Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Using endothelium-denuded and intact rat aortic rings, we have determined the contractile and relaxant structure-activity profile for a series of thrombin receptor-derived polypeptides (TRPs) based on the human and rat receptor sequences: SFLLR (P5), SFLLR-NH2 (P5-NH2) SFFLR (Rat P5), SFFLR-NH2 (Rat P5-NH2), SFLLRNP (P7), SFLLRNP-NH2 (P7-NH2), SFFLRNP (Rat P7), SFFLRNP-NH2 (Rat P7-NH2), and SFLLRNPNDKYEPF (P14). 2. A contractile response to thrombin and the TRPs in the endothelium-denuded aortic tissue was minimal or absent in preparations obtained from animal weighing less than 180 g (< 6 weeks of age), but increased with animal size, plateauing in tissues derived from animals weighing between 320 and 420 g (about 9 to 14 weeks of age). In contrast, the contractile responses to KCl and noradrenaline did not differ in the tissues and relaxant responses to the TRPs in endothelium-intact aortic preparations were comparable for tissues obtained from either young (< or = 180 g) or older (> or = 320 g) animals. 3. The contractile response of the endothelium-denuded preparation to thrombin and the TRPs showed marked cross-desensitization: the relaxation response of the intact rings did not desensitize to the TRPs. 4. The relative potencies for the TRPs in the aortic contraction assay were comparable to those for the relaxation assay, but were distinct from the relative potencies we measured previously in a rat gastric longitudinal muscle contraction assay. Further, P5 behaved as a partial agonist in the aortic contraction assay, whereas it had been observed to be a full agonist in the gastric contraction assay. 5. The contractile activity of P5-NH2 in endothelium intact aortic rings was low or absent, but in the presence of the nitric oxide synthase inhibitor, N omega-nitro-L-arginine-methyl ester (L-NAME), the contractions in the intact preparation were equivalent to the response of the endothelium-denuded preparation in the absence of L-NAME.6. The contractile response of the endothelium-denuded aortic preparation to P5-NH2 was inhibited by nifedipine and the kinase C antagonist, chelerythrine, but was resistant to the action of indomethacin,tetrodotoxin and the tyrosine kinase inhibitor, genistein.7 We conclude that the receptor system for the TRPs in the aortic smooth muscle elements, responsible for the contractile response, is similar to the aortic endothelial cell receptor responsible for the relaxation response, but is distinct from the receptor that we have previously characterized in gastric longitudinal smooth muscle, results pointing to the presence of receptor subtypes in the vascular and gastric smooth muscle elements.
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PMID:Vascular actions of thrombin receptor-derived polypeptides: structure-activity profiles for contractile and relaxant effects in rat aorta. 754 Dec 84

1. The biological activities of the proteinase-activated receptor number 2 (PAR-2)-derived peptides, SLIGRL (PP6) SLIGRL-NH2 (PP6-NH2) and SLIGR-NH2 (PP5-NH2) were measured in mouse and rat gastric longitudinal muscle (LM) tissue and in a rat aortic ring preparation and the actions of the PAR-2-derived peptides were compared with trypsin and with the actions of the thrombin receptor activating peptide, SFLLR-NH2 (TP5-NH2). 2. From a neonatal rat intestinal cDNA library, and from intestinal and kidney-derived cDNA, the coding region of the rat PAR-2 receptor was cloned and sequenced, thereby establishing its close sequence identity with the previously described mouse PAR-2 receptor; and this information, along with a reverse-transcriptase (RT) polymerase chain reaction (PCR) analysis of cDNA derived from gastric and aortic tissue was used to establish the concurrent presence of PAR-2 and thrombin receptor mRNA in both tissues. 3. In the mouse and rat gastric preparations, the PAR-2-derived polypeptides, PP6, PP6-HN2 and PP5-NH2 caused contractile responses that mimicked the contractile actions of low concentrations of trypsin (5 u/ml-1; 10 nM) and that were equivalent to contractions caused by TP5-NH2. 4. The cumulative exposure of the rat LM tissue to PP6-NH2 led to a desensitization of the contractile response to this polypeptide, but not to TP5-NH2 and vice versa, so as to indicate a lack of cross-desensitization between the receptors responsive to the PAR-2 and thrombin receptor-derived peptides. 5. In the rat gastric preparation, the potencies of the PAR-2-activating peptides were lower than the potency of TP5-NH2 (potency order: TP5-NH2 > > PP6-NH2 > or = PP6 > PP5-NH2); PP6 was a partial agonist in this preparation. 6. The contractile actions of PP6 and PP6-NH2 in the rat gastric preparation required the presence of extracellular calcium, were inhibited by nifedipine and were blocked by the cyclo-oxygenase inhibitor, indomethacin and by the tyrosine kinase inhibitor, genistein, but not by the kinase C inhibitor, GF109203X. The contractile responses were not blocked by atropine, chlorpheniramine, phenoxybenzamine, propranolol, ritanserin or tetrodotoxin. 7. In a precontracted rat aortic ring preparation, with an intact endothelium, all of the PAR-2-derived peptides caused a prompt relaxation response that was blocked by the nitric oxide synthase inhibitor, N omega-nitro-L-arginine-methyl ester (L-NAME) but not by D-NAME; in an endothelium-free preparation, which possessed mRNA for both the PAR-2 and thrombin receptors, the PAR-2-activating peptides caused neither a relaxation nor a contraction, in contrast with the contractile action of TP5-NH2. The relaxation response to PP6-NH2 was not blocked by atropine, chlorpheniramine, genistein, indomethacin, propranolol or ritanserin. 8. In the rat aortic preparation, the potencies of PP6, PP6-NH2 and PP5-NH2 were greater than those of the thrombin receptor activating peptide, TP5-NH2 (potency order: PP6-NH2 > or = PP6 > PP5-NH2 > TP5-NH2). 9. In the rat aortic preparation, the relaxant actions of the PAR-2-derived peptides were mimicked by trypsin, at concentrations (0.5-1 u ml-1; 1-2 nM) lower than those that can activate the thrombin receptor. 10. The bioassay data obtained with the PAR-2 peptides and with trypsin, along with the molecular cloning/RT-PCR analysis, point to the presence of functional PAR-2 receptors that can activate distinct responses in the gastric and vascular smooth muscle preparations. These responses were comparable to those resulting from thrombin receptor activation in the same tissues, so as to suggest that the receptor for the PAR-2-activating peptides may play a physiological role as far reaching as the one proposed for the thrombin receptor.
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PMID:Rat proteinase-activated receptor-2 (PAR-2): cDNA sequence and activity of receptor-derived peptides in gastric and vascular tissue. 876 73

