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)

Three major lines of evidence support a role of eicosanoids and PAF in shock. Formation of each of the cyclooxygenase metabolites of arachidonate is enhanced at some point during the shock; these metabolites include PGE2, PGF2 alpha, PGI2, and TXA2. Enhanced formation of 5-HETE and the cysteinyl-LTs provides evidence for activation of the 5-lipoxygenase pathway of arachidonate metabolism, and preliminary biochemical evidence suggests that formation of PAF in anaphylactic and endotoxic shock is also enhanced. Second, TXA2, cysteinyl-leukotrienes, and, to an even greater extent, PAF are able to produce shock and death in intact animals. Third, pharmacological studies show that selective antagonists or synthesis inhibitors modify the course of the shock. While any of these lines of evidence may not by itself provide proof for a cause-effect relationship, the data taken together strongly suggest that vasoactive lipids might be involved in fundamental processes in the pathophysiology of shock. However, the role of vasoactive lipids might vary in different shock paradigms, change at various time points during the evolution of the shock, and depend on the species studied. Moreover, while the majority of the reports tend to focus on a specific substance, the metabolism of all of the eicosanoids mentioned, as well as PAF and probably other arachidonate metabolites (e.g. 15-lipoxygenase products such as lipoxins), changes during shock states. This fact probably causes most of the discrepancies in studies using specific antagonists or synthesis inhibitors to modify the state of shock. Thus, while blockade of one mediator might provide some protection, it might not be sufficient to halt or reverse the main course of the pathophysiological process. For example, the increase in vascular permeability, a fundamental phenomenon in trauma, anaphylaxis, or endotoxemia, might be mediated by PAF, LTs, PGs, peptides (e.g. kinins, substance P, CGRP) and amines (e.g. histamine in some species). Attempting to reverse such a complex phenomenon by blocking one specific factor might not be productive unless the specific substance played a key role in generation of the other factors. It seems, however, that while interactions between PGs, LTs, and PAF do occur (31, 32, 70), none of the shock states are crucially dependent on one class of the vasoactive lipids. Therefore, the therapeutic strategy should be based on multiple sites of action, either by drug combinations or multiple actions of a specific drug.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Prostaglandins, leukotrienes, and platelet-activating factor in shock. 303 39

Classical techniques for studying modulations of microvascular permeability have a time resolution of minutes. A newly developed method allows continuous measurement of the electrical resistance of the microvascular membrane in vivo (Olesen & Crone 1983). The technique exploits microelectrodes impaled into the vascular lumen and is based on cable analysis of the vessel. It was applied to venules on the surface of the frog brain to test the effect on microvascular permeability of a wide variety of substances. The following agents increased ionic permeability reversibly within seconds: 5-hydroxytryptamine, bradykinin, ATP, ADP, AMP, phospholipase A2, arachidonic acid, leukotriene C4, oxygen-derived free radicals, ionophore A23187, and unbound Evans blue dye. An irreversible permeability increase was induced by protamine sulphate, neuraminidase, trypsin, melittin, and snake venoms from Crotalus durissus terrificus and Bothrops atrox. The following substances were without effect within an administration period of 5 min: histamine, epinephrine, putrescine, angiotensin II, vasoactive intestinal polypeptide (VIP), substance P, neurotensin, vasopressin, adenosine, PGE2, PGF2 alpha, prostacyclin (PGI2), leukotriene B4, albumin, heparin, plant cytokinins, hyaluronidase, thrombin, wasp venom. Variations in pH between 5.1 and 8.6 did not change permeability. Three conclusions are drawn from the observations: (1) the permeability of cerebral microvessels can be modulated by specific agents, (2) the agents induced changes in the endothelium within a few seconds, and (3) the rapid permeability increase induced by inflammatory mediators was less than two-fold and reversible within minutes.
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PMID:Substances that rapidly augment ionic conductance of endothelium in cerebral venules. 348 16

The release of prostaglandins E2, F2 alpha, I2 and thromboxane A2 from isolated perfused normal and hydronephrotic rabbit kidneys was investigated by extraction and radioimmunoassay. In both types of kidneys, basal PG efflux increased with time and was not altered by co-perfusion with dexamethasone or hydrocortisone. Several vasoactive substances at 1 to 4 micrograms (e.g., bradykinin, angiotensin II, substance P, noradrenaline and vasopressin) caused release of additional amounts of prostaglandins. PGE2 and 6-keto PGF1 alpha were the major prostanoids detected, but substantial amounts of PGF2 alpha were also found. Thromboxane A2 was not released from normal kidneys. In hydronephrotic kidneys there was greatly augmented release of prostaglandins E2 and I2, some increases in PGF2 alpha, and the appearance of substantial amounts of thromboxane A2 (measured as immunoreactive TXB2) when the kidneys were challenged with angiotensin, bradykinin and vasopressin, and smaller augmentation of the response to noradrenaline and substance P. There was no evidence that these evoked increases in renal PG output could be inhibited by dexamethasone or hydrocortisone. Some explanations for the failure of steroids to alter prostanoid metabolism from arachidonate in rabbit kidney are discussed, and it is proposed that there are clear exceptions to the concept that steroids inhibit prostaglandin generation in intact tissues.
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PMID:Failure of anti-inflammatory steroids to inhibit prostaglandin release from the hydronephrotic rabbit kidney. 396 72

