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Query: UNIPROT:P20366 (substance P)
 21,176 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The tridecapeptide neurotensin (NT) is present at high concentrations within the mammalian gut, although its physiological function is undefined. In this study, the actions of NT and structurally related peptides neuromedin N (NM-N) and xenopsin were characterized on ion transport in the porcine distal jejunal mucosa in vitro. The serosal-side administration of these peptides elicited rapid changes in transmural potential difference and short-circuit current (Isc) which were greater in mesenteric than in antimesenteric segments. NT-induced elevations in Isc were dependent upon external permeant anions and were associated with net Cl transport in both segments. In mesenteric segments, NT and its homologs increased Isc with the order of potency: NT greater than NM-N greater than xenopsin. NT produced tachyphylaxis to its own actions and to those of NM-N; NM-N was ineffective in producing tachyphylaxis. Isc elevations produced by NT were inhibited by the neuronal conduction blocker tetrodotoxin (0.1 microM) or the Ca++-channel blocker dl-verapamil (100 microM) and reduced in Ca++-free media. Antagonists to the enteric transmitters acetylcholine, ATP, 5-hydroxytryptamine, substance P and histamine did not alter Isc responses of mesenteric segments to NT. Serosal administration of vasoactive intestinal peptide (10 nM) did not resemble the effects of NT. The magnitude of Isc responses to these agonists was smaller in antimesenteric segments. These results indicate that NT-related peptides present in mucosal endocrine cells or nerves of the porcine jejunum may modulate Cl transport through mechanisms that involve the Ca++-dependent release of unknown enteric neurotransmitters. Moreover, there appear to exist within the distal jejunum circumferential differences in mucosal responses to NT and other neurohumoral factors.
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PMID:Neurohormonal regulation of ion transport in the porcine distal jejunum. Actions of neurotensin and its natural homologs. 246 65

Porcine or bovine endothelial cells cultured on microcarrier beads, packed into adapted chromatographic columns, perfused with Krebs' buffer and activated with appropriate stimuli (e.g. bradykinin, ADP or phospholipase C) release EDRF and prostacyclin into the perfusing fluid. In the effluent EDRF and prostacyclin might be bio-assayed using the Vane's superfusion cascade (rabbit aortic strips and bovine coronary artery strips, respectively) against nitroglycerine (GTN) and synthetic prostacyclin standards. Prostacyclin might be also quantified as 6-keto-PGF1 alpha by RIA. A spatial separation of the generator (endothelial cells) from the effector (vascular smooth muscle) has allowed to prove that EDRF is nitric oxide, that its activity is inhibited by superoxide anions and by chemicals which act via free radicals, finally, that the release of EDRF and prostacyclin is coupled by a receptor-mediated activation of phospholipase C. Although so successful, the above technique suffers from its essentials, i.e. from using cultured cells instead of fresh intact endothelial cells. Cultured endothelial cells are not responsive to many receptor agonists including acetylcholine, substance P and 5-hydroxytryptamine. Unlike fresh intact endothelial preparations the cultured cells which are perfused with Krebs' buffer generate superoxide anions at such concentrations that it might be obligatory infusing superoxide dismutase in order to detect EDRF. Nonetheless, a couple of data obtained with the cultured endothelial cells have been reproduced in the fresh cell preparations, e.g. release of EDRF by ADP and ATP, a coupled release of EDRF and prostacyclin by phospholipase C or a paradoxical augmentation of the sodium-nitroprusside-induced vasorelaxation by methylene blue.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Endothelium-derived relaxing factor (EDRF) from cultured and fresh endothelial cells. 247 Mar 61