Vascular expression and cellular functions of the thrombin receptor (PAR-1) and protease activated receptor 2 (PAR-2) suggest similar but distinct vascular regulatory roles. The vascular actions of PAR-1 and PAR-2 in vivo were differentiated by monitoring mean arterial pressure (MAP) and heart rate (HR) of anesthetized mice in response to intravenous SFLLRN (0.1, 0.3, and 1 mumol/kg) and SLIGRL (0.1, 0.3, and 1 mumol/kg), the respective receptor-activating sequences for PAR-1 and PAR-2, and TFLLRNPNDK (0.3, 1, and 3 mumol/kg), a synthetic peptide selective for PAR-1. All peptides dose dependently decreased MAP (order of potency: SLIGRL > SFLLRN > TFLLRNPNDK). SLIGRL induced a more prolonged hypotension with a slow return to baseline, whereas SFLLRN- and TFLLRNPNDK-induced hypotension was followed by a rapid return towards baseline and a sustained moderate hypotension. SFLLRN and TFLLRNPNDK, but not SLIGRL, decreased HR. N omega-Nitro-L-arginine methyl ester HCl (L-NAME), an inhibitor of nitric oxide synthesis, attenuated the cumulative hypotensive response to SLIGRL but had no effect on the SFLLRN and TFLLRNPNDK hypotension. However, L-NAME revealed a rebound hypertension in response to SFLLRN and TFLLRNPNDK but not SLIGRL. In conclusion, activation of either PAR-1 or PAR-2 in vivo results in hypotension. In addition, only PAR-1 activation induced hypertension following L-NAME, reflecting concurrent PAR-1-mediated vasoconstriction. Thus, these different hemodynamic responses in vivo suggest distinct physiological or pathophysiological roles for PAR-1 and PAR-2 in local vascular regulation.
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PMID:Receptor-activating peptides distinguish thrombin receptor (PAR-1) and protease activated receptor 2 (PAR-2) mediated hemodynamic responses in vivo. 956 45

The effect of a thrombin receptor agonist peptide (TRAP-6) on the release of nitric oxide (NO) and platelet activating factor (PAF) from resting and calcium-ionophore (A23187)-activated rat peritoneal mast cells (RPMC) was studied using a platelet aggregation bioassay. RPMC spontaneously released NO, which inhibited TRAP-6-, ADP-, and PAF-stimulated platelet aggregation. This effect of NO was abolished by the addition of an NO binding agent, oxyhemoglobin (oxyHb), to the platelet suspension. The RPMC-induced suppression of platelet aggregation was completely inhibited by the NO-synthase inhibitor L-NAME. TRAP-6 and its high affinity analog haTRAP stimulated the rapid release of NO from RPMC. The effect of TRAP-6 was inhibited by pretreatment of the RPMC with L-NAME or with the inhibitor of the constitutive NO-synthase isoform (cNOS) calmidazolium. TRAP-6 inhibited PAF release from A23187-activated RPMC via an NO-dependent mechanism. Platelet aggregation induced by PAF release from activated RPMC was also confirmed in experiments using the PAF receptor antagonist ginkgolide B. Thus, TRAP-6 is a rapidly acting modulator of mast cell reactivity; it stimulates NO release and inhibits PAF secretion.
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PMID:Modulation of mast cell activity by a peptide agonist of the thrombin receptor: role of nitric oxide. 1039 81

