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)

The interaction of angiotensin-converting enzyme (ACE) inhibitors and bradykinin was investigated in isolated bovine and human coronary arteries. Rings with and without endothelium were mounted in organ chambers for measurement of isometric force. The effects of the ACE inhibitors lisinopril, enalaprilat, fosinoprilat, ramiprilat, and captopril were determined during submaximal stimulation with bradykinin or other vasodilators. Lisinopril and captopril alone did not affect vascular tone; however, in rings with endothelium partially relaxed with bradykinin (> or = 10(-10) M), all ACE inhibitors caused further relaxations. Lisinopril did not affect bradykinin concentrations in the incubation medium. Mechanical removal of the endothelium or incubation with nitro-L-arginine or the bradykinin2-receptor antagonist Hoe 140 prevented the relaxations to bradykinin and lisinopril. Other vasodilators including acetylcholine, adenosine diphosphate, substance P, or SIN-1 did not prime the rings to respond to ACE inhibitors. Endothelium-dependent relaxations to lisinopril were also observed in human coronary arteries treated with bradykinin (> or = 10(-7) M). Thus, ACE inhibitors potentiate endothelium-dependent relaxations to submaximal concentrations of bradykinin in bovine and human coronary arteries. This local mechanism occurs regardless of elevated bradykinin concentrations in the blood and reduced angiotensin II generation.
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PMID:Local potentiation of bradykinin-induced vasodilation by converting-enzyme inhibition in isolated coronary arteries. 128 32

1. Release of endothelium derived relaxing factor (EDRF) and prostacyclin (PGI2) from endothelial cells (EC) cultured from bovine aortae was measured by bioassay and radioimmunoassay, respectively, during infusions (10 min) of bradykinin (BK), adenosine diphosphate (ADP), arachidonic acid (AA), alkaline buffers and the free-bases (FB) of L-arginine or D-arginine. Release of EDRF from the luminally perfused rabbit aorta was also measured during infusions (10 min) of acetylcholine (ACh), substance P and ADP. 2. Bradykinin (10 or 30 nM) infused through the column of EC induced release of both EDRF and PGI2, neither of which was maintained for the duration of the infusion. 3. ADP (1.6 or 4 microM) infused through the column of EC induced release of a EDRF which was maintained for the duration of the infusion and a release of PGI2 which lasted for a much shorter period. 4. Arachidonic acid (30 or 90 microM) infused through the column of EC caused a sustained release of EDRF and PGI2, both of which outlasted the infusion of AA. 5. L-Arginine FB, D-arginine FB or alkaline buffer infused through the column of EC released EDRF, but only small amounts of PGI2. The release of EDRF outlasted the period of infusion and was due to an increase in the pH of the Krebs solution perfusing the EC. 6. Infusions of ACh (0.25-1 microM) or ADP (4-16 microM) caused a sustained release of EDRF from the luminally-perfused rabbit aorta, whereas infusion of substance P (3.3-10 microM) caused only a transient release of EDRF. 7. These results show that distinct patterns of EDRF release exist to different agonists in both cultured and in situ EC, and that EDRF and PGI2 do not necessarily follow the same time course of release. Furthermore, sustained release of EDRF does not require the constant infusion of the precursor, L-arginine, whereas sustained release of PGI2 only occurs when AA, the precursor of PGI2, is present in the extracellular medium.
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PMID:Different patterns of release of endothelium-derived relaxing factor and prostacyclin. 137 3

