Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.11 (CD10)
 9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

All four components of the kallikrein-kinin system--kininogens, tissue kallikreins, kinins, and kininases--have been found in human male genital secretions. Kinins are continuously released from seminal plasma kininogens through limited proteolysis by kininogenases like tissue kallikrein from prostate and sperm acrosin. Kinins are the terminal effectors of the kallikrein-kinin system and increase sperm motility and sperm metabolism at nanomolar concentrations. Recent investigations indicate that these effects are possibly mediated by a specific sperm membrane integrated bradykinin receptor, subtype B2. The two major kininase that are present in seminal plasma are kininase II and neutral metallo-endopeptidase. Kininase II, which is identical with angiotensin-converting enzyme, is also involved in the renin-angiotensin system as it converts angiotensin I into angiotensin II and thus is the connecting enzyme of both systems. Apart from the observed effects of kinins on sperm motility, the kallikrein-kinin system is thought to be involved in the regulation of spermatogenic functions of the testis: in the rat, kallikrein activates Sertoli cell function, increases the relative number of spermatocytes and the [3H] thymidine incorporation of testicular tissue, enhances glucose-intake, and increases testicular blood flow. Clinical trials showed that systemic administration of kallikrein may be particularly useful for treatment of infertile men suffering from asthenozoospermia and/or oligozoospermia. During kallikrein therapy, the number of spermatozoa and both quantitative and qualitative sperm motility increased, and a significant improvement of the conception rate was achieved. An increased sperm number was also observed after application of the specific kininase II inhibitor captopril.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Possible effects of the kallikrein-kinin system on male reproductive functions. 131 46

To explore whether pathophysiological plasma levels of atrial natriuretic peptide (ANP) actually involve sodium excretion in spontaneously hypertensive rats (SHR), we examined the in vivo and ex vivo effects of ANP and an endopeptidase inhibitor, thiorphan, on urinary sodium excretion and the elimination rate of ANP. We found the following: 1) The basal plasma ANP level was higher in 16-week-old SHR than in Wistar-Kyoto (WKY) rats (109 +/- 10 [SEM] versus 63 +/- 4 pg/ml, p less than 0.001). Thiorphan (30 mg/kg i.v.) significantly increased plasma ANP by 60% in both SHR and WKY rats. However, increases in urinary sodium excretion (+290% versus +130%, p less than 0.05) and cyclic GMP (+160% versus +60%, p less than 0.05) were greater in SHR than in WKY rats. Urinary excretion of ANP was markedly increased by thiorphan, and its increase was greater in SHR than in WKY rats. 2) The thiorphan-induced natriuresis was substantially attenuated by antiserum for ANP but not by a bradykinin receptor antagonist. 3) Isolated SHR kidneys excreted 50% less sodium than WKY rat kidneys at perfusion pressures of 100 and 160 mm Hg (p less than 0.05). Urinary sodium excretion was increased at the perfusate ANP level of 100 pg/ml, a concentration similar to the SHR plasma ANP (+70% at 160 mm Hg). 4) After bolus administration of ANP to the isolated kidney, the ANP concentration of the recirculating perfusate decreased rapidly in a log-linear fashion.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of endogenous atrial natriuretic peptide in regulating sodium excretion in spontaneously hypertensive rats. Effects of neutral endopeptidase inhibition. 182 56

Experiments were performed on anesthetized rats to determine whether inhibition of endopeptidase 24.11 (EP) potentiates the biological activity of atrial natriuretic peptide, ANP-(99-126), and to examine the mechanisms that underlie this effect. Thiorphan (30 mg/kg iv), an inhibitor of EP, produced a modest increase in urinary sodium excretion when administered alone but did not affect urine flow, mean arterial pressure (MAP), or the endogenous level of plasma ANP. The infusion of ANP-(99-126) alone (67 ng.kg-1.min-1 iv) produced a modest natriuresis and decrease in MAP while increasing plasma ANP levels fivefold. When thiorphan (30 mg/kg iv) was administered during the ANP infusion, urine flow and urinary sodium excretion increased markedly but no further decrease in MAP or increase in plasma ANP levels was observed. This potentiation of the renal actions of ANP was not mediated by inhibition of angiotensin-converting enzyme, an increase in glomerular filtration rate, or an increase in renal blood flow but was completely abolished by a specific antagonist of the bradykinin receptor [( DArg0, Hyp3, Thi5, DPhe7, Thi8]bradykinin, 30 micrograms.kg-1.min-1 iv). These data suggest that inhibitors of EP can potentiate the renal activity of ANP by a mechanism which is independent of altered ANP catabolism and which may involve the accumulation of bradykinin, another substrate for EP, within the kidney.
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PMID:Interaction of ANP and bradykinin during endopeptidase 24.11 inhibition: renal effects. 214 18

