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)

Substance P is a peptide implicated in the control of a variety of physiological processes. Although substance P-containing neurons impinge on the pulmonary vasculature, the effects of substance P on the pulmonary circulation have not been systematically investigated. Rabbits were anesthetized with methohexital sodium and paralyzed with pancuronium bromide. Injection of substance P (0.002-0.10 microgram/kg) in the vena cava produced dose-dependent pulmonary vasoconstriction and systemic vasodilation. Pulmonary arterial pressure reached a peak within 15-20 s and declined toward base line over 10 min. Aortic pressure fell rapidly, reaching minimum at 5-10 s. At higher doses cardiac output fell transiently, resulting in a 65% fall in pulmonary vascular conductance. If repeat substance P dosages were administered 15 min apart, there was no tachyphylaxis. Pulmonary vasoconstriction was inhibited by the cyclooxygenase blocker meclofenamate (10 mg/kg) and the thromboxane synthase inhibitor Dazmegrel (UK-38,485) (2 mg/kg). In contrast, vasoconstriction was enhanced by atropine (2 mg/kg). In Dazmegrel-treated animals in whom pulmonary vasoconstriction was established by epinephrine infusion, low doses of substance P produced vasodilation. Our findings indicate that substance P produces pulmonary vasoconstriction via prostaglandin (particularly thromboxane) generation and pulmonary vasodilation via activation of cholinergic pathways.
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PMID:Opposing hemodynamic effects of substance P on pulmonary vasculature in rabbits. 241 67

Increased release of endothelium-derived relaxing factor/nitric oxide has been proposed as the final common pathway for vasodilator responses to gram-negative lipopolysaccharide (endotoxin). To test this hypothesis, we examined endothelium-dependent and endothelium-independent vasodilator agents in vascular smooth muscle isolated from guinea pigs 16 hours after injection of saline (control group) or induction of Escherichia coli endotoxemia; aortic rings (approximately 1 mm in diameter) were studied with standard isometric tension techniques. Endotoxemia resulted in a significant loss of vasodilator responses to the endothelium-dependent receptor agonists acetylcholine (10(-10)-10(-5) M) and ADP (10(-8)-10(-5) M). In contrast, endotoxemia did not affect vasodilator responses to either the endothelium-dependent receptor agonist substance P (10(-11)-10(-7) M), the endothelium-dependent and receptor-independent agonist A23187 (10(-9)-10(-6) M), or the endothelium-independent agonist nitroprusside (10(-10)-10(-4) M). The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME) inhibited the vasodilator response to acetylcholine more in vessels from lipopolysaccharide-injected than control guinea pigs. Unexpectedly, L-NAME converted the endothelium-dependent vasodilator action of ADP to an endothelium-dependent vasoconstrictor response that was blocked individually by the cyclooxygenase inhibitor indomethacin, the thromboxane synthase inhibitor dazoxiben, and the thromboxane A2 receptor antagonist SQ29548. We conclude that in vivo endotoxemia inhibits the constitutive isoform of nitric oxide synthase in endothelial cells by selectively disrupting receptor-coupled activation mechanisms shared by acetylcholine and ADP. Furthermore, since L-NAME unmasks a thromboxane A2-mediated vasoconstrictor action of the endogenous purinoceptor agonist ADP, drugs that inhibit nitric oxide synthase could exacerbate sepsis-induced vasoconstriction and ischemia by synergizing with lipopolysaccharide-induced inhibition of endothelial nitric oxide synthase.
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PMID:Selective inhibition of endothelium-dependent vasodilator capacity by Escherichia coli endotoxemia. 767 34

We studied the effect of sensory nerve peptide substance P (SP) and neurokinin A (NKA) in isolated perfused guinea pig lungs. SP and NKA increased pulmonary arterial pressure, capillary pressure, pulmonary venous resistance, and lung weight, but they did not change pulmonary arterial resistance or pulmonary vascular permeability. The effects of SP on pulmonary vascular dynamics were greater than those of NKA. Ozagrel hydrochloride, a thromboxane synthase inhibitor, partially attenuated the effect of SP. This indicates that thromboxane contributes to SP-induced pulmonary vasoreactivity. However, ozagrel hydrochloride did not change the effects of NKA. FK224, an NK-1/NK-2 receptor antagonist, abolished both SP- and NKA-induced pulmonary vasoconstriction. This indicates that SP and NKA acted on the pulmonary vasculature through the NK-1 or NK-2 receptor, or both. Papaverine, a smooth muscle relaxant, abolished the effects of SP. The SP-induced increase in lung weight was caused by a rise in pulmonary hydrostatic pressure, especially that caused by pulmonary venoconstriction.
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PMID:[Effects of substance P and neurokinin A on pulmonary circulation in the isolated perfused guinea pig lung]. 871 86