It has been proposed that mastoparan (INLKALAALAKKIL) and other mast cell secretagogues such as substance P (SP) or compound 48/80 act by direct activation of the pertussis toxin (PTX)-sensitive G-proteins in intact cells. Here we have investigated whether or not the antagonists of SP, [D-Trp7,9,10] SP1-11 and [D-Trp7,9,10, N-leu11]SP1-11, can similarly induce exocytosis from RINm5F cells. In intact cells mastoparan and the SP antagonists stimulated insulin release in a dose-dependent manner at concentrations ranging from 10 to 100 microM. The maximal effect on insulin release, of both mastoparan and the SP antagonists was comparable to that obtained with 100 microM forskolin. Pretreatment of the intact cells, for 18 h with PTX or 6 h with cholera toxin, did not change the responses induced by both mastoparan and the SP antagonists. This absence of PTX effect, despite the fact that the three PTX substrates at 41, 40 and 39 kDa were ADP ribosylated after pretreatment suggests intrinsic differences between mast and RINm5F cells. Thus the SP antagonists behave similarly to mastoparan in its ability to induce insulin release in RINm5F cells. However, the higher concentrations required with RINm5F cells compared to that needed for mast cells suggest differences either in G-proteins composition or in the phospholipid composition of the membranes.
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PMID:Insulin releasing effects of mastoparan and amphiphilic substance P receptor antagonists on RINm5F insulinoma cells. 137 73

Substance P and selective neurokinin receptor agonists have been tested for their ability to induce shape change in rabbit platelets. Substance P and the NK1 receptor agonist Ac [Arg6,Sar9,Met(O2)11]-substance P (6-11) induced shape change (EC50 = 3 and 6 nM, respectively), whereas the selective NK2 agonist [Nle10]-Neurokinin A (4-10) and the selective NK3 agonist [MePhe7]-Neurokinin B did not show any effect. Moreover, the specific NK1 receptor antagonist CP-96,345 selectively and dose-dependently counteracted the effect of substance P or of the NK1 receptor agonist (IC50 = 2 and 0.8 nM, respectively), whereas the selective NK2 receptor antagonist, SR 48968, had no effect. Unlike for serotonin or low doses of ADP, epinephrine did not allow substance P or the NK1 receptor agonist to become a proaggregating substance. These data therefore show that the NK1 receptor is solely involved in the neurokinin-induced shape change of rabbit platelets.
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PMID:The NK1 receptor is involved in the neurokinin-induced shape change of rabbit platelets. 138 16

We investigated the influence of exogenously administered acetylcholine, nitric oxide, ADP, ATP, bradykinin, and substance P on coronary vascular tone in isolated, neonatal pig hearts (less than or equal to 4 d). Paced (180 bpm), isovolumically beating hearts underwent retrograde aortic perfusion, with an erythrocyte-enriched solution (hematocrit 0.15-0.20) at constant coronary flow (approximately 2.5 mL/min/g) corresponding to a perfusion pressure of approximately 60 mm Hg. Agonists were injected into the aortic root, and the peak change in coronary perfusion pressure from baseline and left ventricular pressure development were assessed. Nitric oxide (3 microL), ADP (30 nmol), ATP (30 nmol), bradykinin (125 ng), and substance P (50 ng) decreased the perfusion pressure (vasodilation) by 16.9 +/- 1.2, 25.3 +/- 4.4, 18.3 +/- 1.2, 18.9 +/- 1.4, and 7.1 +/- 1.6 mm Hg, respectively. Acetylcholine (0.5 and 1.0 nmol) produced a modest decrease in perfusion pressure (vasodilatation) of 4.2 +/- 0.8 and 3.8 +/- 0.5 mm Hg, respectively, whereas acetylcholine (5, 20, and 100 nmol) increased the perfusion pressure (vasoconstriction) by 16.7 +/- 2.7, 48.2 +/- 8.2, and 85.3 +/- 15.1 mm Hg, respectively. Acetylcholine also decreased left ventricular peak systolic pressure from 108.7 +/- 5.0 to 69.2 +/- 4.6, 56.3 +/- 6.1, and 48.2 +/- 6.4 mm Hg, for the 5, 20, and 100 nmol doses, respectively. Responses to acetylcholine were abolished by atropine (50 nmol). In a separate group of hearts, indomethacin (10(-6) M) reduced the peak change in perfusion pressure for the 5, 20, and 100 nmol doses of acetylcholine by 87%, 66%, and 48%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Acetylcholine-induced coronary vasoconstriction and negative inotropy in the neonatal pig heart. 150 17

