Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.15.1 (ACE)
 18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Since 1984 25 cases of enalapril induced angioedema have been reported to the Netherlands Center for Monitoring of Adverse Reactions to Drugs. Two patients with enalapril induced angioedema are described. The pathophysiological mechanism of this potentially life-threatening adverse effect is probably not a direct allergic response to the drug itself. Enalapril inhibits angiotensin converting enzyme, which not only metabolizes angiotensin I but also bradykinin and 'substance P'. Bradykinin and 'substance PH may then accumulate and cause angioedema in a direct or indirect way. It is of great importance that instances of oropharyngeal swelling are considered a possible result of an adverse reaction to ACE-inhibitors.
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PMID:[Angioedema caused by enalapril]. 200 23

Bradykinin (BK) in an asanguinous salt solution was perfused through intact rat lung. BK concentration varied from 0.0015 to 89 microM. Below 17 microM, the amount degraded was greater than or equal to 90% of the dose. The BK fragment distributions expressed as a percentage of the BK dose degraded were constant. The BK fragments formed and percentage yields were Pro-Pro (2-3) 49%, Arg-Pro-Pro-Gly-Phe (1-5) 32%, Pro-Pro-Gly-Phe-Ser-Pro (2-7) 6%, Arg-Pro-Pro-Gly-Phe-Ser-Pro (1-7) 6%, Arg-Pro-Pro (1-3) 3% and residual BK 4%. Above 17 microM, the amount of BK degraded was not proportional to the dose. Captopril and enalaprilat inhibited BK degradation, and their maximum inhibitions were about 50% and 30%, respectively. The percentage yield of the 1-5 fragment was greatly reduced by both inhibitors, but the percentage yields of the 2-3 and 1-8 fragments were moderately increased. It was concluded that (1) the intact rat lung itself has a very large capacity to degrade BK in the range of 2 mumoles/min/kg body weight; (2) two major and several minor enzyme pathways exist to degrade BK; (3) the relative contributions of these pathways to overall BK degradation remain essentially constant over a bradykinin concentration range from 0.0015 to 17 microM; (4) ACE/kininase-II catalyzed hydrolysis is one of the major pathways but is not the single major route for BK degradation; and (5) the other major BK degradation pathway involves enzymes cleaving the Arg1-Pro2 and Pro3-Gly4 bonds of BK.
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PMID:Kinin metabolism in the perfused ventilated rat lung. I: Bradykinin metabolism in a system modeling the normal, uninjured lung. 200 2

We studied the effects of platelet-activating factor (PAF) on the conversion of angiotensin I to angiotensin II in pulmonary artery endothelial cells. PAF had a novel effect on angiotensin I conversion. The apparent Vmax and Km for angiotensin converting enzyme (ACE) were 2.5 nmol/min per dish and 50 mumol/l, respectively. This activity was enhanced by the addition of PAF to cells. When PAF was added to pulmonary artery endothelial cells, the conversion of angiotensin I to angiotensin II was enhanced about twofold at 10(-6) mol/l PAF. Maximal stimulation was achieved at 10(-5) mol/l PAF. This stimulatory effect was suppressed by ACE inhibitors such as enalapril and PAF antagonist CV3988. When cells were incubated with 10(-6) mol/l PAF, the conversion of angiotensin I to angiotensin II stimulated with PAF was suppressed by CV3988. Enalapril (10(-6) mol/l) completely inhibited the conversion of angiotensin I to angiotensin II in the presence of PAF. Bradykinin also suppressed ACE activity, but phosphatidylcholine and lysophosphatidylcholine did not affect its activity. These results suggest that PAF may have an important role in regulating vascular tone by modulating angiotensin conversion.
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PMID:Platelet-activating factor stimulates angiotensin converting enzyme activity. 216 81

Alpha-adrenergic, cholinergic, and serotonergic receptor-mediated contractile responses have been well characterized in the genitourinary tissues of several mammalian species. The present study characterizes the in vitro contractile responsiveness of canine bladder and prostate to the peptides, bradykinin, angiotensin I, and angiotensin II. All preparations contracted to 0.15 M KCl. Bradykinin elicited contractile responses in both prostate (10(-10) to 10(-7) M) and bladder (10(-10) to 10(-6) M). In both tissues, angiotensin II produced minimal responses and angiotensin I failed to elicit contractions. The potent angiotensin converting enzyme (ACE) inhibitor, enalaprilic acid [MK-422] (10(-6) M) increased the contractile response to the prostate to bradykinin two-fold while having no effect on bradykinin-induced contractions in the bladder. Enalaprilic acid did not affect the contractile responses of the two tissues to angiotensin I or angiotensin II. The canine urogenital tissue contractile responses to bradykinin, angiotensin I, and angiotensin II may have relevance to human physiology. Previous studies have demonstrated that human prostatic tissue, specifically benign prostatic hyperplasia (BPH), has the highest concentration of ACE activity of tissues evaluated. Bradykinin is a potent peptidergic contractile agent in canine bladder and prostate. The activity of enalaprilic acid to amplify the bradykinin-induced contractions in the canine prostate is consistent with high levels of ACE in the tissue. These data confirm the sensitivity of the canine prostate to bradykinin and report for the first time, the ability of bradykinin to induce contractions in the prostate. These studies support the possibility that bradykinin may be involved in mediating micturition under normal and pathological states such as infravesical obstruction secondary to BPH. Furthermore, the results from these investigations in canine urogenital tissues, if applicable to humans, suggest that urinary function be closely monitored in patients receiving ACE inhibitor therapy.
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PMID:Bradykinin-induced contractions of canine prostate and bladder: effect of angiotensin-converting enzyme inhibition. 216 84

