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)

Transmural electrical stimulation and nicotine produced a relaxation of dog cerebral artery strips denuded of endothelium, which was abolished by tetrodotoxin and hexamethonium, respectively, and also suppressed by treatment with NG-nitro-L-arginine (L-NA), a nitric oxide (NO) synthesis inhibitor. The inhibition was reversed by L-arginine but not by the D-enantiomer. L-NA also suppressed the endothelium-dependent relaxation by substance P but not the response to NO and nitroglycerin. Treatment with high concentrations of nitroglycerin or sodium nitroprusside markedly inhibited the relaxant response to nicotine, substance P and NO but not the response to papaverine. Slight, slowly developing relaxations caused by L-arginine in the endothelium-denuded arteries were not potentiated by repeated applications of the amino acid or by exposure of the strips for 24 hr to the bathing medium. Ca++ ionophore-induced contractions in the denuded strips were not potentiated by L-NA. Nicotine significantly increased the level of cyclic GMP in the arteries without endothelium; the increment was abolished by treatment with L-NA and hexamethonium. NO does not seem to be synthesized in smooth muscle in an amount sufficient to produce significant relaxation. It may be concluded that NO liberated from vasodilator nerves activates guanylate cyclase in smooth muscle and produces cyclic GMP, resulting in cerebroarterial relaxation.
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PMID:Role of nitric oxide in neurally induced cerebroarterial relaxation. 165 33

There are four main classes of membrane-bound receptors: receptors which are also enzymes (tyrosine protein-kinase or guanylate cyclase), receptor channels, receptors coupled to G proteins (GTP binding proteins) and receptors with unknown transduction mechanisms. Receptors coupled to G proteins which have been cloned, constitute a superfamily of proteins containing seven hydrophobic transmembrane helices. The binding site of the ligand is within the hydrophobic core of the protein and the domain of interaction of the G proteins is constituted by the N- and C-terminal parts of the third intracellular loop, plus the C-terminal tail, adjacent to the transmembrane VII. G proteins themselves are also members of another superfamily. These proteins have highly conserved domains constituting the GTP binding site and they interact with the receptors by their C-terminal parts. Compounds such as mastoparan, substance P and 48/80 directly stimulate G proteins, an action which probably mediates their exocytotic properties. A high degree of homologies between G protein-linked receptors explains the non-specificity of some antagonists (like beta-adrenergic blocking agents on 5-HT1 receptors). The discovery of new members of the G protein-linked receptors which have not yet been pharmacologically characterized, raises the problem of receptor classification.
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PMID:Coupling of receptors to G proteins, pharmacological implications. 166 41

The great discovery by Furchgott of the relaxing factor released from the endothelium (EDRF) awakened us to the necessity to reevaluate the functional importance of endothelial cells that have been chemically or physically stimulated. EDRF was first demonstrated to be released by acetylcholine, substance P, bradykinin and calcium ionophore A23187; thereafter, many substances have been found to release EDRF. This factor is quite unstable, is not produced by cyclooxygenase, and is an activator of soluble guanylate cyclase that synthesizes cyclic GMP; its action is suppressed by antioxidants via the superoxide anions produced, potentiated by superoxide dismutase and abolished by methylene blue and oxyhemoglobin. Recently, the role of lipoxygenase products in the production of EDRF was evaluated with new 5-lipoxygenase inhibitors without antioxidant activity. During the last couple of years, the actions and chemical properties of EDRF were verified to be quite similar to those of nitric oxide (NO); therefore, the hypothesis of "EDRF = NO" is widely being accepted. NO is produced from L-arginine via catalysis by an enzyme that is activated by Ca2+. The enzyme activity is inhibited by L-monomethyl arginine and other L-arginine analogs. Chemical and physical stimulations increase intracellular Ca2+ in endothelial cells that seems to be associated with K(+)-channel opening and hyperpolarization. Current interests are directed to the possible roles of NO in the regulation of nerve function. There are evidences suggesting that NO modulates adrenergic nerve function in blood vessels and some brain cell functions regulated by cellular cyclic GMP. Particularly, NO may be a transmitter substance in non-adrenergic, non-cholinergic vasodilator nerves innervating the cerebral arteries. Future investigations will determine the physiological roles of EDRF or NO and its relationships to pathophysiology of vascular dysfunctions, such as vasospasm and those related to hypertension, diabetes, aging, etc., and the extended roles of NO in nerve function, inflammation, immune reactions, etc. would be clarified more extensively by accelerated progress in this field of research.
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PMID:[Endothelium-derived relaxing factor (EDRF)]. 216 93

