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)

The present studies were performed in order to examine the possible role of cyclic GMP-stimulated phosphodiesterase (cGMP-PDE) activity in the inhibitory action of the inflammatory peptide bradykinin on cyclic AMP (cAMP) accumulation in D384 cells. Bradykinin decreased the forskolin-stimulated cAMP accumulation in the presence of the phosphodiesterase inhibitor rolipram, and caused a transient 50% rise in cellular cGMP in the presence of the nonselective PDE inhibitor 3-isobutyl-1-methylxanthine (IBMX). Both basal and bradykinin-stimulated cGMP accumulation were about 8 times higher in the presence of IBMX than in the presence of rolipram. Sodium nitroprusside, which caused a 20-70-fold increase in cGMP levels reduced forskolin stimulated cAMP accumulation, whereas hydroxylamine, which maximally caused a 16-fold increase in cGMP, did not. 8-bromo-cGMP or dibutyryl cGMP had no effect on cAMP accumulation induced by forskolin. The inhibitory effect of nitroprusside was totally reversed by blocking the soluble guanylate cyclase activity by methylene blue treatment; however, the inhibitory action of bradykinin on cAMP accumulation was not changed by this treatment. Additionally, inhibition of nitric oxide synthesis, which is known to be regulated by Ca2+ and in turn stimulates cGMP production, by N omega-nitro-L-arginine (L-NAME) treatment did not alter the inhibitory effect of bradykinin on forskolin-induced cAMP accumulation. These results indicate that large increases in cGMP may regulate cAMP via cGMP-PDE whereas the small increase induced by bradykinin is insufficient and that cGMP is not involved in the inhibitory action of bradykinin on cAMP levels in D384 cells.
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PMID:Bradykinin inhibition of cyclic AMP accumulation in D384 astrocytoma cells. Evidence against a role of cyclic GMP. 128 20

1. Male, homozygous Brattleboro (i.e. vasopressin-deficient) rats were chronically instrumented with pulsed Doppler flow probes and intravascular catheters, and were studied 5 h after a subcutaneous injection of an hyperoncotic solution of polyethylene glycol to render them hypovolaemic, and hence dependent on the renin-angiotensin system for maintenance of haemodynamic status. Pilot experiments showed that, in this model, primed infusion of perindoprilat (0.05 mg kg-1 bolus, 0.05 mg kg-1 h-1 infusion) or captopril (0.2 mg kg-1 bolus, 0.2 mg kg-1 h-1 infusion) just abolished the pressor effect of angiotensin I (120 pmol), and had similar initial hypotensive and renal hyperaemic vasodilator effects. 2. Perindoprilat had more sustained hypotensive, and mesenteric and hindquarters vasodilator effects than captopril in the presence of saline. In the presence of NG-nitro-L-arginine methyl ester (L-NAME 3 mg kg-1 h-1), the renal vasodilator effects of perindoprilat were unchanged, whereas the other haemodynamic effects of perindoprilat and captopril were reduced. Hence, in the presence of L-NAME, all haemodynamic effects of perindoprilat were greater than those of captopril. 3. The renal hyperaemic vasodilator effects of acetylcholine were abolished by L-NAME and by perindoprilat, and were markedly reduced by captopril. However, since perindoprilat and captopril caused such marked renal hyperaemic vasodilatation themselves, it is feasible this change in baseline status contributed to their effects. It is unlikely this could be a full explanation of the results, because the haemodynamic effects of lemakalim were unchanged under any experimental conditions. 4. Bradykinin alone, or in the presence of saline, caused mesenteric hyperaemic vasodilatation whereas, in the presence of perindoprilat or captopril, bradykinin caused marked renal and mesenteric vasoconstrictions. However, in the additional presence of L-NAME, the mesenteric vasoconstriction was reduced, yet the hypotensive effect of bradykinin was augmented. One possible explanation of these observations is that, in the presence of L-NAME and either perindoprilat or captopril, bradykinin caused marked coronary vasoconstriction, leading to a reduction in cardiac output. 5. Neither perindoprilat nor captopril impaired the pressor, or renal, mesenteric, or hindquarters vasoconstrictor effects of L-NAME. Indeed, in their presence, the effects of L-NAME were generally enhanced, consistent with perindoprilat and captopril causing activation of nitric oxide-dependent mechanisms that were subsequently inhibited by L-NAME.
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PMID:Involvement of nitric oxide in the regional haemodynamic effects of perindoprilat and captopril in hypovolaemic Brattleboro rats. 146 39

