whereas responses to ADO were not affected. Presence of superoxide dismutase (120 U/mL) and catalase (80 U/mL), but not catalase alone, in the perfusate solution prevented the reduction in dilation of arterioles to flow and agonists after pressure treatment by restoring NO mediation. We conclude that high intravascular pressure per se elicits the release of superoxide, which then interferes with NO, a mechanism that contributes to the elevation of wall shear stress and peripheral resistance in hypertension.
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PMID:Superoxide released to high intra-arteriolar pressure reduces nitric oxide-mediated shear stress- and agonist-induced dilations. 979 46

1. Lipopolysaccharide (LPS) is implicated in many pulmonary and airway inflammatory diseases. Tachykinins released from nerve endings increase vascular permeability. In this study, we have assessed the enhancement by LPS of tachykinin-mediated plasma exudation in guinea-pig airways, and examined the role of oxidants as well as leukocyte adherence. 2. LPS (100 microg kg(-1), i.v.) was administered 0-3 h before bilateral electrical stimulation of the cervical vagus nerves in animals anaesthetized with urethane and ventilated. Vagal stimulation increased vascular permeability in the airways. LPS enhanced the vagally-mediated plasma exudation with the peak effect at 1 h after LPS administration. LPS alone induced no significant plasma exudation. LPS also enhanced exogenous substance P (10(-8) mol kg(-1), i.v.)-induced plasma exudation. 3. The NK-1 receptor antagonist L-732,138 abolished vagally-induced plasma exudation and significantly inhibited the enhancement by LPS. Pretreatment with superoxide dismutase (SOD, 5000 U kg(-1), i.p.) did not affect the vagally-induced plasma exudation, but inhibited the LPS-enhanced neurogenic plasma leakage. The LPS-enhanced vagally-induced plasma exudation was not completely inhibited by either L-732,138 or SOD pretreatment alone, but was blocked by the combination of both pretreatments. 4. Neutrophil depletion by cyclophosphamide alone did not influence vagally-induced plasma exudation, but significantly inhibited the LPS-enhanced response. 5. In conclusion, we have demonstrated LPS enhanced neurogenic plasma exudation by augmenting the response to tachykinins, partly through NK-1 receptors, to directly increase vascular permeability or to enhance leukocyte adhesion-mediated endothelial cell injury. Tachykinins released from nerve endings may contribute to endotoxin-related airway inflammatory responses.
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PMID:Lipopolysaccharide enhances neurogenic plasma exudation in guinea-pig airways. 983 6

We previously reported that the time frame and the extent of the changes in the peripheral neurogenic inflammatory response in the skin area, innervated by an injured nerve, coincide with those of pain behaviours. We raised the possibility that common factors might operate to modulate neuropathic pain and peripheral neurogenic processes in rats with chronic constriction nerve injury (CCI). In the present study we examined the role of free radicals in modulating the neurogenic vascular response and thermal hyperalgesia in rats with CCI of the sciatic nerve. Free radicals, via an interaction with nitric oxide (NO) to form peroxynitrite, have previously been implicated in the maintenance of thermal hyperalgesia in CCI rats. In this study, we induced CCI of the sciatic nerve and the activity of xanthine oxidase (XO), which catalyzes the formation of superoxide anions, was measured in the injured nerve. In addition, we examined the effect of antioxidants on thermal hyperalgesia and on the neurogenic vascular response to substance P (SP) perfused over the base of a blister induced on the hind footpad skin which is innervated by the injured sciatic nerve. Compared with the sham operated group, CCI rats had a significantly higher XO activity in the injured sciatic nerve and significantly reduced thermal threshold and peripheral neurogenic vascular response to SP. Treatment with antioxidants, superoxide dismutase (SOD) or tirilazad significantly improved the neurogenic vascular response while tirilazad treatment significantly alleviated thermal hyperalgesia. The results therefore, suggest that free radicals are elevated in CCI animals and that they contribute to the maintenance of thermal hyperalgesia and the reduction in peripheral microvascular blood flow in the area innervated by the injured nerve. We raise the possibility that common mechanisms may govern the changes in neuropathic pain and in the peripheral neurogenic vascular responses in tissues innervated by the injured nerve.
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PMID:Free radicals contribute to the reduction in peripheral vascular responses and the maintenance of thermal hyperalgesia in rats with chronic constriction injury. 992 73

