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

This study determines the release of nitric oxide (NO) from the coronary circulation of Langendorff hearts of rabbits, subsequent to administration of glyceryl trinitrate (GTN) and SIN-1. NO was measured on-line in the coronary effluent by the oxyhaemoglobin technique. Infusion of either GTN (10-40 mumoles/l) or SIN-1 (0.1-2.3 mumoles/l) into the coronary inflow resulted in a concentration-dependent NO release into the coronary effluent and a decrease in the coronary vascular resistance. NO generation from SIN-1 was identical with and without passage of the coronary circulation whereas NO generation from GTN was only detected after passage of the coronary vascular bed. NO generation by both substances was in the same range as endogenous NO release by two endothelium-dependent vasodilators, bradykinin (0.05 mumoles/l) and substance P (0.05 mumoles/l). Oxyhaemoglobin used for the assay of NO, inhibited the relaxation by SIN-1, but did not reduce vessel relaxations induced by GTN or iloprost, a stable prostacyclin analogue. Removal of the coronary endothelium by trypsin or pretreatment with L-NG-Monomethylarginine (30 mumoles/l) did neither affect NO release from GTN and SIN-1 nor the vasodilatory effect of both substances. These data are the first to directly demonstrate endothelium-independent NO release from organic nitrates during passage of an intact organ circulation. They additionally suggest a subendothelial site of metabolic NO formation from GTN.
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PMID:On-line measurement of nitric oxide release from organic nitrates in the intact coronary circulation. 171 35

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

In canine and porcine coronary arteries, experimental atherosclerosis (induced by endothelial denudation followed by a high-cholesterol diet) potentiates the vasoconstrictor effects of histamine, serotonin, and ergonovine. In isolated human atherosclerotic coronary arteries, only hypersensitivity to histamine has been demonstrated. This discrepancy could be due to several factors. First, the atherosclerotic lesions in human vessels are different from those observed in the animal, since experimental atherosclerosis often corresponds only to the early stage of the disease in humans. Second, the human atherosclerotic coronary arteries were isolated mainly from patients with cardiac failure, a condition that alters the responses of coronary smooth muscle to vasoactive amines. With regard to endothelium-dependent vasodilators, marked attenuations of the relaxations to substance P, bradykinin, and the Ca2+ ionophore A23187 have been described in isolated human atherosclerotic arteries. Acetylcholine elicits variable responses in these preparations and even if the arteries are devoid of atherosclerotic lesions, it often fails to relax them. In addition to this endothelial dysfunction, severely atherosclerotic human coronary vessels exhibit a slightly decreased responsiveness to nitroglycerin and SIN-1 but not to forskolin. Another abnormality of the smooth muscle is a marked attenuated beta-adrenergic relaxation. Thus, atherosclerosis of human coronary vessels induces not only marked alterations in endothelium-dependent responses but also modifies the sensitivity to several endothelium-independent vasodilators.
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PMID:Atherosclerosis and responses of human isolated coronary arteries to endothelium-dependent and -independent vasodilators. 248 97

Human epicardial coronary arteries were obtained from the hearts of 15 patients who received cardiac transplantation for cardiomyopathy. Transverse strips of these arteries were mounted in organ baths for isometric tension recording. The arteries were constricted with prostaglandin F2 alpha and then exposed to the endothelium-dependent relaxants substance P (1 nM), bradykinin (1 nM-1 microM), and the Ca2+ ionophore A23187 (1 nM-1 microM). The effects of the endothelium-independent relaxants glyceryl trinitrate (1 nM-10 microM) and SIN-1, the active metabolite of molsidomine (1 nM-10 microM), were also tested. In control strips of human coronary arteries, all vasodilators caused concentration-dependent relaxations. Pretreatment of human coronary arteries with glyceryl trinitrate (0.5 mM for 60 min) shifted the concentration-response curve to glyceryl trinitrate to the right by a factor of approximately 800 (increase in EC50 from 10 nM to 8 microM). In contrast, endothelium-dependent relaxations to substance P, bradykinin, and A23187 and relaxations to SIN-1 were not changed significantly. Previous exposure of human coronary arteries to SIN-1 (0.5 mM for 60 min) did not modify relaxations to any of the agents tested. Our results show that (a) the responsiveness to SIN-1 is not modified in nitrate-tolerant strips of human coronary arteries, (b) prolonged exposure of human coronary arteries to SIN-1 does not cause tolerance, and (c) endothelium-dependent relaxations are not influenced by exposure of human coronary arteries to either glyceryl trinitrate or SIN-1.
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PMID:Endothelium-dependent vasodilatation in human epicardial coronary arteries: effect of prolonged exposure to glyceryl trinitrate or SIN-1. 248 99

We investigated the action of oral naftidrofuryl, a serotonin (5-HT2)antagonist, on atheromatous plaque formation, endothelial function, and neutrophil activity in cholesterol-fed (1% for 12 weeks) rabbits. Cholesterol feeding caused almost complete (84 +/- 4%) coverage of the aortic surface with atheromas and a marked intimal thickening. The endothelium-dependent relaxation to acetylcholine (ACh 1 nM-10 microM) and substance P (30 nM) was considerably reduced, whereas the relaxing effect to the endothelium-independent nitric oxide donor linsidomine (SIN-1) (100 microM) was unchanged. Treatment of hypercholesterolemic rabbits with naftidrofuryl (50 mg/kg body weight) resulted in a marked (54 +/- 6%, p < 0.05) reduction in aortic plaque formation. Endothelium-dependent relaxation to ACh was significantly improved in rings of both thoracic aorta: 33 +/- 5 versus 14 +/- 5% (p < 0.05) and abdominal aorta 68 +/- 9 versus 37 +/- 10% (p < 0.05). Similar results were obtained with substance P, but the responses to SIN-1 were unchanged. Zymosan-induced, luminol-enhanced chemiluminescence of polymorphonuclear leukocytes (PMN) was markedly stimulated in cholesterol-fed rabbits. Naftidrofuryl reduced this hyperreactivity to that of control rabbits. There was no change by naftidrofuryl in any of these parameters in control rabbits, precluding a direct action of the compound in nonhypercholesterolemic conditions. These data demonstrate significant endothelium-protective actions of long-term oral naftidrofuryl in cholesterol-fed rabbits that involve inhibition of cholesterol-induced neutrophil activation.
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PMID:Antiatherosclerotic effects of oral naftidrofuryl in cholesterol-fed rabbits involve inhibition of neutrophil function. 754 72

