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)

A congenitally dysfunctional form of prothrombin, prothrombin Quick, was isolated from the plasma of an individual with less than 2% of normal prothrombin activity. Following activation of prothrombin Quick, two dysfunctional thrombins, thrombin Quick I and thrombin Quick II, were isolated. Functional characterization of thrombin Quick I indicated an increase in KM and a decrease in kcat, relative to thrombin, for release of fibrinopeptide A. Comparison of kcat/KM for thrombin Quick I to the value obtained for thrombin yielded a relative catalytic efficiency of 0.012 for thrombin Quick I [Henriksen, R. A., & Owen, W. G. (1987) J. Biol. Chem. 262, 4664-4669]. Lysyl endopeptidase digestor of reduced and S-carboxymethylated thrombin and thrombin Quick I has resulted in the identification of an altered peptide in this dysthrombin. Edman degradation of the isolated peptide has shown that the altered residue in this protein is Arg-382 which is replaced by Cys. This could result from a point mutation in the Arg codon, CGC, to yield TGC. Together, these results indicate that Arg-382 is a critical residue in determining the specificity of thrombin toward fibrinogen. Similar relative activities for thrombin Quick I in stimulating platelet aggregation, in the release of prostacyclin from human umbilical vein endothelium, and in the release of fibrinopeptide A suggest that these activities of thrombin share the same specificity determinants.
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PMID:Identification of the primary structural defect in the dysthrombin thrombin Quick I: substitution of cysteine for arginine-382. 324 19

1. The blood pressure-lowering and cardioprotective actions of angiotensin converting enzyme (ACE) inhibitors are thought to be based primarily on a reduction in vascular angiotensin II (Ang-II) formation. However, since ACE also degrades the potent endothelium-dependent vasodilator bradykinin, it has been proposed that the local accumulation of this peptide represents an additional mechanism by which ACE inhibitors exert their cardiovascular effects. 2. Incubation of endothelial cells with ACE inhibitors indeed causes an enhanced formation of nitric oxide (NO) and prostacyclin (PGI2) which can be completely blocked by the B2-kinin receptor antagonist Hoe 140, suggesting that the vascular endothelium is capable of generating vasoactive kinins from an endogenous source. 3. Moreover, ACE inhibitors not only prevent the breakdown of bradykinin but, by virtue of an as yet unidentified mechanism, also enhance the potency of bradykinin at the receptor level and reverse the desensitization of the B2-kinin receptor following continuous exposure to bradykinin. Both of these effects may enhance or sustain the bradykinin-induced formation of NO and PGI2 by the endothelium. 4. Furthermore, ACE inhibition leads to the accumulation of Ang-I which can be metabolised to Ang-(1-7) by another endothelial enzyme, neutral endopeptidase 24.11. By activating an as yet unidentified angiotensin receptor, Ang-(1-7), but not other known angiotensin peptides, stimulates endothelial NO release in porcine coronary arteries as well as in the isolated perfused rat heart. This effect is, albeit to a different degree, dependent on the release of vasoactive kinins from the endothelium. The shift in Ang-I metabolism towards an enhanced formation of Ang-(1-7) in the presence of an ACE inhibitor may thus contribute to the hypotensive action of this class of compounds as well.
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PMID:Mechanisms involved in the angiotensin II-independent hypotensive action of ACE inhibitors. 774 81

The beneficial cardiovascular effects of ACE inhibitors are thought to be based primarily on a reduction in vascular angiotensin II formation. However, since ACE also degrades the potent endothelium-dependent vasodilator bradykinin, it has been proposed that the local accumulation of this peptide in the vascular wall represents an additional mechanism by which ACE inhibitors exert their cardiovascular effects. In this context it has been demonstrated that incubation of cultured endothelial cells with ACE inhibitors leads to an enhanced formation of nitric oxide (NO) and prostacyclin (PGI2). This effect is believed to be the consequence of an accumulation of endothelium-derived bradykinin in the vicinity of the endothelial cells. Moreover, by virtue of an as yet unidentified mechanism, ACE inhibitors may also enhance the potency of bradykinin at the receptor level and/or activate the B2-kinin receptor following pre-exposure to bradykinin. Both of these effects may enhance or sustain the bradykinin-induced formation of NO and PGI2 by the endothelium. ACE inhibition also leads to the accumulation of angiotensin I which can be metabolized to angiotensin-(1-7) by another endothelial enzyme, the neutral endopeptidase 24.11. Activating an as yet unidentified receptor, angiotensin-(1-7) (but not other known angiotensin peptides) stimulates endothelial NO release in coronary arteries from different species as well as in the isolated perfused rat heart. This effect also seems to involve the release of vasoactive kinins from the endothelium. The shift in angiotensin I metabolism towards an enhanced formation of angiotensin-(1-7) in the presence of an ACE inhibitor may thus also contribute to the hypotensive action of this class of compounds.
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PMID:[Endothelial mechanisms in vasomotor effects of ACE inhibitors]. 785 74