The plasma extravasation evoked by instillation of 5% ovalbumin in the nasal mucosa of sensitized guinea-pigs was potentiated by the neutral endopeptidase inhibitor, phosphoramidon, and was reduced by the tachykinin NK1 receptor antagonist, CP-96,345. The bradykinin B2 receptor antagonist, HOE 140, also reduced the plasma extravasation evoked by the antigen. The combination of HOE 140 and CP-96,345 did not increase further the inhibition caused by HOE 140 alone. Plasma extravasation evoked by instillation of capsaicin was abolished by CP-96,345. HOE 140 blocked and CP-96,345 markedly reduced plasma extravasation caused by instillation of bradykinin. Plasma extravasation evoked by instillation of substance P was not affected by HOE 140. We conclude that antigen challenge causes plasma extravasation in the nasal mucosa of sensitized guinea-pigs, an effect that is due in part to the release of tachykinins from sensory nerve endings. Our evidence suggests that tachykinin release in response to antigen is provoked mainly by the release of kinins.
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PMID:Tachykinins and kinins in antigen-evoked plasma extravasation in guinea-pig nasal mucosa. 752 44

Cold air was delivered to anesthetized, artificially ventilated, pathogen-free F344 rats via a tracheal cannula. Inhalation of cold air increased Evans blue dye extravasation in the trachea in a time-dependent (1 to 10 min) manner. Plasma extravasation increased after 3 min exposure to cold air and reached a maximum after 10 min exposure. The neutral endopeptidase inhibitor, phosphoramidon (2.5 mg/kg, intravenously), increased by 84% the plasma extravasation induced by inhalation of cold air for 1 min. The plasma extravasation evoked by 5 min exposure to cold air was abolished by the NK1 tachykinin receptor antagonist, CP-99,994 (4 mg/kg, intravenously); was reduced 30% by the B2 bradykinin receptor antagonist, HOE140 (0.1 mumol/kg, intravenously); and was not affected by H1 (pyrilamine, 10 mg/kg, intraperitoneally) or H2 (cimetidine, 10 mg/kg, intraperitoneally) histamine receptor antagonists or the cyclooxygenase inhibitor indomethacin (5 mg/kg, intravenously). In rats infected with Sendai virus, plasma extravasation evoked by inhalation of cold air was greater than in pathogen-free rats. Pretreatment with CP-99,994 (4 mg/kg, intravenously) inhibited completely the plasma extravasation induced by cold air in virus-infected rats. These findings indicate that cold air increases plasma extravasation in the rat trachea by a neurogenic mechanism that involves the release of tachykinins from sensory nerves. Kinin release may also play a role in this neurogenic inflammatory response.
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PMID:Plasma extravasation in the rat trachea induced by cold air is mediated by tachykinin release from sensory nerves. 769 24

1. In the present study, we have investigated the role of kinins in allergen-induced bronchoconstriction. 2. Anaesthetized guinea-pigs were sensitized to ovalbumin, ventilated artificially, pretreated with atropine (1.4 mumol kg-1, i.v.) and total pulmonary resistance (RL) measured. In preliminary studies in the presence of the neutral endopeptidase inhibitor, phosphoramidon (4.5 mumol kg-1, i.v.), the bradykinin B2 receptor antagonist Hoe 140 (0.1 mumol kg-1, i.v.) completely abolished the increase in RL following aerosolized bradykinin (1 mM, 40 breaths), but had no effect on the increase in RL following aerosolized neurokinin A (NKA, 10 microM, 40 breaths). On the other hand, a combination of the NK1 (CP-96,345, 2 mumol kg-1, i.v.) and NK2 (SR 48968, 0.3 mumol kg-1, i.v.) tachykinin receptor antagonists abolished completely the increase in RL produced by NKA and partially inhibited the increase in RL produced by bradykinin. These results confirm previous studies that suggest that bradykinin induces the release of tachykinins from sensory nerves in guinea-pig airways. 3. Aerosolized ovalbumin (0.5%, 5 breaths) increased RL in sensitized guinea-pigs pretreated with atropine (1.4 mmol kg-1, i.v.), an effect that began within 2 min and reached a maximum within 5 min; RL remained above baseline at 20 min. Pretreatment with the bradykinin B2 receptor antagonist, Hoe 140, decreased the bronchoconstrictor effect of ovalbumin markedly at 10 to 20 min. In the presence of phosphoramidon (4.5 mumol kg-1, i.v.) the inhibition induced by Hoe 140 was apparent earlier and remained over the 20 min period of study. 4. Pretreatment with a combination of NK1 (CP-96,345) and NK2 (SR 48968) tachykinin receptor antagonists also markedly inhibited ovalbumin-induced bronchoconstriction; addition of the bradykinin B2 receptor antagonist to the NK1 and NK2 tachykinin receptor antagonists had no additional inhibitory effect on antigen-induced bronchoconstriction.5. These findings confirm that activation of sensory nerves to release tachykinins in guinea-pig airways contribute to antigen-induced bronchoconstriction, and provide evidence that tachykinin release is due to kinins generated during the allergic response.
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PMID:Role of kinins in anaphylactic-induced bronchoconstriction mediated by tachykinins in guinea-pigs. 783 2