The aim of the present in vitro study was to provide information on the pharmacologic properties of the muscularis mucosae in three regions of the rabbit colon. Proximal muscularis mucosae exhibited spontaneous contractions whose frequency was independent of endogenous acetylcholine. In the mid and distal colon, spontaneous contractile frequencies were depressed by atropine and enhanced by eserine. Muscularis mucosae from all regions responded to acetylcholine, ADP, AMP, ATP, bradykinin, histamine, methoxamine, substance P, vasoactive intestinal polypeptide but not cholecystokinin octapeptide or gamma-aminobutyric acid. Low concentrations of norepinephrine caused propranolol-sensitive relaxations of proximal colonic muscularis mucosae whereas high concentrations evoked phentolamine-sensitive contractions. In the mid and distal colon, norepinephrine caused relaxations which were poorly antagonized by propranolol. Proximal colonic muscularis mucosae responded to electrical stimulation with an atropine- and tetrodotoxin-sensitive "on contraction." Responses from the mid and distal colon were tetrodotoxin-sensitive and consisted of an atropine-sensitive "duration contraction" followed by a propranolol-insensitive "off relaxation" which was not mediated by prostaglandin synthesis, a purine, or vasoactive intestinal polypeptide. These data suggest that the rabbit colonic muscularis mucosae possesses alpha-1 adrenoceptors, histamine H1, muscarinic, P2 purinoceptors and beta adrenoceptors. However, their relative importance and the nature of the intrinsic innervation suggests considerable specialization of this muscle layer in different regions of the rabbit colon.
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PMID:Pharmacologic characterization of the muscularis mucosae in three regions of the rabbit colon. 160 78

We have compared several known releasers of endothelium-derived relaxing factor (EDRF)(13) in respect to their potencies to generate EDRF by endothelium of rabbit aortic strips (RbA) superfused with Krebs' buffer. The vasorelaxation by EDRF which is equivalent to 10 pmoles of GTN was evoked by 0.7 pmoles of substance P(SP), 50 pmoles of acetylcholine (Ach), 521 pmoles of calcium ionophore A 23187, 2720 pmoles of ADP. Threshold potencies of these agonists are inversely proportional to the maximum amount of EDRF released. Phospholipase C (PLC) from Clostridium perfringens at a dose of 0.1 U caused the relaxation of a similar magnitude. Phospholipase A2 (1 U), thrombin (1 U), bradykinin (30 nmoles) and serotonin (10 pmoles) did not release EDRF. It is concluded that endothelial cells of RbA differ from endothelial cells of other species in their susceptibility to release EDRF in response to various agonists.
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PMID:Quantification of the potencies of EDRF-releasers from isolated rabbit aortic strips. 166 77