Bradykinin (BK) induces bronchoconstriction in asthmatic but not in normal individuals. Studies in vivo in the human suggest that BK causes cholinergic nerve activation, release of prostanoids, and local axon reflexes with release of tachykinins in the airways. To determine the mechanisms of BK-induced airway narrowing, we investigated the effects of epithelium removal, inhibition of the enzymes neutral endopeptidase (NEP) and cyclooxygenase, and blockade of neural conductance with tetrodotoxin (TTX) on BK-induced responses of human isolated peripheral airways. Responses to BK were recorded from airways with spontaneous intrinsic tone and from airways precontracted with methacholine. Furthermore, we measured the BK-induced release of the prostanoids PGE2, PGI2, and TXA2 from airways with and without epithelium in the absence and presence of indomethacin by radioimmunoassay. Finally, we examined the effect of the bradykinin beta 2 receptor antagonist Hoe 140 and the thromboxane prostanoid (TP) receptor blocking drug GR32191 on BK-induced responses. BK contracted intact and epithelium-denuded airways with spontaneous intrinsic tone, whereas precontracted airways either relaxed or contracted to BK. Removal of the epithelium increased the sensitivity to BK sevenfold without changing the direction of the response. The NEP inhibitor phosphoramidon tended to increase the sensitivity to BK (NS) and did not change the direction of the response. Both contractile and relaxation responses to BK and the release of the prostanoids PGE2, PGI2, and TXA2 by the airway tissues were largely inhibited by indomethacin, whereas TTX had no effect. PGE2, PGI2, and TXA2 were released by both intact and epithelium-denuded airways.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Bradykinin-induced contraction of human peripheral airways mediated by both bradykinin beta 2 and thromboxane prostanoid receptors. 773 35

Endothelin-1 (ET-1) is the predominant endothelin isopeptide generated by the vascular wall and therefore appears to be the most important peptide involved in regulation of cardiovascular events. Many pathologic conditions are associated with elevations of ET-1 in the blood vessel wall. Because these conditions are often cytokine driven, we examined the effects of a mixture of cytokines on ET-1 production in human vascular smooth muscle cells (VSMCs) derived from internal mammary artery and saphenous vein (SV). Incubation of IMA and SV VSMCs with tumor necrosis factor-alpha (10 ng/ml) and interferon-gamma (1000 U/ml) in combination for up to 48 h markedly elevated the expression of mRNA for prepro-ET-1 and the release of ET-1 into the culture medium. This cytokine-stimulated release of ET-1 was inhibited by a series of dual endothelin-converting enzyme (ECE)/neutral endopeptidase inhibitors, phosphoramidon, CGS 26303, and CGS 26393, with an accompanying increase in big ET-1 release but with no effect on expression of mRNA for prepro-ET-1. These same compounds were 10 times more potent at inhibiting the conversion of exogenously applied big ET-1 to ET-1. ECE-1b/c mRNA is present in SV VSMCs, however no ECE-1a is present in these cells. Thus VSMCs most probably contain, like endothelial cells, an intracellular ECE responsible for the endogenous synthesis of ET-1. Under the influence of pro-inflammatory mediators the vascular smooth muscle can therefore become an important site of ET-1 production, as has already been established for the dilator mediators nitric oxide, prostaglandin I2, and prostaglandin E2.
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PMID:Endothelin-1 is induced by cytokines in human vascular smooth muscle cells: evidence for intracellular endothelin-converting enzyme. 1022 May 69