Peptide mediators may play a role in the control of myocardial perfusion. We found immunohistochemical evidence of the peptide-degrading enzyme neutral endopeptidase (NEP) in cultured rat myocytes. Therefore, we examined the effect of an NEP inhibitor, phosphoramidon, on myocardial perfusion in rats after (1) stimulating sensory nerves with capsaicin and (2) inducing myocardial hypoperfusion with isoproterenol, with or without pretreatment with selective antagonists of the substance P (NK1) and bradykinin (B2) receptors. Three to five sequential determinations of myocardial blood flow were made in anesthetized rats by injecting 100,000 radionuclide-labeled microspheres suspended in 70% dextrose into the left ventricle. Phosphoramidon doubled coronary blood flow in response to a dose of capsaicin that was ineffective in the absence of the inhibitor. Isoproterenol (50 mg/kg IP) caused an immediate fall in blood pressure and coronary blood flow; after 20 minutes, flow had returned to normal but pressure was still subnormal. Administration of phosphoramidon reduced the recovery of blood pressure but greatly increased coronary blood flow. These changes were not altered by a substance P NK1 receptor blocker but were completely abolished by a selective bradykinin B2 receptor blocker. Our data indicate that (1) NEP is present in the rat myocardium, (2) sensory nerve-induced coronary vasodilation is markedly potentiated by NEP inhibition, (3) isoproterenol-induced myocardial hypoperfusion is prevented by NEP inhibition, and (4) this effect of NEP inhibition is due to reduced degradation of bradykinin.
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PMID:Neutral endopeptidase in the heart. Neutral endopeptidase inhibition prevents isoproterenol-induced myocardial hypoperfusion in rats by reducing bradykinin degradation. 792 22

We studied the effect of exogenous bradykinin on blood flow in the airway microcirculation of anesthetized F344 rats in vivo. We made three successive determinations of airway blood flow and cardiac output using a modification of the reference sample microsphere technique. Injection of bradykinin into the left ventricle increased airway blood flow in a dose-related manner. Pretreatment with the bradykinin B2 receptor antagonist, Hoe 140, completely abolished bradykinin-, but not histamine-induced vasodilation. A bradykinin B1 receptor agonist, [des-Arg9]bradykinin, did not affect airway blood flow. We also studied the effect of inhibitors of angiotensin-converting enzyme (captopril) and neutral endopeptidase (phosphoramidon) on bradykinin-induced vasodilation. Pretreatment with captopril, but not phosphoramidon, potentiated the bradykinin-induced vasodilation. However, the addition of phosphoramidon further potentiated the effect of captopril. We conclude that injection of bradykinin into the left ventricle produces a dose-related vasodilation in the airway microcirculation mediated via B2 receptors, an effect that is modulated primarily by angiotensin-converting enzyme and, to a lesser extent, by neutral endopeptidase.
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PMID:Airway vasodilation by bradykinin is mediated via B2 receptors and modulated by peptidase inhibitors. 814 11

