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)

Angiotensin-converting enzyme (ACE) is mainly responsible for converting angiotensin I (AI) to angiotensin II (AII), and ACE inhibitors prevent atherosclerosis in animal models. Neutral endopeptidase 24.11 (NEP) degrades substance P, kinins and atrial natriuretic peptide (ANP), and aortic wall NEP activity was found to be increased in atherosclerosis. In the present study, we have evaluated the effect of candoxatril, a NEP inhibitor, and of omapatrilat, a dual ACE and NEP inhibitor, on the development of fatty streak in apolipoprotein E (apoE)-deficient mice. Groups of ten male apoE-deficient mice were given either placebo, candoxatril 50 mg/kg per day, or omapatrilat 10, or 100 mg/kg per day for 4 months. None of the treatments influenced body weight, serum total or HDL-cholesterol. Compared with the placebo, candoxatril did not protect the mice from fatty streak deposit. In contrast, omapatrilat dose dependently inhibited the constitution of fatty streak in apoE-deficient mice. The precise advantages of the dual ACE and NEP inhibition versus the inhibition of only ACE should now be considered in the prevention of atherosclerosis as well as in the occurrence of its complications.
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PMID:Omapatrilat, a dual angiotensin-converting enzyme and neutral endopeptidase inhibitor, prevents fatty streak deposit in apolipoprotein E-deficient mice. 1125 98

In both diabetic and nondiabetic renal disease, reducing blood pressure with antihypertensive therapy has beneficial effects on renal function. The key role of the renin-angiotensin system in blood pressure and volume homeostasis has long been established, but its importance for the overall normal functioning of the kidney itself is also increasingly being recognized. Angiotensin-converting enzyme (ACE) inhibitors, widely and successfully used in the treatment of hypertension, may also provide renal protection independent of blood pressure reduction; however, their relatively nonspecific mode of action in blocking an early metabolic step entails major clinical disadvantages, such as accumulation of bradykinin and substance P, that may cause the characteristic ACE-inhibitor side effects of persistent dry cough and, more rarely, angioneurotic edema. Angiotensin II antagonists or receptor blockers, a new class of antihypertensive agent, selectively antagonize the AT1 receptor subtype and, because of greater specificity, do not give rise to the side effects associated with ACE inhibitors. More important, these new drugs may have mechanistic advantages over other antihypertensives, including ACE inhibitors.
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PMID:Valsartan and the kidney: review of preclinical and clinical data. 1144 69

Angiotensin-converting enzyme (ACE) inhibitors are among the first-choice drugs for treating hypertension and congestive heart disease. It has been reported, however, that these drugs could induce chronic cough and airway hyperresponsiveness. The aim of this work was to assess in pigs the effects of bradykinin and tachykinins on citric-acid-induced coughing after ACE inhibitor pretreatment. Coughing was induced by challenging pigs with an aerosol of 0.8 M citric acid over 15 min. Coughs were counted by a trained observer for 30 min. The animals underwent two cough induction tests two days apart (days 1 and 3), the first being taken as a control. All drugs were injected intravenously 30 min before the second challenge. In the control group, no difference was observed between days 1 and 3. The ACE inhibitor enalapril (7.5 and 15 microg/kg) caused the cough frequency to increase significantly. In contrast, a dose-related decrease was observed with Hoe140 (icatibant), a bradykinin B2 receptor antagonist (0.5 and 1 mg/kg). When both drugs were administered simultaneously (15 microg/kg for enalapril and 1 mg/kg for Hoe140), a significant increase was observed as compared with the control value obtained on day 1. When enalapril was combined with the three tachykinin receptor antagonists SR 140333 (NK1 receptor antagonist), SR 48968 (NK2 receptor antagonist) and SR 142801 (NK3 receptor antagonist), a significant decrease was observed as compared with control value obtained on day 1; the percentage of variation was also significantly different as compared with those observed in enalapril groups at both doses. These data suggest that ACE-inhibitor-induced enhancement of the cough reflex is mainly due to tachykinins and not to bradykinin in our pig model. Bradykinin, however, plays a major role in coughing induced by citric acid alone.
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PMID:Role of bradykinin and tachykinins in the potentiation by enalapril of coughing induced by citric acid in pigs. 1146 10

Angiotensin-converting enzyme (ACE) inhibitor has mood-elevating effects, and central ACE activity is increased for suicidal patients. In addition, substance P (SP), which is degraded by ACE, has been implicated in the pathogenesis of, and evaluated in the treatment for, major depressive disorder (MDD). The present study has tested the hypothesis that an ACE-gene insertion/deletion (I/D) polymorphism is associated with onset age, clinical manifestations, suicide history, and/or antidepressant response for two groups of MDD patients. No significant differences were demonstrated for onset age (p = 0.520), suicide history (p = 0.823), or baseline, total and cluster scores for Hamilton Depression Rating Scale comparing the three ACE genotypes. Further, previous findings that this ACE polymorphism is associated with therapeutic antidepressant effects were not replicated. The results demonstrate that these ACE variants did not play a major role in the clinical manifestations or antidepressant response for our MDD patients.
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PMID:Association study of angiotensin I-converting enzyme polymorphism and symptomatology and antidepressant response in major depressive disorders. 1220 48