Bradykinin (BK) and its analogues induce a typical biphasic response (relaxation followed by contraction) in the isolated rat duodenum. We studied the role of B1 and B2 BK receptors and nitric oxide (NO) in relaxation and contraction of the isolated rat duodenum. Both effects are concentration-dependent: BK has shown an EC50 (contraction) of 3.8 +/- 1.9 x 10(-7) M and an IC50 (relaxation) of 3.0 +/- 0.7 x 10(-9). Similar results were obtained with the selective B2 receptor agonists [Hyp3,Tyr(Me)8]-BK and [Phe8 psi (CH2-NH)Arg9]-BK, showing an EC50 of 9.6 +/- 1.9 x 10(-7) M and 5.6 +/- 2.9 x 10(-7) M and an IC50 of 3.5 +/- 0.6 x 10(-10) M and 6.8 +/- 1.7 x 10(-10) M, respectively. Furthermore, the effects induced by these three agonists were not altered when tissues were treated with 42.1 microM Mergetpa, a carboxypeptidase N inhibitor. While the relaxant and contractile effects elicited by BK were significantly inhibited in the presence of Hoe 140 (0.7 microM), a selective B2 receptor antagonist, those induced by the selective B1 receptor agonist desArg9-BK were not. Furthermore, [Leu8]-desArg9-BK (2.6 microM), which is both a pure and selective B1 receptor antagonist, acted as an agonist on the rat duodenum, inducing a biphasic relaxant and contractile effect. These relaxant and contractile effects were not altered by drugs that inhibit or stimulate NO production, such as L-NAME (200 microM), a combination of L-NAME (200 microM) and indomethacin (2.5 microM), L-arginine (1 mM), or superoxide dismutase (20 U/ml). However, the contractile effect was significantly reduced when tissues were preincubated with methylene blue (100 microM), which inhibits activation of guanylate cyclase. We conclude that 1) BK and its analogues selectively activate a B2 receptor, producing a biphasic effect (relaxation and contraction); 2) DesArg9-BK may either acts via a different receptor which might be another B1 receptor subtype or a typical B1 receptor where [Leu8]-desArg9-BK acts as a partial agonist; and 3) neither NO nor the prostaglandin pathway mediates BK-induced relaxation in the isolated rat duodenum.
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PMID:Role of B1 and B2 receptors and of nitric oxide in bradykinin-induced relaxation and contraction of isolated rat duodenum. 752 22

Nitric oxide (NO) may play a part in pulmonary vascular regulation and bronchomotor control and has been detected in exhaled air. We report the release of NO from airway epithelial cells and its regulation by cyclic adenosine monophosphate (cAMP). To directly measure NO release, a highly specific amperometric sensor for NO made of Pt/Ir alloy coated with a three-layered membrane consisting of KCI, NO-selective resin, and normal silicon resin was developed. Immersion of this sensor in the medium containing canine cultured tracheal epithelium detected baseline levels of NO at 9.6 +/- 1.6 nM (mean +/- SE), which was reduced by NG-nitro-L-arginine methylester (L-NAME) but not by D-NAME. This inhibition was reversed by L-arginine. Addition of isoproterenol, 3-isobutyl-1-methylxanthine, and forskolin caused a rapid increase in NO, an effect that was not altered by Ca(2+)-free medium in the presence of the intracellular Ca2+ chelator BAPTA-AM and the calmodulin antagonist W-7. Bradykinin, ionomycin, and ATP were without effect on NO release. The forskolin-induced NO release was accompanied by intracellular accumulation of cAMP and Ca2+. In contrast, bradykinin increased intracellular Ca2+ but not cAMP levels. Cytochemistry of cultured tracheal epithelium showed a positive staining with NADPH diaphorase activity. These results suggest that airway epithelial cells spontaneously release NO and that the release may be stimulated specifically through cAMP-dependent mechanism.
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PMID:Cyclic adenosine monophosphate-mediated release of nitric oxide from canine cultured tracheal epithelium. 755 90