To determine the presence of bradykinin receptors in skeletal muscle, we examined in both displacement and saturation studies the binding of [125I-Tyr8]bradykinin or [3H]bradykinin in three types of skeletal muscle preparations: membrane fractions from guinea pig hindlimb quadriceps, dog semimembranosus and semitendinosus muscles, and L8 rat skeletal muscle myoblasts. Scatchard analysis of [125I-Tyr8]bradykinin x bradykinin competition binding demonstrated specific bradykinin binding of 4.9 and 3.2 fmol/mg protein in dog and guinea pig skeletal muscle preparations, respectively. Unlabeled bradykinin specifically displaced [125I-Tyr8]bradykinin with IC50 values of 36.5 +/- 6 and 118.0 +/- 16.0 pmol/l from dog and guinea pig muscle membranes, respectively. The B2 bradykinin receptor antagonist HOE 140 and the B1 bradykinin receptor antagonist des-Arg9[Leu8]bradykinin displaced the binding of [3H]bradykinin from dog membranes with IC50 values of 0.38 and 217.3 nmol/l, respectively, suggesting that bradykinin binds to a B2-type receptor. In addition, unlabeled bradykinin competed with [3H]bradykinin for binding to dog skeletal muscle membrane preparations in a biphasic manner. To assess whether this represents multiple bradykinin receptor subtypes present in skeletal muscle homogenates or several affinity states of a single binding site, we examined bradykinin receptors on a pure skeletal muscle system, the L8 neonatal rat skeletal muscle myoblast cell line. These myoblasts also contain specific [3H]bradykinin-binding sites with a Bmax of 271 fmol/mg protein and a Kd of 0.83 nmol/l. Competitive agonist binding curves were biphasic (high-affinity IC50 = 3.9 pmol/l, low-affinity IC50 = 22.6 nmol/l) in the absence of guanosine 5'-O-(3-thio-trisphosphate) (GTP gamma S); they shifted to a model of one affinity (8.1 nmol/l) in the presence of GTP gamma S. Because the enzyme neutral endopeptidase 24.11 is an important kininase in skeletal muscle, we examined the effect of the neutral endopeptidase inhibitor phosphoramidon on the binding of bradykinin to dog skeletal muscle membranes. We found that phosphoramidon decreased the apparent Bmax from 7.3 to 5.8 fmol/mg protein. In addition, in this cell line we investigated the action of bradykinin on phosphoinositide hydrolysis. Inositol 1,4,5-trisphosphate (IP3) was measured with a radioreceptor assay. Bradykinin (0.1 nmol/l to 1 mumol/l) induced IP3 formation in a dose-dependent manner (EC50 = 1.42 nmol/l) from a basal level of 72.8 +/- 16 pmol/mg protein to 433 +/- 35.5 at the highest (1 mumol/l) concentration. We conclude that bradykinin B2 receptors are expressed in skeletal muscle. Phosphoinositide hydrolysis upon stimulation of this receptor is an indicator of intracellular signal transduction. Part of the bradykinin binding in skeletal muscle is due to interaction with the enzyme neutral endopeptidase.
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PMID:Bradykinin B2 receptors on skeletal muscle are coupled to inositol 1,4,5-trisphosphate formation. 852 97

The present study was undertaken to characterize the direct chronotropic effect of bradykinin in isolated spontaneously beating atria of the guinea pig. Bradykinin caused concentration-dependent increases in the beating rate of atria. In contrast, the active metabolite of bradykinin and the typical bradykinin B1 receptor agonist, Des-Arg9-bradykinin, had no effect on the beating rate of atria. Inhibition of converting enzyme or neutral endopeptidase by captopril or SQ-28603, respectively, did not affect beating rate but potentiated bradykinin-induced increase in beating rate. The potent bradykinin B2 receptor antagonist, HOE 140, antagonized bradykinin-induced chronotropic effect. In contrast, the bradykinin B1 receptor antagonist, Lys-[Leu8]Des-Arg9-bradykinin, had no effect. The increase in beating rate caused by bradykinin was not affected by blockade of beta 1-adrenoceptors, cyclooxygenase, or nitric oxide synthesis using atenolol, indomethacin and N omega-nitro-L-arginine, respectively. Unlike bradykinin, angiotensin I and angiotensin II caused very small or no change in beating rate in the presence or absence of captopril and SQ-28603. These results indicate that bradykinin causes a direct positive chronotropic effect which is mediated by activation of bradykinin B2 receptors independently of prostaglandins and beta 1-adrenoceptors.
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PMID:Bradykinin B2 receptor-mediated chronotropic effect of bradykinin in isolated guinea pig atria. 856 11


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