The response to small peptides such as Arg-vasopressin, oxytocin and tachykinins was investigated in cultured porcine aortic endothelial cells. The production of endothelium-derived nitric oxide was assessed indirectly by the accumulation of cyclic GMP, a response that is due to the increased activity of soluble guanylate cyclase of the endothelial cells after release of the mediator. Arg-vasopressin, oxytocin, substance P and physalae-min (an analog of substance P, pGlu-Ala-Asp-Pro-Asn-Lys-Phe-Tyr-Gly-Leu-Met-NH2) markedly and transiently stimulated the production of cyclic GMP without affecting that of cyclic AMP. Treatment of endothelial cells with either hemoglobin or methylene blue reduced significantly both the basal and stimulated level of cyclic GMP. The production of cyclic GMP evoked by Arg-vasopressin and substance P was inhibited selectively by NG-monomethyl-L-arginine but not by its D-enantiomer. The neurohypophyseal hormones and related peptides stimulated the accumulation of cyclic GMP in a concentration-dependent manner, with the following relative order of potency: oxytocin greater than Lys-vasopressin greater than Arg-vasopressin much greater than [deamino-Cys1, D-Arg8]-vasopressin. The production of cyclic GMP evoked by oxytocin was inhibited selectively by [d(CH2)5, Tyr(OMe)2, Orn8]-vasotocin, an oxytocin antagonist. The production of cyclic GMP evoked by Arg-vasopressin and Lys-vasopressin was inhibited by [beta-mercapto-beta, beta-cyclopentamethylene-propionyl1, O-Me-Tyr2, Arg8]-vasopressin, a selective V1-receptor antagonist. The moderate production of cyclic GMP evoked by [deamino-Cys1, D-Arg8]-vasopressin was inhibited significantly by the V1-receptor antagonist. The peptide antagonists affected only minimally or not at all the production of cyclic GMP evoked by a donor of nitric oxide, SIN-1 (3-Morpholino-Sydnonimine). These observations indicate that 1) neurohypophyseal hormones and tachykinins stimulate the accumulation of cyclic GMP in cultured porcine aortic endothelial cells by increasing the production of endothelial-derived nitric oxide, which in turn enhances the activity of soluble guanylate cyclase; 2) the production of cyclic GMP in response to oxytocin is due to activation of oxytocinergic receptors; and 3) the production of cyclic GMP evoked by Arg-vasopressin and Lys-vasopressin is due mostly to activation of V1-vasopressinergic receptors.
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PMID:Neurohypophyseal peptides and tachykinins stimulate the production of cyclic GMP in cultured porcine aortic endothelial cells. 217 9

