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)

Angiotensin II (Ang II) is an important regulator of proximal tubule salt and water reabsorption. Recent studies indicate that rabbit proximal tubule angiotensin II receptors are the type-1 (AT1R) subtype. We studied the effect of Ang II on proximal tubule receptor expression. Rabbits were treated with either angiotensin converting enzyme inhibitors or a low salt diet to modulate endogenous Ang II levels. In captopril-treated rabbits, liver and glomerular AT1R mRNA levels increased 242 +/- 125 and 141 +/- 60%, respectively (n = 6-7; P < 0.05), as determined by quantitative PCR. In contrast, proximal tubule AT1R mRNA levels decreased 40 +/- 11% (n = 6; P < 0.05). Binding of 125I Ang II to renal cortical basolateral membranes of captopril-treated rabbits decreased from 2.9 +/- 0.55 to 1.4 +/- 0.17 fmol/mg protein (n = 6; P < 0.025). In rabbits fed a sodium chloride-deficient diet for 4 wk, AT1R mRNA levels decreased 52 +/- 11% in liver and 43 +/- 7% in glomeruli (n = 4-5; P < 0.05), whereas they increased 141 +/- 85% (n = 5; P < 0.05) in proximal tubule. In basolateral membranes from rabbits on the sodium chloride-deficient diet, specific binding of 125I Ang II increased from 2.1 +/- 0.2 to 4.3 +/- 1.1 fmol/mg protein (n = 7; P < 0.05). To determine whether Ang II directly regulates expression of proximal tubule AT1 receptors, further studies were performed in cultured proximal tubule cells grown from microdissected S1 segments of rabbit proximal tubules and immortalized by transfection with a replication-defective SV40 vector. Incubation of these cells with Ang II (10(-11) to 10(-7) M) led to concentration-dependent increases in both AT1R mRNA levels and specific 125I Ang II binding. Pretreatment with pertussis toxin inhibited Ang II stimulation of AT1R mRNA. AT1R mRNA expression was decreased by either forskolin or a nonhydrolyzable cAMP analogue (dibutryl cAMP). Simultaneous Ang II administration overcame the inhibitory effect of forskolin but not dibutryl cAMP. These results indicate that proximal tubule AT1R expression is regulated by ambient Ang II levels, and Ang II increases AT1R mRNA at least in part by decreasing proximal tubule cAMP generation through a pertussis toxin-sensitive mechanism. Upregulation of proximal tubule AT1R by Ang II may be important in mediating enhanced proximal tubule sodium reabsorption in states of elevated systemic or intrarenal Ang II.
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PMID:Angiotensin II upregulates type-1 angiotensin II receptors in renal proximal tubule. 773 68