Thromboxane A2(TxA2) is a potent vasoconstrictor associated with cerebrovascular disease and is thought to be synthesized within tissues of the brain. In order to determine the cellular sources of TxA2 in the central nervous system (CNS), we measured the release of the stable metabolite TxB2 in cultures of mixed or highly enriched populations of brain glia. Using techniques which isolated large numbers of highly enriched microglia and astroglia, we found that only microglia release TxB2. Moreover, microglia, not astroglia, contain the requisite synthetic enzyme thromboxane synthase. Phagocytic signals and lipopolysaccharide are potent stimulants of microglial release of thromboxane, with lesser effects shown by platelet activating factor and substance P. We conclude that microglia, when activated, are the principal source of brain-derived thromboxane and may help to control vascular flow at sites of acute CNS injury.
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PMID:Activated microglia are the principal glial source of thromboxane in the central nervous system. 880 90

The isolated human bronchus model is interesting for the study of drug-receptor interactions in 'normal' preparations. Several attempts have been made to prepare in vitro models of airway hyperresponsiveness close to the pathophysiology of asthma. In this paper, we shall present some results obtained with LPS and interleukin 1 beta (IL-1 beta). LPS (100 ng/ml, for 3 to 6 h) or IL-1 beta potentiated bradykinin and the tachykinin NK-1 selective receptor agonist [Sar9, Met-O2] SP -induced human isolated bronchi contraction in vitro (IL-1 beta 3 10(-10) M, at 37 degrees C for 1 to 3 h for bradykinin or at 21 degrees C for 15 h for [Sar9, Met-O2] SP in Krebs-Henseleit solution). As in control bronchi, the effects of bradykinin and of [Sar9, Met-O2] SP after interleukin 1 beta pre-treatment were abolished by indomethacin (10(-6) M), the thromboxane A2 receptor antagonist GR 32191 suggesting that prostanoids remain involved under these experimental conditions. Although bradykinin and [Sar9, Met-O2] SP -induced contractions were mediated by thromboxane receptor stimulation, the thromboxane A2 (TxA2) mimetic U46619 induced contraction of human bronchi was not enhanced by IL-1 beta pre-treatment. The cyclooxygenase 2 (cox 2) inhibitor GGP 28238 (10(-6) M) inhibited IL-1 beta-induced potentiation of [Sar9, Met-O2] SP but not of bradykinin effect. Bradykinin and [Sar9, Met-O2] SP induced a release of TxB2, the stable metabolite of TxA2, in the organ bath and this release was increased by IL-1 beta pre-treatment. Bradykinin-induced release of 6 keto prostaglandin F1 alpha (the stable metabolite of prostaglandin I2) was not enhanced by IL-1 beta. Taken together, our results suggest that IL-1 beta is able to potentiate the effect of bradykinin or tachykinin receptor agonists on the human isolated bronchus. Several mechanisms might be involved, including an increase of thromboxane synthase synthesis and/or activity in the case of bradykinin and of short term incubation (3 h, 37 degrees C) or an increase of synthesis and/or activity of cox-2 for tachykinin and for long-term incubation (15 h, 21 degrees C).
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PMID:[Approach to bronchial hyperreactivity in vitro]. 1021 28

We have investigated sensitization of reflexes in the isolated rat colon in order to develop a model that might prove useful for investigating how the sensitivity of enteric reflexes can be altered by prior stimulation. Records were taken of circular muscle tension, 7-10 mm oral and anal to radial distension exerted by a hook passed through the wall of the colon. A test stimulus of 1.5 g produced consistent contractions both oral and anal to the distension. A conditioning protocol, consisting of repeated application of 3 g for 30 s with 30 s between the stimuli for 30 min, doubled the amplitudes of reflex contractions that were evoked by the test stimuli but did not change the sensitivity of the muscle to the direct action of carbachol. The enhanced responses persisted for at least 40 min. The enhancement of reflexes was not reduced by antagonists of tachykinin NK3 receptors or of 5-HT3 receptors, but the reflex oral to stimulation was reduced by NK1 and NK3 antagonists added together. Sensitization was abolished by the cyclo-oxygenase and thromboxane synthase inhibitor, indomethacin. We conclude that sensitization can be reliably induced in vitro and that the model described in the present work can be used to investigate drugs that interfere with the sensitization process.
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PMID:Sensitization of enteric reflexes in the rat colon in vitro. 1203 82