Isolated urethral preparations from rabbit and man responded to transmural electrical stimulation with contraction when the basal tension was low, and with relaxation when the preparations were contracted by noradrenaline, clonidine, 5-hydroxytryptamine and lysine vasopressin. Both contractant and relaxant responses were abolished by tetrodotoxin, suggesting that they were caused by the action of transmitters released from nerves. The electrically induced contractions in the rabbit urethra had a threshold frequency of 5 to 6 Hz and maximum was reached at 40 Hz. The responses were markedly reduced by alpha-receptor blockers suggesting that the released contraction-mediating transmitter was mainly noradrenaline. The relaxant response was immediate and rapidly reversible. It was obtained at a threshold frequency of 1 to 2 Hz and maximum was reached at 10 to 15 Hz. It was not inhibited by propranolol, indomethacin, atropine or peptides such as substance P, VIP, vasopressin or somatostatin. Prostaglandin E2, isoprenaline, adenosine-5'-triphosphate and VIP relaxed the noradrenaline contracted rabbit urethra with a time course different from that of the electrically induced relaxation. Nifedipine and "calcium free" solution decreased the noradrenaline induced contraction but did not influence the relaxant response to electrical stimulation. It is suggested that the relaxant response of the isolated noradrenaline-contracted urethra to electrical stimulation is caused by an unknown transmitter released from nerves.
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PMID:Electrically induced relaxation of the noradrenaline contracted isolated urethra from rabbit and man. 613 Nov 47

Salivary flow and amylase secretion induced by substance P(SP) administered intraventricularly were considerably less than that by SP given intravenously (i.v.). Salivary flow induced by SP (i.v.) was partially inhibited by baclofen, atropine, d-tubocurarine, alcuronium, phenylephrine and PGE2, while it was enhanced by arachidonic acid and indomethacin. Salivary amylase secretion induced by SP given i.v. was enhanced markedly by isoproterenol, phenoxybenzamine, phentolamine and No. 865-123 (an adrenergic neuron blocking agent), and moderately by baclofen, PGE2 and arachidonic acid, while it was not influenced by propranolol. The enhancements of amylase secretion by adrenergic alpha-blockers were completely inhibited by propranolol. The in vitro examination using rat brain synaptosomes showed that SP promoted markedly the synthesis of PGs, especially of PGE2. These results suggest that the SP-receptor has a nicotinic receptor-like property and may be closely related to adrenergic alpha-receptors situated postsynaptically and presynaptically and to postsynaptic PGE2-receptors. From these results, it is concluded that SP-induced salivary flow and amylase secretion are modulated by the promotion of PGs synthesis in the autonomic nervous system.
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PMID:[Mechanism of substance P-induced salivary secretion in the rat: effect of substance P on autonomic nervous system and prostaglandin synthesis (author's transl)]. 615 81

In the dog anesthetized with pentobarbital, the effect of bradykinin on the lowering of renal blood flow produced by bolus injections of angiotensin II was studied. Injection into the renal artery of angiotensin II (0.06--0.50 microgram) caused vasoconstriction and decreased blood flow to the kidney in a dose-related manner. Renal arterial infusion of bradykinin (10 ng kg-1 min-1), prostaglandin (PG) E2 (4 ng kg-1 min-1) or PGI2 (4 ng kg-1 min-1) produced renal vasodilation and inhibited the vasoconstrictor effect of angiotensin II. However, renal arterial infusion of another vasodilatory peptide, substance P (2 ng kg-1 min-1), did not alter the effect of angiotensin II on the renal vasculature. Pretreatment of dogs with an inhibitor of PG synthesis, sodium meclofenamate (5 mg/kg), abolished the inhibitory effect of bradykinin on angiotensin II-induced renal vasoconstriction. In contrast, renal arterial infusion of either PGE2 or PGI2 was equally effective in reducing the renal vascular effect of angiotensin II in animals with and without meclofenamate pretreatment. These results suggest that bradykinin reduces the reactivity of the renal vasculature to angiotensin II by a mechanism dependent upon PG synthesis.
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PMID:Inhibition by bradykinin of the vascular action of angiotensin II in the dog kidney. 616 19