The quantitative contribution of endothelin and free radicals in modulating peripheral endothelial and smooth muscle-dependent vascular responses in 4 weeks streptozotocin-induced diabetic rats was investigated. Skin blood flow was monitored in base of blisters raised on the hind footpad. Smooth muscle-dependent vasodilation was tested using sodium nitroprusside (SNP). Endothelial-mediated inflammatory responses were induced via either electrical stimulation (ES) of the sciatic nerve or substance P (SP) perfusion over the blister base. Role of endothelin and free radicals was examined using ET-A or ET-B receptor antagonists (BQ-123 or BQ-788) and superoxide anions or hydroxyl radicals scavengers (superoxide dismutase (SOD) or N-acetyl cysteine (NAC)). Diabetic rats showed a significant reduction (75%) in SNP responses that coincided with a 70 and 60% reduction in responses to ES and SP. Their basal plasma extravasation (PE) was significantly higher while PE response to SP was significantly reduced. BQ-788, was more potent than BQ-123, improving responses to ES and SP in diabetic rats by 85%. Likewise, NAC was more potent than SOD normalizing the ES response and improving SP response by 85%. Combined treatment with BQ-123 and SOD normalized all vasodilatation responses in diabetic rats. BQ-123 and BQ-788 were equally potent normalizing the PE responses to SP whereas SOD and NAC had no effect. We conclude that endothelin and free radicals play a role in altering microvascular function in diabetes and that their effect could be reversed early in the disease.
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PMID:Endothelin and free radicals modulate microvascular responses in streptozotocin-induced diabetic rats. 1062 75

Modifications by atherosclerosis of endothelium-dependent and -independent relaxations were evaluated in carotid arteries isolated from Watanabe heritable hyperlipidemic (WHHL; age 20-29 months) and age-matched Japanese white (JW) rabbits. Marked, patchy atherosclerotic lesions were observed in all WHHL rabbit arteries. Endothelium-dependent relaxations induced by acetylcholine, partly depressed by N(G)-nitro-L-arginine (L-NA), were significantly inhibited in the WHHL rabbit arteries with atherosclerosis, compared with those in the arteries without atherosclerotic lesions from JW and WHHL rabbits. No difference was observed in the relaxation caused by superoxide dismutase in these arteries. Conversely, endothelium-dependent relaxations by substance P were greater in the arteries with and without atherosclerosis from WHHL rabbits than in the arteries from JW rabbits. Endothelium-independent relaxations elicited by sodium nitroprusside and 2,2-(hydroxynitrosohydrazino)bis-ethanamine (NOC18) did not differ in the arteries from JW and WHHL rabbits. The responses to acetylcholine and substance P of JW rabbit arteries with the endothelium were not attenuated by treatment with pertussis toxin. L-NA-resistant, endothelium-dependent relaxations by substance P were almost abolished by charybdotoxin, and atherosclerosis did not alter the response. It is concluded that endothelial functions, evaluated by substance P, in rabbit carotid arteries are not impaired by atherosclerosis and by long exposure to hyperlipidemia in vivo. Dysfunction of muscarinic receptors may be involved in the depressed response to acetylcholine. As far as the arteries used in the present study are concerned, responses mediated possibly by endothelium-derived hyperpolarizing factor (EDHF) are unlikely to be modulated by atherosclerosis.
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PMID:Comparison of endothelium-dependent relaxation in carotid arteries from Japanese white and Watanabe heritable hyperlipidemic rabbits. 1106 23


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