1. In the present work, we have studied the microvascular reactivity of the arterial and venous mesenteric beds of the guinea-pig to bradykinin, neurokinins and other agents. 2. The vasoactive properties of three selective agonists for neurokinin receptors, namely [Sar9, Met (O2)11]SP (NK1), [beta-Ala8]NKA(4-10) (NK2) and [MePhe7]NKB (NK3), were evaluated on precontracted arterial and venous mesenteric vasculatures of the guinea-pig. The NK1-selective agonist, [Sar9,Met(O2)11]SP (1 to 1000 pmol), induced an endothelium-dependent and N omega-nitro-L-arginine methyl ester (L-NAME)-sensitive relaxation of the arterial vasculature precontracted with methoxamine, whereas the NK2 and NK3-selective agonists were virtually inactive at high doses (1000 pmol). 3. The three selective neurokinin receptor agonists were inactive in the non-precontracted arterial and venous mesenteric vasculatures as well as in the precontracted venous mesenteric vasculature. 4. Bradykinin (0.1 to 100 pmol) induced a marked dose- and endothelium-dependent vasodilatation of the precontracted arterial and venous vasculatures. ED50 values were 5.5 pmol on the arterial side and 1.9 pmol on the venous side. In contrast, desArg9-bradykinin was inactive at doses up to 1000 pmol. Furthermore, on the arterial and venous sides, a higher dose of bradykinin (1000 pmol), induced a biphasic effect, a transient constriction followed by a marked and sustained vasodilatation. The vasodilator effects of bradykinin were abolished by Hoe 140 (0.1 microM) and CHAPS, markedly reduced by L-NAME and were unaffected by [Leu8]desArg9-bradykinin (0.1 microM) on both sides of the mesenteric vasculature. Hoe 140 also abolished the arterial vasoconstrictions induced by high doses of bradykinin. 5. Noradrenaline, angiotensin II and endothelin-1 produced contractions on both sides of the mesenteric circulation, while acetylcholine (arterial side) and sodium nitroprusside (arterial and venous sides) caused vasodilatation.6. Our study supports the view that NK1 receptors responsible for vasodilatation are present solely in the endothelium of the arterial mesenteric vasculature of the guinea-pig. On the other hand, bradykinin(0.1 to 100 pmol) exerts predominantly vasodilator effects on both sides of the mesenteric vasculature via selective activation of B2 receptors located on the endothelium. The same receptor type located on the smooth muscle appears to be responsible for the arterial and venous constriction with high doses of bradykinin.
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PMID:Characterization of receptors for kinins and neurokinins in the arterial and venous mesenteric vasculatures of the guinea-pig. 758 63

The effect of bradykinin on nitric oxide generation and eicosanoid production in the early stage of an experimental model of acute necrotizing pancreatitis induced by sodium taurocholate has been evaluated. We have compared the effect of administering a long-acting bradykinin antagonist, HOE 140, and an inhibitor of nitric oxide synthase, NG-nitro-L-arginine methyl esther L-NAME) on pancreatic prostanoid synthesis. Plasma lipase levels were increased after acute pancreatitis induction, and reduced after HOE 140 or L-NAME administration. Nitric oxide production and thromboxane B2 levels were increased after pancreatitis induction and the increases were reduced by L-NAME or HOE 140 administration. In contrast, increased prostacyclin production, reflected as 6-keto-PGF1 alpha levels, was not modified by L-NAME or HOE 140. Bradykinin seems to be involved in nitric oxide and thromboxane synthesis during the initial phases of acute necrohemorrhagic pancreatitis.
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PMID:A bradykinin antagonist inhibited nitric oxide generation and thromboxane biosynthesis in acute pancreatitis. 765 83

Endothelium-derived relaxing factor-nitric oxide (EDRF-NO) has been studied in isolated, pulmonary resistance vessels from term fetal lambs at a fetal (21 +/- 0.2 mmHg) and neonatal (69 +/- 0.4 mmHg) PO2. Bradykinin dose dependently (0.1-100 nM) relaxed arteries and veins that had been precontracted with a thromboxane A2 analogue. Their response did not differ at low PO2, whereas the response of the arteries was greater at high PO2. Sodium nitroprusside was almost as potent as bradykinin on the arteries, but its action did not vary with PO2. Acetylcholine also relaxed the arteries at higher concentrations (0.1-100 microM). N omega-mono-methyl-L-arginine (L-NMMA) and N omega-nitro-L-arginine methyl ester (L-NAME) (both at 100 microM) weakly contracted arteries at low PO2. The contraction to L-NAME, but not L-NMMA, increased with the PO2. In the arteries, L-NAME had no effect on bradykinin relaxation at low PO2, whereas it was an inhibitor at high PO2. Conversely, L-NMMA slightly inhibited bradykinin relaxation regardless of PO2. In the veins, L-NAME transiently increased basal tone and inhibited bradykinin relaxation at either PO2. Indomethacin (2.8 microM) had no effect on arteries at low PO2, whereas it was a constrictor at high PO2. No indomethacin constriction occurred in the veins. We conclude that fetal pulmonary resistance vessels possess an EDRF-NO relaxing mechanism that is stimulated by bradykinin. In the arteries, this mechanism is more effective at high PO2.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:EDRF in pulmonary resistance vessels from fetal lamb: stimulation by oxygen and bradykinin. 816 Aug 41