1. An epithelium-derived inhibitory factor (EpDIF) released by guinea-pig tracheal epithelium was evaluated in a co-axial bioassay system consisting of an epithelium-intact guinea-pig tracheal tube surrounding endothelium-denuded rat aortic strip. 2. Histamine and several muscarinic agonists induced concentration-dependent relaxation of phenylephrine-contracted rat aorta via the release of EpDIF. However, several other agonists did not induce the release of EpDIF from guinea-pig trachea. These included the nicotinic cholinoceptor agonists nicotine (25 microM), 1,1-dimethyl-4-phenylpiperazinium (DMPP) (25 microM), calcium ionophore A23187 (0.5 microM), bradykinin (0.05-0.5 microM), substance P (5 microM), platelet activating factor (PAF, 1-100 nM), the leukotrienes (LT) LTC4, LTD4 and LTE4 (0.1-10 nM) as well as hyperosmotic stimuli. 3. Prostaglandin E2 (PGE2) induced concentration-dependent contraction of endothelium-denuded rat aortic preparations, indicating that this prostanoid could not be EpDIF. Furthermore, relaxation to histamine and methacholine, mediated via EpDIF, was not significantly altered in the presence of phenidone (50 microM) the cyclo-oxygenase/lipoxygenase inhibitor with radical scavenging properties or the cytochrome P-450 inhibitors metyrapone (1 mM) and SKF 525A (25 microM). This suggests that EpDIF is neither a prostanoid nor a cytochrome P-450 metabolite of arachidonic acid. 4. The soluble guanylate cyclase inhibitor, methylene blue (50 microM), caused small but significant increases in the potencies of both histamine and methacholine in co-axial assemblies, indicating that EpDIF did not activate this enzyme and therefore was not NO or a related substance. The beta-adrenoceptor antagonist, (-)-propranolol (1 microM), and the PAF-receptor antagonist, WEB 2086 (50 microM), also failed to alter significantly EpDIF-modulated relaxations. These data suggest that EpDIF is neither a stimulant of fiadrenoceptors nor of PAF receptors. 5. The present study provides some evidence that this vascular smooth muscle-sensitive EpDIF may not be related to the putative EpDIF previously hypothesized to modulate directly spasmogen-induced airway smooth muscle tone.
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PMID:Pharmacological evaluation of a guinea-pig tracheal epithelium-derived inhibitory factor (EpDIF). 239 Jun 83

Substance P is a vasoactive peptide. Nerve fibers containing substance P are present in the media of pulmonary arteries but the physiologic function of substance P in the pulmonary vasculature is unknown. Several doses of substance P were infused intravenously in the anesthetized dog to ascertain its effects on the pulmonary vasculature, both during normoxia and following preconstriction with hypoxia (F1O2 0.1) or prostaglandin F2 alpha (PGF2 alpha 5 mug/kg/min). Substance P resulted in systemic vasodilation during normoxia but had minimal effect on the pulmonary vasculature. During hypoxia and PGF2 alpha-induced pulmonary vasoconstriction, substance P significantly lowered pulmonary artery pressure, pulmonary vascular resistance, mean aortic pressure, and total systemic resistance. It had no effect on cardiac output, wedge pressure, and arterial blood gases. To investigate possible mechanisms for substance P-induced vasodilation, substance P was studied following pretreatment with N-acetylcysteine (a radical scavenging agent), methylene blue (an inhibitor of guanylate cyclase), meclofenamate (a cyclooxygenase inhibitor), and atropine (a muscarinic receptor antagonist). None of these agents impaired substance P-induced vasodilation. Substance P given intravenously is a nonselective vasodilator in the dog but the mechanism of its action remains uncertain.
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PMID:The effects of substance P on the preconstricted pulmonary vasculature of the anesthetized dog. 242 48

Endothelial cells are known to contain both soluble and particulate guanylate cyclase, but the functional role of cyclic guanosine monophosphate (cGMP) in endothelial cells remains unknown. We have investigated the effects of 8-bromo-cGMP on endothelium-dependent relaxations to acetylcholine, substance P, ATP, and the calcium ionophore A23187, and on endothelium-independent relaxations to sodium nitroprusside and glyceryl trinitrate (GTN). The ability of each of these agents to relax phenylephrine-preconstricted rings of rabbit aorta was tested in the absence and presence of 8-bromo-cGMP. In the presence of 8-bromo-cGMP, a greater concentration of phenylephrine had to be used to produce a similar level of tone and then endothelium-dependent relaxations to acetylcholine and substance P were inhibited, whereas endothelium-dependent relaxations to ATP and A23187 were unaffected. Endothelium-independent relaxations to sodium nitroprusside and GTN were only inhibited at the highest concentrations of nitroprusside and GTN. These results suggest that: (a) increasing GMP levels in endothelial cells inhibit agonist-induced release of endothelium-derived relaxing factor (EDRF); (b) a negative feedback mechanism may exist whereby EDRF stimulates soluble guanylate cyclase in endothelial cells to inhibit its own release; and (c) ATP does not induce EDRF release via phosphoinositol hydrolysis.
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PMID:Release of endothelium-derived relaxing factor is inhibited by 8-bromo-cyclic guanosine monophosphate. 246 85