Animal studies have demonstrated that CNP causes endothelium-independent vasodilation, which is limited by neutral endopeptidase (NEP) activity. However, the vasodilating mechanism of CNP in humans is still unknown. Therefore, we investigated the vasodilator actions of CNP in human forearm resistance vessels before and after inhibition of nitric oxide (NO) and then prostacyclin production and after inhibition of Ca(2+)-dependent potassium channel activation and NEP activity. Three separate studies were performed. In each study, forearm blood flow was recorded by venous occlusion plethysmography in 8 healthy nonsmoking subjects. Brachial artery infusion of CNP (70, 140, 280, and 560 ng per 100 mL forearm volume per minute) caused significant forearm vasodilation in all studies (forearm blood flow from 3.94 to 8.50 mL per 100 mL forearm volume per minute). Inhibition of the endogenous generation of NO by L-N(G)-monomethyl arginine (by use of the NO-clamp technique) did not block the maximal vasodilating effects of CNP (forearm blood flow from 3.69 to 6.93). In addition, when the cyclooxygenase system was inhibited by 600 mg of acetylsalicylic acid (aspirin) administered orally 30 minutes before start of measurements, the rise in forearm blood flow remained intact (forearm blood flow from 3.31 to 8.27 mL per 100 mL forearm volume per minute). However, inhibition of Ca(2+)-dependent potassium channels with tetraethylammonium chloride (0.1 mg per 100 mL forearm volume per minute) significantly attenuated vasodilation caused by CNP (forearm blood flow from 2.28 to 3.06 mL per 100 mL forearm volume per minute), which suggests that CNP opens vascular potassium channels. Vasodilation to all doses of CNP was significantly increased when activity of NEP was blocked with thiorphan (30 nmol/min), which suggests that NEP activity limits vasodilation of CNP. CNP is a dilator of human resistance vessels that mediates its effects through hyperpolarization of the vessel wall independent of the NO and prostaglandin system. Inhibition of local NEP activity increases CNP bioavailability. This may be of relevance to cardiovascular disease, given that vascular tone is well balanced between NO and an endothelium-derived hyperpolarizing factor, which suggests that in pathological situations, impaired NO activity can be compensated for by enhanced endothelium-derived hyperpolarizing factor release to maintain vascular homeostasis.
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PMID:C-type natriuretic peptide-induced vasodilation is dependent on hyperpolarization in human forearm resistance vessels. 1130 21

Endothelial cells are strategically located between the circulating blood and the vascular smooth muscle. These cells are involved in regulating the functions of vascular smooth muscle and circulating blood cells by releasing numerous vasoactive substances. Important endothelium-delivered vasodilators include prostacyclin, bradykinin, nitric oxide and endothelium-derived hyperpolarising factor. Nitric oxide is also important in inhibiting cellular growth and migration, and acts in concert with prostacyclin to exert potent antiatherogenic and thromboresistant effects by preventing platelet aggregation and cell adhesion. These effects are counterbalanced by vasoconstrictors such as angiotensin II and endothelin-1, which exert prothrombotic inflammatory and growth-promoting properties. Cardiovascular risk factors give rise to cardiovascular disease by causing endothelial dysfunction. Consequently, modern therapeutic strategies focus on preserving or restoring endothelial integrity. Calcium antagonists counteract the effects of angiotensin II and endothelin-1 at the level of vascular smooth muscle by reducing Ca2+ inflow and facilitating the vasodilator effects of nitric oxide. In addition to their role in inhibiting the renin-angiotensin system, angiotensin-converting enzyme (ACE) inhibitors raise the activity of bradykinin, thereby leading to an increase in nitric oxide release. In patients with cardiovascular risk, chronic ACE inhibition improves endothelial function. This may explain why patients treated with ACE inhibitors experience a greater cardiovascular benefit than is attributable to the decrease in blood pressure. Recently developed neutral endopeptidase inhibitors, particularly in combination with ACE inhibitors, induce potent antihypertensive effects. These effects are due partly to decreased breakdown of natriuretic peptides but also as a result of the inhibition of endothelin-1 production. Experimental studies suggest that endothelin-1 antagonists are effective in lowering blood pressure in hypertensives, and also exert beneficial clinical and haemodynamic effects in patients with congestive heart failure. Further clinical studies are under way to determine whether restoration of endothelial function has clinical benefits for patients with cardiovascular disease.
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PMID:Vascular protection: current possibilities and future perspectives. 1171 56