The proteolytic enzyme thrombin activates its receptor by cleavage of a peptide from the extracellular N-terminus. The newly generated N-terminus acts as a tethered ligand to activate the receptor. Receptor-mediated cellular effects of thrombin can be mimicked by synthetic peptides, which correspond to the amino acid sequence of the newly formed N-terminus. The aim of the present study was to investigate vascular effects of thrombin and the thrombin receptor activating peptide (TRAP: SFLLRN) in vitro and in vivo in rats. In precontracted rat aortic rings, both thrombin (0.3, 1, 3 U/ml) and TRAP (1, 3, 10, 20, 40 microM) induced endothelium-dependent relaxant responses. In anaesthetized rats, the mean arterial blood pressure (MAP) was measured continuously in the carotid artery by a pressure transducer. Thrombin and TRAP were administered as intravenous bolus injection via the femoral vein. Thrombin at doses of 3-100 U/kg, as well as TRAP at doses of 0.1-0.6 mg/kg i.v., caused a reversible decrease in MAP. Administration of TRAP at doses of 0.3 and 0.6 mg/kg led to a triphasic response in most of the animals treated (50% and 75%, respectively), i.e. a short drop of MAP was followed by an increase and finally a longer lasting decrease in MAP. Pretreatment with the nitric oxide (NO)-synthase inhibitor N(G)-nitro-L-arginine-methylester (L-NAME) suppressed the dose-dependent vasodilator effects of thrombin. Heparin and hirudin also inhibited the hypotensive response to thrombin. The TRAP-induced triphasic reaction on MAP was not affected by the serotonin antagonists ketanserin and tropisetron, as well as the aminopeptidase inhibitor amastatin. Pretreatment with L-NAME led to an inhibition of hypotension induced by TRAP at 0.1 mg/kg, as well as of the initial transient fall in blood pressure at doses of 0.3 and 0.6 mg/kg. The studies suggest that the thrombin- and TRAP-induced vasodilation in vitro and in vivo is in part due to the release of endothelial NO. In the blood pressure response to TRAP, additional effects seem to be involved.
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PMID:Systemic vascular effects of thrombin and thrombin receptor activating peptide in rats. 1132 4

Platelet-leukocyte aggregation (PLA) links haemostasis to inflammation. The role of nitric oxide (NO) and matrix metalloproteinases (MMP-1, -2, -3, -9) in PLA regulation was studied. Homologous human platelet-leukocyte suspensions were stimulated with thrombin (0.1-3 nM) and other proteinase activated receptor-activating peptides (PAR-AP), including PAR1AP (0.5-10 microM), PAR4AP (10-70 microM), and thrombin receptor-activating peptide (1-35 microM). PLA was studied using light aggregometry with simultaneous measurement of oxygen-derived free radicals, dual colour flow cytometry, and phase-contrast microscopy. The release of NO was measured using a porphyrinic nanosensor, while MMPs were investigated by Western blot, substrate degradation assays, immunofluorescence microscopy, and flow cytometry. The levels of P-selectin and microparticles (MP) in PLA were measured by flow cytometry. PLA was also characterized using pharmacological agents: S-nitroso-glutathione (GSNO, 0.01-10 microM), 1H-Oxadiazole quinoxalin-1-one (ODQ, 1 microM), N(G)-L-nitro-L-arginine methyl ester (L-NAME, 100 microM) and compounds that modulate the actions of MMPs such as phenanthroline (100 microM), monoclonal anti-MMP antibodies, and purified MMPs. PAR agonists concentration-dependently induced PLA, an effect associated with the release of microparticles (MP) and the translocation of P-selectin to the platelet surface. NO and radicals were also released during PLA. Inhibition of NO bioactivity by the concomitant release of free radicals or by the treatment with L-NAME or ODQ stimulated PLA, while pharmacological administration of GSNO decreased PLA. PAR agonist-induced PLA resulted in the liberation of MMP-1, -2, -3, and -9. During PLA, MMPs were present on the cell surface, as shown by flow cytometry and immunofluorescence. PLA led to the activation of latent MMPs to active MMPs, as shown by Western blot and substrate degradation assays. Inhibition of MMPs actions by phenanthroline and by the antibodies attenuated PLA. In contrast, purified active, but not latent, MMPs amplified thrombin-induced PLA. It is concluded that NO and MMP-1, -2, -3, and -9 play an important role in regulation of PAR agonist-induced PLA.
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PMID:Platelet-leukocyte aggregation induced by PAR agonists: regulation by nitric oxide and matrix metalloproteinases. 1553 89