1. The effects of capsaicin, calcitonin gene-related peptide and substance P were studied via three parameters in the guinea-pig vas deferens: the overflow of ATP and of tritiated noradrenaline, the mechanical responses to field stimulation and the mechanical responses to exogenous noradrenaline and alpha, beta-methylene ATP. 2. At 2 Hz, capsaicin inhibited the stimulus-evoked release of ATP, whereas it was without effect on the release of noradrenaline. At 20 Hz capsaicin did not affect the release of either of the cotransmitters. Capsaicin enhanced responses to alpha, beta-methylene ATP, but not to exogenous noradrenaline. 3. Calcitonin gene-related peptide, like capsaicin, inhibited the release of ATP, but not noradrenaline at 2 Hz and was without effect on release at 20 Hz. However, calcitonin gene related peptide inhibited responses to alpha, beta-methylene ATP and was without effect on responses to exogenous noradrenaline. 4. Substance P had no effect on the release of either noradrenaline or ATP at either frequency. However, like capsaicin it enhanced responses to alpha, beta-methylene ATP and was without effect on exogenous noradrenaline. 5. These results suggest that the actions of capsaicin on the guinea-pig isolated vas deferens are mediated via the release of both calcitonin gene-related peptide and substance P. Furthermore, as capsaicin and calcitonin gene-related peptide prejunctionally modulate purinergic, but not noradrenergic transmission, this suggests that the mechanisms for the storage and release of the sympathetic co-transmitters noradrenaline and ATP may not be the same.
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PMID:Modulation of neurotransmission in the guinea-pig vas deferens by capsaicin: involvement of calcitonin gene-related peptide and substance P. 247 44

A sympathetic neurone blocking drug, guanethidine, and a tachykinin antagonist, [D-Arg1, D-Pro2, D-Trp7,9, Leu11]-substance P (rpwwL-SP), partially inhibited the contractile response to nicotine to the same degree in the isolated detrusor strips of guinea-pig urinary bladder. Application of rpwwL-SP completely abolished the inhibitory effect of guanethidine on the nicotine-induced contraction, suggesting that the tachykinin(s)-ergic transmission might be involved in the sympathomimetic effect of nicotine. Conversely, when the preparation was treated with guanethidine to block release of a mediator from the sympathetic nerve, the inhibitory effect of rpwwL-SP was diminished, suggesting an exclusive contribution of the sympathetic nerve communications to the action of the tachykinin(s). We previously suggested that nicotine may release acetylcholine and ATP to contract the detrusor strips, and that acetylcholine output may be increased by an unknown substance released from the sympathetic nerve by nicotine. In preparations treated with atropine, rpwwl-SP had no effect on the nicotine-induced contraction. The concentration-response curves for carbachol and ATP were not influenced by rpwwl-SP. After tachyphylaxis to capsaicin developed, the nicotine-induced contraction was not affected. It is suggested that in guinea-pig detrusor, tachykinin(s) from capsaicin-insensitive sites is (are) involved in the excitatory sympathomimetic effect of nicotine, and that the tachykinin(s) behave(s) as a modulator finally to increase the acetylcholine output from the parasympathetic cholinergic nerve.
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PMID:Mechanism of action of nicotine in isolated urinary bladder of guinea-pig: involvement of tachykinin(s) released by nicotine in the drug's sympathomimetic effect. 248 45

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

1. The effects of some possible inhibitors of ectonucleotidases on the breakdown of extracellular ATP by strips of guinea-pig urinary bladder were investigated. 2. Suramin and ethacrynic acid (10 mM) both inhibited ATP breakdown significantly, and difluorodinitrobenzene (10 mM) inhibited it slightly whereas N-ethylmaleimide, adenosine 5'-(gamma-thiotriphosphate) (ATP-gamma-S) and reactive blue-2 (10 mM) were without effect. 3. The inhibitory effects of suramin on ATP breakdown were non-competitive. 4. Ethacrynic acid (1 mM) irreversibly inhibited contractions of the guinea-pig bladder induced by ATP, substance P, histamine, non-adrenergic, non-cholinergic nerve stimulation or KCl, whereas suramin (100 microM) had no inhibitory effect. 5. The results suggest that suramin might provide a starting point for the design of selective inhibitors of ectonucleotidases.
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PMID:The effects of some possible inhibitors of ectonucleotidases on the breakdown and pharmacological effects of ATP in the guinea-pig urinary bladder. 254 53