The role of nerve conduction was studied in acute experimental uveitis caused by antidromic trigeminal nerve stimulation, prostaglandin E1 and E2 (PGE1 and PGE2), capsaicin and substance P (SP). Systemic indomethacin was used to prevent formation of endogenous prostaglandins, and intracameral injection of tetrodotoxin (TTX) was used to block nerve conduction. 10 micrograms TTX prevented the miosis and reduced the rise in intraocular pressure (IOP) usually caused by antidromic trigeminal nerve stimulation. At a low dose of PGE1 the IOP rise was blocked by TTX. At higher doses of PGE1 and PGE2 the pressure effect was not blocked by TTX; the miotic effect was markedly diminished. Capsaicin caused a rise in IOP that was almost totally blocked by TTX, while the miosis at high doses seemed unaffected. At low doses, capsaicin-induced miosis could be abolished by TTX. SP caused miosis in TTX treated eyes similar to that in untreated eyes; the IOP rise was delayed by TTX. The results indicate that nerve conduction plays a role in the IOP reaction caused by low doses of PGE1 and by capsaicin and SP. The mechanism suggested is an axon reflex, elicited in the anterior uvea and resulting in transmitter release in the ciliary processes. Nerve conduction with release of SP or a similar substance in the iris seems to be required for the miotic effects of PGE1 and PGE2. SP and capsaicin are similar in not requiring nerve conduction to cause miosis, but the capsaicin effect probably requires presence of nerves, since denervated eyes--which respond to SP--have been reported no to respond to capsaicin does similar to those used here.
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PMID:Ocular responses to antidromic trigeminal stimulation, intracameral prostaglandin E1 and E2, capsaicin and substance P. 617 Feb 10

Peptide and non-peptide agents were tested for their stimulatory or inhibitory effects on circular strips of guinea pig isolated tracheae. Substance P, eledoisin, physalaemin, neurotensin, angiotensin, histamine and carbachol were found to contract, while noradrenaline, dopamine, bradykinin, nucleotides (AMP, ADP, ATP) and prostaglandins (PGE1, PGE2, PGA2) induced concentration-dependent relaxations of tracheae contracted with substance P or carbachol. Indomethacin (2.8 X 10(-6) M) significantly potentiated the effect of substance P and blocked that of bradykinin. The contractions to substance P of tissues treated with indomethacin were not modified by atropine, methysergide, diphenhydramine, cimetidine, propranolol, phentolamine, [Leu8]-ATII, [Leu8]-des-Arg9-bradykinin, naloxone and baclofen. The order of potency of C-terminal fragments of substance P was: hexa(6-11) greater than hepta(5-11) greater than substance P greater than = octa(4-11). It is concluded that the guinea pig isolated trachea is a pharmacological preparation sensitive to numerous agents and useful for studying structure-activity relationship and the mechanism of cellular action of several peptides, particularly substance P.
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PMID:Pharmacological effects of peptides on tracheal smooth muscle. 618 32

We studied the effects of a variety of noncholinergic, nonadrenergic agents on the smooth muscles of the cat urethra. Prostaglandin F2 alpha contracted both urethral muscle layers to a similar extent. Prostaglandin E2 contracted the longitudinal and relaxed the circular muscle layers. The effects of the prostaglandins seem to be directly myogenic since cholinergic and adrenergic blockers and tetrodotoxin did not affect them. Bradykinin and substance P contracted both urethral muscle layers. Other tested agonists (neurotensin, vasoactive intestinal peptide, cyclic 3,5 adenosine monophosphate, adenosine diphosphate sodium, cyclic 3,5 guanosine monophosphate sodium, bombesin) had no effect on the cat urethral smooth muscles.
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PMID:Response of urethral smooth muscles to pharmacological agents. II. Noncholinergic, nonadrenergic agonists and antagonists. 619 58

Luminal application of acid was recently shown to stimulate surface epithelial HCO3(-) transport in stomach and duodenum. Effects of some potential transmitters of this response were therefore studied in amphibian gastric fundic and proximal duodenal mucosa in vitro. Duodenal HCO3- transport, which could be titrated directly, was stimulated by dibutyryl cAMP (DBcAMP, 10(-6) M), the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (10(-6) M), noradrenaline (10(-6) M), pancreatic glucagon (10(-8) M), and gastric inhibitory peptide (GIP, 10(-10) M). Stimulation by glucagon, but not by prostaglandin E2 (PGE2, 10(-6) M), required Cl- in the luminal solution and was prevented by furosemide (10(-3) M). This suggests that glucagon may affect HCO3(-)-Cl- exchange at the luminal membrane while transport stimulated by prostaglandins may be electrogenic. Stimulatory effects of glucagon and PGE2 were also additive. Gastric HCO3- transport, studied in tissues after inhibition of H+ secretion by histamine H2-antagonists, clearly differed from duodenum in that noradrenaline and GIP were inhibitory and DBcAMP was without effect. Stimulation of gastric HCO3- transport was observed with glucagon (10(-8) M), natural cholecystokinin (CCK, 10(-8) M), and CCK octapeptide (10(-7) M), CCK preparations had no effect in the duodenum. Although tested over a wide range of concentrations, no effect on either duodenal or gastric HCO3- transport was observed with histamine, pentagastrin, tetragastrin, urogastrone, ACTH, bombesin, motilin, secretin, serotonin, somatostatin, substance P, or vasoactive intestinal peptide.
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PMID:Gastric and duodenal HCO3- transport in vitro: effects of hormones and local transmitters. 697 77


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