Endothelium-dependent relaxation of blood vessels is produced by a large number of agents (e.g., acetylcholine, ATP and ADP, substance P, bradykinin, histamine, thrombin, serotonin). With some agents, relaxation may be limited to certain species and/or blood vessels. Relaxation results from release of a very labile non-prostanoid endothelium-derived relaxing factor (EDRF) or factors. EDRF stimulates guanylate cyclase of the vascular smooth muscle, with the resulting increase in cyclic GMP activating relaxation. EDRF is rapidly inactivated by hemoglobin and superoxide. There is strong evidence that EDRF from many blood vessels and from cultured endothelial cells is nitric oxide (NO) and that its precursor is L-arginine. There is evidence for other relaxing factors, including an endothelium-derived hyperpolarizing factor in some vessels. Flow-induced shear stress also stimulates EDRF release. Endothelium-dependent relaxation occurs in resistance vessels as well as in larger arteries, and is generally more pronounced in arteries than veins. EDRF also inhibits platelet aggregation and adhesion to the blood vessel wall. Endothelium-derived contracting factors appear to be responsible for endothelium-dependent contractions produced by arachidonic acid and hypoxia in isolated systemic vessels and by certain agents and by rapid stretch in isolated cerebral vessels. In all such experiments, the endothelium-derived contracting factor appears to be some product or by-product of cyclooxygenase activity. Recently, endothelial cells in culture have been found to synthesize a peptide, endothelin, which is an extremely potent vasoconstrictor. The possible physiological roles and pathophysiological significance of endothelium-derived relaxing and contracting factors are briefly discussed.
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PMID:Endothelium-derived relaxing and contracting factors. 254 95

Binding of atrial natriuretic peptide (ANP) to rat submandibular gland and its effect on guanosine 3',5'-cyclic monophosphate (cGMP) formation and salivary secretion were investigated. Membranes rapidly and specifically bound 125I-ANP. Binding was inhibited by unlabeled ANP (IC50 approximately 1.6 nM), but not by atriopeptin I, other COOH- and NH2-terminal deleted ANP fragments, or agents such as pilocarpine or substance P. Scatchard analysis revealed a single class of high-affinity sites (dissociation constant 0.74 +/- 0.25 nM; maximal binding capacity 20.5 +/- 6.3 pmol/mg protein). Intravenous infusion of ANP with pilocarpine caused a significant dose-dependent increase in the levels of cGMP detected in plasma and saliva. Because salivary cGMP may have originated in plasma, the effect of ANP on cGMP formation was evaluated in dispersed cells. ANP evoked a concentration-dependent increase in both cGMP synthesis and secretion (EC50 approximately 1.7 x 10(-8) M). The atrial peptide did affect basal or l-isoproterenol-stimulated adenosine 3',5'-cyclic monophosphate synthesis in dispersed cells. When infused by itself and/or with pilocarpine, ANP did not alter the rate of spontaneous or pilocarpine-induced salivary flow, secretion of chloride, or protein release. The data demonstrate the presence of guanylate cyclase-coupled ANP receptors in submandibular gland; the atrial peptide, however, does not exert an effect of the secretory function of the gland.
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PMID:Atrial natriuretic peptide stimulates submandibular gland synthesis and secretion of cGMP. 255 37

Substance P enhanced guanylate cyclase (E.C.4.6.1.2) two- to fourfold in pancreas, small intestine, cerebellum, liver, kidney, and lung. Dose response relationship revealed that substance P caused a maximal augmentation of guanylate cyclase activity at concentration of 1 micromolar. Increasing substance P's concentration to the millimolar range caused no further increase in activity. There was an absolute cation requirement for substance P's enhancement of guanylate cyclase activity. Substance P could increase guanylate cyclase activity with either calcium or manganese in the incubation medium but more augmentation was observed with manganese. The data in this investigation suggest that guanylate cyclase may play a role in the mechanism of action of substance P.
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PMID:Cation-dependent substance P activation of the enzyme guanylate cyclase. 258 May 27


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