Bradykinin-induced relaxation of precontracted, porcine coronary artery (PCA) rings is mediated by distinctly different endothelium-derived relaxing factors depending on the contractile agent used. Thus when contracted with KCl, bradykinin-induced relaxation of PCA rings is mediated solely by nitric oxide (NO), whereas when contracted with the thromboxane mimetic U46619, a small component of the relaxation is attributable to NO and a large component is attributable to a non-NO mechanism that is independent of cyclooxygenase activity. We hypothesized that the non-NO component was mediated by arachidonic acid (AA) or by a non-cyclooxygenase product of AA metabolism. Bradykinin-induced relaxations of PCA rings precontracted with U46619 in the presence of indomethacin (10 mumol/L) were moderately attenuated by the NO synthase inhibitor N omega-nitro-L-arginine methyl ester (L-NAME, 100 mumol/L), whereas when precontracted with KCl, L-NAME abolished the relaxations. AA produced endothelium-dependent relaxations of rings precontracted with U46619 that were unaffected by L-NAME, whereas AA did not relax rings precontracted with KCl. In rings precontracted with U46619, in the presence of L-NAME and indomethacin the phospholipase inhibitors quinacrine (50 mumol/L) and 4-bromophenacyl bromide (10 mumol/L) attenuated bradykinin- but not AA-induced relaxations. Inhibitors of both lipoxygenase (BW 755c [100 mumol/L] and nafazatrom [20 mumol/L]) and cytochrome P-450 (proadifen [10 mumol/L] and clotrimazole [10 mumol/L]) pathways did not eliminate bradykinin- or AA-induced relaxations, although clotrimazole partially attenuated AA-induced relaxations. These findings suggest that bradykinin-induced relaxation of PCA rings is mediated by AA through a mechanism that is not dependent on cyclooxygenase, lipoxygenase, or cytochrome P-450 pathways.
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PMID:Relaxation of porcine coronary artery to bradykinin. Role of arachidonic acid. 820 38

In the perfused rat mesentery, when adrenergic nerves were blocked with guanethidine and vascular smooth muscle tone was increased with methoxamine, transmural field stimulation caused a dilator response. Bradykinin significantly suppressed vasodilator responses to a transmural field stimulation in a concentration-dependent manner. After pretreatment with saponin to damage endothelial cells, bradykinin still suppressed vasodilator responses to transmural field stimulation. The effect of bradykinin was unaltered by indomethacin. N omega-Nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthesis, abolished the inhibition of vasodilator responses to transmural field stimulation elicited by bradykinin. However, in the presence of L-arginine and L-NAME the inhibitory effect of bradykinin reappeared. Furthermore, methylene blue itself caused potentiation of vasodilator responses to transmural field stimulation and reversed the effect of bradykinin. These findings suggest that bradykinin can produce an inhibitory modulation of the actions of sensory nerves in the perfused rat mesentery and that the effect of bradykinin may be mediated by nitric oxide released from non-adrenergic, non-cholinergic nerves.
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PMID:The regulatory effect of bradykinin on the actions of sensory nerves in the perfused rat mesentery is mediated by nitric oxide. 822 22

Bradykinin, applied locally to the airways, is a weak bronchoconstrictor agent in guinea pigs in vivo and it may cause constriction or dilatation of guinea pig airways smooth muscle in vitro. We examined the motor effect of bradykinin perfused through the lumen of isolated guinea pig tracheal tubes with or without nitric oxide (NO) synthase inhibitors. In the presence of NG-nitro-D-arginine methyl ester (D-NAME) or NG-monomethyl-D-arginine (D-NMMA) intraluminal bradykinin caused a moderate concentration-dependent relaxation. In contrast, in the presence of NG-nitro-L-arginine methyl ester (L-NAME) or NG-monomethyl-L-arginine (L-NMMA) tracheas developed a sustained increase in tone, and bradykinin caused a marked, concentration-dependent contraction, both effects being reversible by pretreatment with L-arginine, but not with D-arginine. The ability of bradykinin to relax (in the presence of D-NAME) or contract (in the presence of L-NAME) guinea pig tracheal tubes was not affected by indomethacin. Bradykinin contracted epithelium-denuded tracheas in the presence of either L-NAME or D-NAME. Both contraction and relaxation by bradykinin were blocked by the kinin B2 receptor antagonist, HOE 140. Baseline production of guanosine 3',5'-cyclic monophosphate (cyclic GMP) in strips of guinea pig trachealis in vitro was markedly reduced by L-NAME, but not by D-NAME. Bradykinin increased baseline cyclic GMP concentration. These results indicate that bradykinin releases NO or a NO-related molecule, which, possibly by increasing cyclic GMP concentrations, mediates relaxation and opposes contraction induced by bradykinin itself, and further, that bradykinin releases NO from the tracheal epithelium.
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PMID:Evidence that epithelium-derived relaxing factor released by bradykinin in the guinea pig trachea is nitric oxide. 863 May 73


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