Angiotensin-converting enzyme (ACE) is a dipeptidyl carboxypeptidase, which cleaves dipeptides and, in some instances, dipeptide or tripeptide amides from the C-terminus of regulatory peptides (e.g. angiotensin I, bradykinin and substance P). The expression of ACE is highly regulated in insects, where it is thought to have a role in the metabolism of peptide hormones involved in regulating reproduction. After a blood meal, ACE activity in the female mosquito Anopheles stephensi, increases four-fold with much of the enzyme finally accumulating in the ovary. In the present study, we have studied the effect on reproduction of adding two selective inhibitors of ACE, captopril and lisinopril, to the blood meal. Both ACE inhibitors reduced the size of the batch of eggs laid by females in a dose-dependent manner, with no observable effects on the behaviour of the adult insect. The almost total failure to lay eggs after feeding on either 1 mM captopril or 1 mM lisinopril, did not result from interference with the development of the primary follicle, but was due to the inhibition of egg-laying. Since very similar effects on the size of the egg-batch were observed with two selective ACE inhibitors, belonging to different chemical classes, we suggest that these effects are mediated by the selective inhibition of the induced mosquito ACE, a peptidase probably involved in the activation/inactivation of a peptide regulating egg-laying activity in A. stephensi.
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PMID:ACE inhibitors reduce fecundity in the mosquito, Anopheles stephensi. 1267 Jul 86

Angioneurotic edema is a rare (0.1-0.2%) but potentially life-threatening side effect of angiotensin-converting enzyme inhibitors. It can result in serious respiratory distress, airway obstruction and death. Angiotensin-converting enzyme inhibitors associated angioedema is clinically poorly recognized and frequently underestimated condition. A case history of patient with angioneurotic edema due to treatment with ramipril is presented. A 51-year-old man has been sequentially treated for two years with atenolol, indapamide, enalapril, and fosinopril due to primary arterial hypertension. When the treatment was switched to ramipril 5 mg twice a day the fourth dose of the drug was followed by swelling of lips, tongue, and pharynx without symptoms of airway obstruction. Ramipril was discontinued, prednisolone 120 mg and loratidine 10 mg were given. Symptoms of angioedema gradually disappeared. Mechanisms of angioedema are not fully clear. Pharmacological action of angiotensin-converting enzyme inhibitors on bradykinin and substance P, immunological mechanisms and disarrangements in complement system are discussed. Treatment includes immediate withdrawal of angiotensin-converting enzyme inhibitors and acute therapy with epinephrine 0.3-0.5 ml subcutaneous, 50 mg diphenhydramine s/c or i/v, 40-50 mg methylprednisolone. Future treatment with angiotensin-converting enzyme inhibitors is contraindicated.
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PMID:[Tongue angioedema associated with angiotensin-converting enzyme inhibitor (diagnosis, differential diagnosis, treatment)]. 1282 80

Angiotensin-converting enzyme (ACE) inactivates bradykinin, substance P, and neurokinin A, which are thought to play important roles in the pathogenesis of inflammatory diseases. Expression of angiotensinogen, a precursor of angiotensin, is enhanced by augmented secretion of proinflammatory cytokines (eg, interleukin-1) in the site of inflammation. Insertion or deletion (I/D) ACE and M235T angiotensinogen gene polymorphisms were reported to be associated with atopy in a Czech population. Using polymerase chain reaction restriction fragment length polymorphism and SNaPshot typing analysis, we investigated the frequencies of the genotypes and alleles of the ACE gene in 137 patients with allergic rhinitis, of the M235T angiotensinogen gene in 186 patients with allergic rhinitis, and of both in 219 healthy control subjects. There was no difference in the frequency of the DD genotype of the ACE gene in the controls and patients (odds ratio, 1.32 [0.66-2.60]; p > .05). The D allele was more frequent in patients, but the difference was not statistically significant (odds ratio, 1.21 [0.89-1.64]; p > .05). There was no difference in the frequency of the TT genotype of the angiotensinogen gene in the controls and patients (odds ratio, 1.01 [0.38-2.69]; p > .05). The T allele was more frequent in patients, but the difference was not statistically significant (odds ratio, 1.10 [0.78-1.55]; p > .05). Our results indicate that polymorphisms in the genes for ACE and angiotensinogen may not be related to the development of allergic rhinitis in the Korean population.
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PMID:Association between polymorphisms of the angiotensin-converting enzyme and angiotensinogen genes and allergic rhinitis in a Korean population. 1511 73