1. Bradykinin (BK) instilled directly into the airway lumen caused bronchoconstriction in anaesthetized, mechanically ventilated guinea-pigs in the presence of propranolol (1 mg kg-1 i.v.). The geometric mean dose of BK required to produce 100% increase in airway opening pressure (PD100) was 22.9 nmol (95% c.i. 11.7-44.6 nmol). 2. The dose-response curve for the effect of instilled BK was significantly shifted to the left by the angiotensin converting enzyme (ACE) inhibitor, captopril (5 and 50 nmol instillation, PD100 = 3.0, 95% c.i. 0.98-8.9, and 2.0 nmol, 95% c.i. 0.65-6.2 nmol, respectively). 3. The neutral endopeptidase (NEP) inhibitor, phosphoramidon (5 and 50 nmol instillation) also shifted the dose-response curve for the effect of instilled BK; the PD100 values = 2.2 (95% c.i. 0.40-11.7) and 1.8 nmol (95% c.i. 0.87-3.5 nmol), respectively. 4. After pretreatment with captopril (50 nmol) and phosphoramidon (50 nmol) in combination, the dose-response curve for the effect of instilled BK (PD100 = 1.1 nmol, 95% c.i. 0.37-3.2 nmol) was similar to that obtained in the presence of each inhibitor used alone. 5. The kinase I inhibitor, DL-2-mercaptomethyl-3-guanidinoethylthiopropionic acid (50 nmol instillation) failed to alter the dose-response curve to instilled BK (PD100 = 14.6 nmol, 95% c.i. 6.7-32.0 nmol). 6. These data suggest that both ACE and NEP degrade BK in the airway lumen, but that kininase I is not involved.
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PMID:The effect of peptidase inhibitors on bradykinin-induced bronchoconstriction in guinea-pigs in vivo. 228 70

The relative contribution of plasma carboxypeptidase N (kininase I), angiotensin-converting enzyme (ACE) (kininase II), neutral endopeptidase 24.11 (enkephalinase A) and postproline cleaving enzyme to total kininase activity in rat plasma was determined by measuring bradykinin hydrolysis with and without various concentrations of inhibitors of these enzymes. We used DL-2-mercaptomethyl-3-guanidinoethyl-thiopropanoic acid to inhibit kininase I, enalaprilat for ACE, phosphoramidon for neutral endopeptidase 24.11 and N-benzyloxycarbonyl-Pro-prolinal for postproline cleaving enzyme. Bradykinin was added to rat plasma and incubated at 37 degrees C. Kininase activity was evaluated based on the decrease in bradykinin during incubation. Bradykinin was measured by radioimmunoassay, using an antibody that recognizes its carboxyl group. Of the total plasma kininase activity, carboxypeptidase N was responsible for 11.0 +/- 2.5% (N = 5; P less than .05) and ACE for 46.8 +/- 1.5% (N = 5; P less than .001), whereas the contribution of neutral endopeptidase 24.11 and postproline cleaving enzyme turned out to be negligible. Of the kininase activity in rat plasma, 42% could not be explained by any of these four enzymes. We concluded that ACE is responsible for most of the kininase activity in rat plasma; carboxypeptidase N contributes to a slight degree. The fact that 42% of total plasma kininase activity could not be explained by any of the enzymes tested suggests that there are still other kininases in rat plasma which remain to be discovered.
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PMID:Contributions of various rat plasma peptidases to kinin hydrolysis. 255 17

In our studies we investigated the vasodepressor effects of bradykinin in vivo in normotensive and hypertensive subjects. Bradykinin was injected intravenously and intraarterially (40-6050 pM/kg) respectively was infused intraarterially (40-6050 pM/kg/min). The investigations were performed in 21 normotensives and 15 hypertensives. Bradykinin injections were performed after the following pharmacological interventions: salt restriction (10 mmol Na/d), salt loading (300 mmol Na/d), captopril (50 mg), ramipril (5 mg), lisinopril (20 mg), ketotifen (2 x 1 mg), indomethacin (2 x 50 mg), and propranolol (80 mg). The results show that bradykinin lowers blood pressure dose related by marked reduction in peripheral vascular resistance. The blood pressure reduction was strongly correlated with the increase in kinin concentration. This effect of bradykinin appears to be independent of changes in sodium metabolism, of beta adrenoceptors, of histamine-1 receptors, and of prostaglandins. ACE-inhibitors potentiate the blood pressure lowering effect of bradykinin about 20- to 50-fold. In case of an intraarterial injection of bradykinin in only 2-5% o the intravenously used dose of bradykinin are needed to produce an identical fall in blood pressure. From this experiments a pulmonary clearance rate of bradykinin over 95% can be calculated. In the pulmonary arteries bradykinin has no effect on the vascular resistance. In patients suffering from primary or renovascular hypertension the blood pressure response to bradykinin was enhanced. The bradykinin potentiating effect of the ACE-inhibitors was not altered in the hypertensives. In patients suffering from bradykinin hypertension or primary hyperaldosteronism bradykinin developed the same blood pressure lowering effect as in the normotensives.
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PMID:[Effect of bradykinin on systemic and pulmonary hemodynamics in the human]. 258 15