1. Endothelin-1(1-31) (ET-1(1-31); 0.25 to 4 nmol kg(-1); i.v.) induced, in the guinea-pig, graded increases in MAP and an indomethacin-sensitive enhancement of pulmonary insufflation pressure (PIP). At all doses, ET-1(1-31) induced a monophasic pressor response, except at 4 nmol kg(-1), which caused a rapid and transient response (first phase: over first 10 min after injection) followed by a more slowly-developing and sustained (second phase: between 10 and 45 min after injection) increase in MAP. ET-1(1-31) was 4 to 10 fold less potent than ET-1 on PIP responses. 2. Phosphoramidon (5 and 10 mg kg(-1)) reduced both pressor and PIP effects of ET-1(1-31). Thiorphan (0.25 and 2.5 mg kg(-1)) did not affect the pressor responses to ET-1(1-31) although its PIP effects were markedly reduced by the NEP inhibitor. A selective endothelin-converting enzyme (ECE) inhibitor, CGS 35066 (1 mg kg(-1)), significantly reduced the second phase pressor response and increase in PIP triggered by ET-1(1-31). 3. The second (but not the first) pressor phase of ET-1(1-31) (4 nmol kg(-1)) was markedly reduced by BQ-123 (selective ET(A) antagonist), whereas the increase of PIP was significantly reduced by BQ-788 (selective ET(B) antagonist). Co-administration of BQ-123 plus BQ-788 abolished ET-1(1-31)-induced increase in PIP, but blockade of the second pressor phase afforded by BQ-123 was now reversed. 4. In guinea-pig isolated perfused lungs, ET-1(1-31) (50 nM) induced the release of prostacyclin and thromboxane A(2), which was inhibited by BQ-788 (5 nM) or thiorphan (25 microM), but not BQ-123 (1 microM). 5. These results suggest that ET-1(1-31) enhances MAP. Its sustained, but not transient, pressor effects are mediated via ET(A) receptor activation. Furthermore, ET-1(1-31) increases airway resistance in vivo and triggers prostacyclin and thromboxane A(2) release from perfused lungs predominantly via ET(B) receptor activation. ET-1(1-31) failed to display any selectivity of action towards either ET(A) or ET(B) receptors in these models. 6. We suggest that, in order to raise MAP, ET-1(1-31) requires conversion to ET-1, predominantly by ECE and to a lesser extent neutral endopeptidase 24.11, whereas the reverse holds true regarding its pharmacological effects in airways.
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PMID:Pressor and pulmonary responses to ET-1(1-31) in guinea-pigs. 1211 Jun 6

Maturation of big endothelin-1 (big ET-1) commonly produces the 21 amino acid vasoactive ET-1, which binds two ET receptors (ET(A) and ET(B)) to produce its effects. In the guinea pig, the systemic administration of ET-1 produces a bronchoconstrictor response that is mediated indirectly via the release of thromboxane A(2) through ET(B) receptor activation. A new potent metabolite of big ET-1, ET-1 (1-31), has been reported to act as an ET(A) receptor selective agonist. In this study we investigated the effects of ET-1 (1-31), compared with ET-1, on the release of eicosanoids in the isolated and perfused guinea pig lung. We also clarified the implication of ET receptors in these effects using selective ET(A) or ET(B) receptor antagonists, BQ-123 and BQ-788 respectively. Finally, using the neutral endopeptidase 24.11 (NEP 24.11) inhibitor, thiorphan, we determined the involvement of this enzyme on ET-1 (1-31) effects. Infusion of ET-1 (1-31) (50 nM) stimulates a marked release of thromboxane A(2) and prostacyclin equivalent to that observed with a ten times lower concentration of ET-1 (5 nM). BQ-788 (5 nM and 10 nM), but not BQ-123 (1 microM), decreases the release of thromboxane A(2) and prostacyclin triggered by both agonists. Interestingly, thiorphan (25 microM) abolishes the eicosanoid-releasing properties of big ET-1 (100 nM) and ET-1 (1-31). This study demonstrates that ET-1 (1-31) is less potent than ET-1 in stimulating the release of eicosanoids through ET(B) receptor activation in the guinea pig perfused lung. Moreover, the inhibitory properties of thiorphan indicate the possible existence of a bioactive metabolite of ET-1 (1-31). We therefore suggest that NEP 24.11 in the pulmonary vasculature, is implicated in the cleavage of ET-1 (1-31) to produce ET-1 which will further act on both ET receptors.
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PMID:Endothelin-1 (1-31) induces a thiorphan-sensitive release of eicosanoids via ET(B) receptors in the guinea pig perfused lung. 1219 70