The effects of nitric oxide (NO) on the spontaneous release of 5-hydroxytryptamine (5-HT) were studied in the in vitro vascularly perfused guinea-pig small intestine. The NO donor SIN-1 concentration-dependently decreased 5-HT release with an EC50 of 1.34 microM, whereas the NO synthase inhibitor N(G)-nitro-L-arginine (100 microM) was without effect. The inhibition by SIN-1 of 5-HT release was enhanced by superoxide dismutase (150 U/ml) and antagonized by the selective inhibitor of soluble guanylyl cyclase, ODQ (1 microM). Tetrodotoxin (1 microM) prevented the inhibition by SIN-1 of 5-HT release, which suggests that the effect of SIN-1 is indirectly mediated via release of an inhibitory neurotransmitter. Substance P could be excluded as inhibitory transmitter because the effect of SIN-1 remained unchanged in the presence of the NK1 receptor antagonist CP 99994 (100 nM). The cyclic GMP analogue, 8-bromo cyclic GMP (300 microM), also decreased basal release of 5-HT, but this decrease was not tetrodotoxin-sensitive. It is concluded that NO inhibits the release of 5-HT from enterochromaffin cells via release of an enteric neurotransmitter. Acetylcholine (via nicotinic receptors) and substance P (via NK1 receptors) are not involved in the NO-mediated inhibition. The inhibition of 5-HT outflow by NO is due to the activation of soluble guanylyl cyclase. 8-Bromo cyclic GMP inhibited 5-HT release by a direct effect on the enterochromaffin cells.
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PMID:Inhibition by nitric oxide and cyclic GMP of 5-hydroxytryptamine release from the vascularly perfused guinea-pig small intestine. 967 48

The substantia gelatinosa of the spinal cord (lamina II) is the major site of integration for nociceptive information. Activation of NMDA glutamate receptor, production of nitric oxide (NO), and enhanced release of substance P and calcitonin gene-related peptide (CGRP) from primary afferents are key events in pain perception and central hyperexcitability. By combining reduced nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemistry for NO-producing neurons with immunogold labeling for substance P, CGRP, and glutamate, we show that (1) NO-producing neurons in lamina IIi are islet cells; (2) these neurons rarely form synapses onto peptide-immunoreactive profiles; and (3) NADPH diaphorase-positive dendrites are often in close spatial relationship with peptide-containing terminals and are observed at the periphery of type II glomeruli showing glutamate-immunoreactive central endings. By means of confocal fluorescent microscopy in acute spinal cord slices loaded with the Ca2+ indicator Indo-1, we also demonstrate that (1) NMDA evokes a substantial [Ca2+]i increase in a subpopulation of neurons in laminae I-II, with morphological features similar to those of islet cells; (2) a different neuronal population in laminae I-IIo, unresponsive to NMDA, displays a significant [Ca2+]i increase after slice perfusion with either substance P and the NO donor 3morpholinosydnonimine (SIN-1); and (3) the responses to both substance P and SIN-1 are either abolished or significantly inhibited by the NK1 receptor antagonist sendide. These results provide compelling evidence that glutamate released at type II glomeruli triggers the production of NO in islet cells within lamina IIi after NMDA receptor activation. The release of substance P from primary afferents triggered by newly synthesized NO may play a crucial role in the cellular mechanism leading to spinal hyperexcitability and increased pain perception.
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PMID:Nitric oxide-producing islet cells modulate the release of sensory neuropeptides in the rat substantia gelatinosa. 985 75

The aim of this study was to determine whether an excess of nitric oxide (NO) (mimicked by addition of NO donors) might produce by itself changes in the contractile responses to acetylcholine (ACh), substance P (SP) and KCl in the longitudinal muscle of the rat ileum. We also studied the calcium handling properties of this tissue in presence of NO donors. The NO donors assayed sodium nitroprusside (SNP) and 3-morpholinosydnonimine hydrochloride (SIN-1), induced different responses. SNP caused an immediate contraction followed by a sustained relaxation, whereas SIN-1 induced an immediate relaxation followed by a contraction. Even after prolonged incubations (up to 90 min), the NO donors SNP and SIN-1 were unable to modify the ACh- and SP-concentration-response curves, as well as the response to 30 mM KCl. The nifedipine-resistant component of the ACh-induced contraction was not modified in presence of SNP. Cyclopiazonic acid (CPA) induced a contraction that was not modified when the tissue was pre-incubated with SNP. Nifedipine caused a sharp relaxation when added during the CPA-induced contraction and, when added previously, it reduced the CPA-induced contractile response. It is concluded that NO excess is not, by itself, responsible for the altered responses to KCl. ACh and SP. The contractility changes observed in the longitudinal muscle of the rat ileum during inflammation could rather be related to the presence of other inflammatory mediators.
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PMID:Lack of effect of nitric oxide on KCl, acetylcholine and substance P induced contractions in ileal longitudinal muscle of the rat. 1099 18