The peptide hormones bradykinin and kallidin (Lys-bradykinin), as well as their analogues [des-Arg9]-bradykinin, a selective B1 agonist, [des-Arg9,Leu8]-bradykinin, a selective B1 antagonist, and [Thi5,8,D-Phe7]-bradykinin and D-Arg0-[Hyp3,D-Phe7]-bradykinin, two selective B2 antagonists, induced rapid histamine release from purified rat peritoneal mast cells. In contrast, the N-terminal fragment bradykinin-(1-5) was inactive. These peptides also activate the GTPase activity of GTP-binding proteins (G proteins) (Go/Gi) purified from calf brain, with an order of potency identical to that observed on mast cells, [Thi5,8,D-Phe7]-bradykinin much greater than kallidin greater than bradykinin greater than D-Arg0-[Hyp3,D-Phe7]-bradykinin greater than [des-Arg9]-bradykinin greater than [des-Arg9,Leu8]-bradykinin greater than bradykinin-(1-5). This correlation suggested that G proteins are the targets of kinins in mast cells. Accordingly, the concomitant increase in inositol trisphosphates and release of histamine elicited by kinins were inhibited by pertussis toxin pretreatment of mast cells. The inhibitory effect of benzalkonium chloride showed that the G proteins involved belong to the Gi type. GTPase activity was measured in the supernatant of homogenized mast cells but not in the membranous fraction. This activity was stimulated by kinins and by the venom peptide mastoparan. The potency of peptides was similar to that observed with purified bovine G proteins. Sodium dodecyl sulfate-gel electrophoresis of mast cell supernatant revealed pertussis toxin-induced ADP-ribosylation of two proteins, in the Mr 41,000 and 40,000 range, i.e., similar to purified alpha-subunits of Gi1 and Gi2 or Gi3 subtypes. The data support the proposal that bradykinin and analogues act like mastoparan, substance P, and compound 48/80, interacting first with sialic acid residues of the cell surface and then with Gi-like proteins, inducing phospholipase C activation and intracellular calcium mobilization.
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PMID:Activation of Gi-like proteins, a receptor-independent effect of kinins in mast cells. 170 Dec 14

Substance P (SP) stimulates polyphosphoinositide breakdown in the rat anterior pituitary through an NK-1 receptor. In the present study we present evidence that the coupling between the SP-NK1 receptor complex and polyphosphoinositide-specific phospholipase C (PI-PLC) in rat anterior pituitary membranes may involve a mechanism consistent with a GTP-binding protein. The formation of inositol phosphates from [3H]myo-inositol-labelled anterior pituitary membranes induced by SP was potentiated by GTP and non-hydrolysable guanine nucleotides. The stimulatory effects of SP alone and SP plus GTP could be blocked by addition of GDP-beta-S (guanosine 5-O-(thiodiphosphate] in excess. Basal and SP plus guanine nucleotide-induced inositol phosphate formation were stimulated by fluoride, whereas the effect of SP alone was inhibited. Pretreatment of anterior pituitary membranes with sodium deoxycholate attenuated the inositol phosphate response elicited by GTP and GTP-gamma-S, whereas basal and SP-stimulated inositol phosphate production showed a peak at 1 mg sodium deoxycholate/ml. SP, fluoride and guanine nucleotide stimulatory effects on hydrolysis of polyphosphoinositide (PPI) were unaffected by pretreatment of anterior pituitary cells with cholera or pertussis toxin for 12h. Treatment of anterior pituitary membranes with cholera and pertussis toxin yielded [32P]ADP-ribosylation of two proteins with molecular masses of 45 and 41 kDa respectively. We conclude that SP coupling to PI-PLC through the NK1 receptor in the rat anterior pituitary involves a GTP-binding mechanism distinct from the G-proteins associated with adenylate cyclase, Gs and Gi.
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PMID:Substance P stimulation of polyphosphoinositide hydrolysis in rat anterior pituitary membranes involves a GTP-dependent mechanism. 171 80

The molecular mechanism of action of several non-immunological histamine releasers has been investigated using pertussis toxin which interfers, via ADP-ribosylation, with some G-proteins. Pertussis toxin (100 ng/ml) inhibited histamine release induced by compound 48/80, substance P, mastoparan, peptide 401, bradykinin and spermine showing that a G-protein sensitive to pertussis toxin was involved in the non-immunological histamine release. All these compounds directly activate purified G-proteins. The sensitivity to pertussis toxin of this direct stimulatory effect was demonstrated for compound 48/80, mastoparan and substance P. Altogether these results suggest that a direct activation of G-protein might be the molecular mechanism of action of histamine secretagogues acting through a pertussis toxin sensitive G-protein and in this way mimic agonist-ligand receptor interaction.
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PMID:G-proteins as targets for non-immunological histamine releasers. 171 43


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