The neuromodulatory action of adenosine and ATP was investigated in isolated guinea pig bronchial strip chain preparations contracted with electrical field stimulation. The tissues were placed in organ baths containing physiological salt solution and stimulated at 8-Hz frequency, 0.5-ms pulse duration, and 30 V (approximately 100 mA) for 5 s. Electrical field stimulation evoked a biphasic contraction of bronchial muscle, consisting of an initial contraction followed by a sustained contraction, which was mediated by intramural cholinergic and noncholinergic nerve stimulations, respectively. Adenosine, at concentrations greater than M, caused a concentration-dependent inhibition in the height of the noncholinergically mediated contraction, accompanied by a very weak inhibition on the cholinergically mediated response. ATP (10(-5) to 3 x 10(-3) M) also produced a similar inhibitory effect on the noncholinergically mediated contraction, but the inhibitory potency was less than that of adenosine. The inhibitory response to adenosine was enhanced by the pretreatment with dipyridamole (2 x 10(-6) M) but antagonized with aminophylline (10(-5) M). Contractions of bronchial muscle evoked by exogenous acetylcholine (2 x 10(-6) M) or substance P (2 x 10(-7) M) were significantly inhibited by the adenosine (3 x 10(-4) M) pretreatment. These data suggest that in isolated guinea pig bronchi adenosine selectively inhibits noncholinergic neurotransmission through prejunctional P1-purinoceptors.
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PMID:Adenosine selectively inhibits noncholinergic transmission in guinea pig bronchi. 274 77

The effects of extracellular ATP on intracellular free calcium concentration [( Ca2+]i), phosphatidylinositol (PtdIns) turnover, amylase release and Ca2+-activated membrane currents were examined in isolated rat parotid acinar cells and contrasted with the effects of receptor agonists known to activate phospholipase C. ATP was more effective than muscarinic and alpha-adrenergic agonists and substance P as a stimulus for elevating [Ca2+]i (as measured with quin2). The ATP effect was selectively antagonized by pretreating parotid cells with the impermeant anion-exchange blocker 4,4'-di-isothiocyano-2,2'-stilbenedisulphonate (DIDS), which also inhibited binding of [alpha-32P]ATP to parotid cells. By elevating [Ca2+]i, ATP and the muscarinic agonist carbachol both activated Ca2+-sensitive membrane currents, which were measured by whole-cell and cell-attached patch-clamp recordings. However, there were marked contrasts between the effects of ATP and the receptor agonists linked to phospholipase C, as follows. (1) Although the combination of maximally effective concentrations of carbachol, substance P and phenylephrine had no greater effect on [Ca2+]i than did carbachol alone, there was some additivity between maximal ATP and carbachol effects. (2) Intracellular dialysis with guanosine 5'-[beta-thio]diphosphate did not block activation of ion channels by ATP, but did block channel activation by the muscarinic agonist carbachol. This suggests that a G-protein is involved in the muscarinic response, but not in the response to ATP. (3) Despite its pronounced effect on [Ca2+]i, ATP had little effect on PtdIns turnover in these cells, in contrast with the effects of carbachol and other Ca2+-mobilizing agents. (4) Although ATP was able to stimulate amylase release from parotid acinar cells, the stimulation was only 33 +/- 9% of that obtained with phospholipase C-linked receptor agonists. These differences suggest that ATP increases [Ca2+]i through specific activation of a pathway which is distinct from that shared by the classical phospholipase C-linked receptor agonists.
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PMID:Extracellular ATP increases free cytosolic calcium in rat parotid acinar cells. Differences from phospholipase C-linked receptor agonists. 284 7

The review deals with the critical analysis of the recent publications showing an important role of the endothelium in the mechanism of vasodilation caused by endogenous agents (acetylcholine, bradykinin, substance P, ATP, histamine, thrombin) and pharmacological agents (clonidine, hydralazine, mellitin, calcium ionophore A 23187). The mechanism of the endothelium-dependent vasodilatation is based on the release of the endothelium-derived relaxant factor (EDRF). In 1987-1988 it was shown that in some cases EDRF is NO. The experimental evidence suggests that EDRF (NO) may directly activate guanylate cyclase that results in vascular smooth muscle relaxation due to cAMP accumulation. The possible physiological and pathophysiological significance of the endothelium-dependent vascular responses is discussed.
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PMID:[The pharmacology of endothelium-dependent vascular reactions]. 285 Feb 22


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