Our investigations started when synthetic bradykinin became available and we could characterize two enzymes that cleaved it: kininase I or plasma carboxypeptidase N and kininase II, a peptidyl dipeptide hydrolase that we later found to be identical with the angiotensin I converting enzyme (ACE). When we noticed that ACE can cleave peptides without a free C-terminal carboxyl group (e.g., with a C-terminal nitrobenzylamine), we investigated inactivation of substance P, which has a C-terminal Met(11)-NH(2). The studies were extended to the hydrolysis of the neuropeptide, neurotensin and to compare hydrolysis of the same peptides by neprilysin (neutral endopeptidase 24.11, CD10, NEP). Our publication in 1984 dealt with ACE and NEP purified to homogeneity from human kidney. NEP cleaved substance P (SP) at Gln(6)-Phe(7), Phe(7)[see text]-Phe(8), and Gly(9)-Leu(10) and neurotensin (NT) at Pro(10)-Tyr(11) and Tyr(11)-Ile(12). Purified ACE also rapidly inactivated SP as measured in bioassay. HPLC analysis showed that ACE cleaved SP at Phe(8)-Gly(9) and Gly(9)-Leu(10) to release C-terminal tri- and dipeptide (ratio = 4:1). The hydrolysis was Cl(-) dependent and inhibited by captopril. ACE released only dipeptide from SP free acid. ACE hydrolyzed NT at Tyr(11)-Ile(12) to release Ile(12)-Leu(13). Then peptide substrates were used to inhibit ACE hydrolyzing Fa-Phe-Gly-Gly and NEP cleaving Leu(5)-enkephalin. The K(i) values in microM were as follows: for ACE, bradykinin = 0.4, angiotensin I = 4, SP = 25, SP free acid = 2, NT = 14, and Met(5)-enkephalin = 450, and for NEP, bradykinin = 162, angiotensin I = 36, SP = 190, NT = 39, Met(5)-enkephalin = 22. These studies showed that ACE and NEP, two enzymes widely distributed in the body, are involved in the metabolism of SP and NT. Below we briefly survey how NEP and ACE in two decades have gained the reputation as very important factors in health and disease. This is due to the discovery of more endogenous substrates of the enzymes and to the very broad and beneficial therapeutic applications of ACE inhibitors.
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PMID:Angiotensin converting enzyme (ACE) and neprilysin hydrolyze neuropeptides: a brief history, the beginning and follow-ups to early studies. 1513 71

Proteolytic processing is a primary means of biological control. Exopeptidases use terminal anchoring interactions to restrict cleavage at peptide substrate N or C termini. In contrast, internal peptide bond targeting by endopeptidases is through context-driven recognition. Angiotensin I-converting enzyme (ACE), a zinc metalloproteinase, has tandem duplicate catalytic domains, N- and C-terminal, each of which is a dual specificity enzyme with exo- and endocarboxypeptidase activities. The mechanisms by which ACE evolved from its endopeptidase ancestors as a dual specificity enzyme have not been defined. Based on kinetic studies of wild-type and mutant forms of the C-terminal catalytic domain of human ACE and of the ACE substrates angiotensin I, substance P, and bradykinin, as well as considerations of the ACE x-ray structure, we provide evidence that the acquisition of its exopeptidase activity is due to novel evolutionary specializations. These involve not only interactions between the S(2)' subsite cognate for the C-terminal substrate P(2)' side chain, acting in concert with carboxylate-docking interactions with Lys(1087) and Tyr(1096), but also electrostatic selection against a cationic C-terminal substrate carboxylate. With a blocked C terminus, substrate side chain interactions are dominant in cleavage site selection. In the evolution of obligate exopeptidases from endopeptidase ancestors, mutations that destroy context-driven peptide bond targeting are likely to have followed the acquisition of terminal docking interactions. Evolutionary intermediates between endopeptidases and obligate exopeptidases could therefore have been dual specificity proteinases like ACE.
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PMID:Molecular basis of exopeptidase activity in the C-terminal domain of human angiotensin I-converting enzyme: insights into the origins of its exopeptidase activity. 1561 92

A renin-angiotensin system, separate to that in the periphery, has been found in the brain. Angiotensin-converting enzyme (ACE) is crucial in the synthesis of angiotensin II, breakdown of bradykinin and the hydrolysis of several other neuropeptides such as enkephalin, substance P, dynorphin and neurotensin. Changes in the levels of ACE have been found in brains of schizophrenia patients, suggesting an involvement of ACE in the illness which awaits further investigation. Prepulse inhibition (PPI) has been suggested to be an operational measure of sensorimotor gating and is disrupted in patients with schizophrenia. We found that ACE knockout mice have increased startle responses but no differences in baseline PPI compared to wildtype controls. Treatment with the dopamine receptor agonist, apomorphine, or the dopamine-releasing drug, amphetamine, produced significant disruption of PPI in control mice but not in ACE knockout mice. Pretreatment with the ACE inhibitor, captopril, which itself did not affect PPI, caused a reduction in the effect of apomorphine on PPI, similar to that seen in the ACE knockout mice. These data suggest an important role of ACE substrates in modulating dopaminergic mechanisms involved in PPI. Further studies are needed to ascertain if angiotensin or other neuropeptides are involved in these interactions and to investigate the neurochemical mechanism behind these effects.
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PMID:Angiotensin-converting enzyme (ACE) interacts with dopaminergic mechanisms in the brain to modulate prepulse inhibition in mice. 1585 41


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