Bradykinin (BK) (Arg1-Pro2-Pro3-Gly4-Phe5-Ser6-Pro7-Phe8-Arg9) was degraded by rat brain synaptic membranes at a rate comparable to that found for Met-enkephalin, but approximately 40 times the rate for vasopressin and oxytocin. The catabolic pathway for BK and its metabolites was elucidated through the use of high performance liquid chromatography for metabolite identification and peptidase inhibitors for blocking specific cleavage sites. BK was hydrolyzed at three sites: at the -Phe5-Ser6- bond by metalloendopeptidase 24.15, at the -Pro7-Phe8- bond by an apparently novel peptidyl dipeptidase, and at the -Phe8-Arg9 bond by a carboxypeptidase B-like enzyme. Each enzyme contributed about equally to BK degradation under the assay conditions used. Some of the resulting metabolites were further hydrolyzed: BK(1-8) to BK(1-7) + Phe by a DFP inhibitable prolyl carboxypeptidase-like enzyme, BK(1-8) to BK(1-5) + BK(6-8) by metalloendopeptidase 24.15, BK(1-7) slowly to BK(1-5) by a second peptidyl dipeptidase which was captopril inhibited, and Phe-Arg to Phe + Arg by a bestatin-inhibited dipeptidase. A number of properties of the individual enzymes were determined including sensitivity to a variety of peptidase inhibitors. These results provide a starting point for investigating the potential physiological role of each enzyme in BK function in the brain.
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PMID:Degradation of bradykinin and its metabolites by rat brain synaptic membranes. 260 54

The purpose of the present study was to test the vasomotor effect of angiotensin I (A I) and angiotensin II (A II) in feline cerebral arteries and to examine the presence of angiotensin converting enzyme (ACE) activity in the vessel wall and cerebrospinal fluid (CSF). A II (10(-8) -10(-5) M) induced concentration-dependent contractions of feline pial arteries (resting diameter, 98-286 microns) in situ with a maximum of 34% at 10(-4) M A II. A I produced dose-related contractions being approximately 20 times less potent than A II. The action of A I was significantly attenuated by the ACE inhibitor captopril (10(-5) M). These findings demonstrate the presence of ACE activity in the vessel wall and/or its surroundings. ACE activity was also found in feline CSF sampled from the cisterna cerebellomedullaris. Bradykinin (BK) was broken down and A I converted to A II by CSF, both effects being inhibited by captopril. This was demonstrated using bioassay and high-performance liquid chromatography. Considering the present and previous studies we conclude that the presence of ACE in the vessel wall and CSF is necessary for the conversion of A I to A II. Although ACE in CSF is able to degrade BK it appears not to be important for the metabolism of BK acting from the perivascular side of pial arteries in situ.
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PMID:Cerebrovascular reactivity to angiotensin and angiotensin-converting enzyme activity in cerebrospinal fluid. 283 Sep 37

1 Bradykinin in carrageenin-induced inflammatory pouch fluid was measured by an enzyme immunoassay method. 2 The bradykinin showed a single peak in the 30-60 min period after the challenge and then decreased quickly, and there was a correlation between the bradykinin level and exudation of fluorescein-labelled bovine serum albumin in the first 60 min period. 3 Captopril (an inhibitor of kininase II) elevated both the bradykinin level in the inflammatory pouch fluid and vascular permeability, while DL-2-mercaptomethyl-3- guanidinoethylthiopropanoic acid (an inhibitor of kininase I) had no effect. 4 Soybean trypsin inhibitor (SBTI) inhibited the vascular permeability response in parallel with the decrease in the bradykinin level. 5 A bradykinin-degrading activity appeared in the pouch fluid within 1 h after the challenge and increased with time. 6 In the period of 3.5-4 h, bradykinin levels were suppressed below the sensitivity limit of the assay, i.e. 0.07 nm ml-1, in spite of active generation. This was because degradation of bradykinin was very rapid in this late stage. Nevertheless, bradykinin still played a definite role in sustaining a high level of vascular permeability response in the late stage in conjunction with prostaglandins.
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PMID:Role of bradykinin in the vascular permeability response induced by carrageenin in rats. 283 62


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