Bradykinin is a mediator of the protection of myocardium by angiotensin I-converting enzyme/kininase II inhibitors. We reported that the activation of B2 bradykinin receptors in neonatal rat cardiac myocytes in primary culture was followed by hydrolysis of phosphatidylinositol 4,5-bisphosphate and formation of inositol 1,4,5-trisphosphate (IP3). Here we examine the regulation of IP3 formation stimulated by bradykinin. Activation of myocytes with 1 mu/L bradykinin increased IP3 production from 117 +/- 8.3 to 1011 +/- 48.6 pmol/mg protein. Treatment of the cells with 10 mu/L indomethacin or 1 mu/L dexamethasone partially blocked this bradykinin-induced response. Moreover, either U73122, a phospholipase C inhibitor, or (p-amylcinnamoyl) anthranilic acid, a phospholipase A2 inhibitor, blunted the IP3 response to bradykinin. Because thromboxane A2 stimulates inositol bisphosphate metabolism in guinea pig atria, we also investigated the effect of the thromboxane A2 receptor antagonist BM 13177 (1 mu/L), which strongly attenuated the stimulated IP3 production. Since thromboxane A2 appears to partly mediate the IP3 response to bradykinin, we examined the effect of the stable thromboxane A2 mimetic U46619. Control cultures were stimulated more by U46619 than by bradykinin (1629 +/- 14.5 versus 1011 +/- 48.6 pmol IP3/mg protein). This property of U46619 was selectively antagonized by BM 13177. Inhibition of either phospholipase C or phospholipase A2 blunted the IP3 response to U46619. Short-term (30 minutes) activation of protein kinase C with phorbol 12-myristate 13-acetate (10 pmol/L to 1 mu/L) attenuated the IP3 accumulation in response to bradykinin; the effect of phorbol 12-myristate 13-acetate was reversed with 1 mu/L staurosporine, a protein kinase C inhibitor. Treatment with 1 microgram/mL cholera toxin or pertussis toxin for 4 hours amplified the IP3 response to 10 nmol/L bradykinin from 570 +/- 20.0 to 1150 +/- 51.3 and to 1016.7 +/- 21.9 pmol/mg protein. Bradykinin mobilized 9.4% of intracellular calcium stores in cardiomyocytes as assessed by chlortetracycline-based fluorometry, and this effect of bradykinin was blocked by BM 13177 or the B2 bradykinin receptor blocker Hoe 140 by more than 70%. In functional studies, bradykinin (1 mu/L) increased by 12% the twitch contractile force of neonatal rat ventricular strips paced at threshold intensity, but this was unaffected by BM 13177. In conclusion, in cardiomyocytes, bradykinin enhances IP3 production mostly via phospholipase A2 stimulation and thromboxane A2 formation. This prostanoid in turn stimulates its receptor and activates phospholipase C, which then splits phosphatidylinositol 4,5-bisphosphate into IP3 and diacylglycerol. The effect of bradykinin on phospholipase C, via thromboxane A2, is negatively regulated by protein kinase C activation.
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PMID:Thromboxane A2 mediates the stimulation of inositol 1,4,5-trisphosphate production and intracellular calcium mobilization by bradykinin in neonatal rat ventricular cardiomyocytes. 879 31

1. Desensitization of the myocardial beta-adrenergic signal transduction pathway is an important mechanism which is involved in the progression of hypertensive heart disease. The aim of the present study was to evaluate the differential effects of chronic pharmacotherapy with an angiotensin converting enzyme (ACE)-inhibitor, an AT1-receptor antagonist and a direct vasodilator on blood pressure, cardiac hypertrophy and the beta-adrenergic signal transduction. Therefore, transgenic TG(mREN2)27 (TG) rats overexpressing the mouse renin gene were used. This strain is characterized by the development of fulminant hypertension with cardiac hypertrophy. 2. Seven week old heterozygous TG(mREN2)27 rats were treated for 11 weeks with the AT1-receptor antagonist losartan (10 mg kg[-1]), the ACE-inhibitor quinapril (15 mg kg[-1]) and the direct vasodilator hydralazine (30 mg kg[-1]). Untreated TG and normotensive Sprague-Dawley rats (SD) served as controls. 3. TG(mREN2)27-rats were characterized by arterial hypertension (TG 194+/-3.2 mmHg vs SD 136+/-2.9 mmHg systolic blood pressure), increased left ventricular weights (TG 4.3+/-0.3 vs SD 3.0+/-0.1 mg g(-1) body weight), decreased myocardial neuropeptide Y (NPY) concentrations (TG 1143+/-108 vs SD 1953+/-134 pg g(-1) wet weight), reduced beta-adrenoceptor densities (TG 51.1+/-1.9 vs SD 63.4+/-3.7 fmol mg[-1]) as assessed by [125I]-cyanopindolol binding studies, and increased Gi(alpha)-activities (TG 4151+/-181 vs SD 3169+/-130 densitometric units) as assessed by pertussis toxin catalyzed [32P]-ADP-ribosylation. Downregulation of beta-adrenoceptors and increased Gi(alpha) were accompanied by significantly reduced isoprenaline-, Gpp(NH)p- and forskolin-stimulated adenylyl cyclase activity. Catalyst activity as determined by forskolin plus Mn2+ co-stimulation of adenylyl cyclase did not differ between TG(mREN2)27- and SD control-rats. 4. Losartan and quinapril significantly restored systolic blood pressures, left ventricular weights, beta-adrenoceptor densities, myocardial neuropeptide Y-concentrations, adenylyl cyclase activities and Gi(alpha)-activities towards the values in Sprague-Dawley-controls. No differences were observed between the effects of quinapril- and losartan-treatment. In contrast, hydralazine had only minor effects on blood pressure reduction, regression of left ventricular hypertrophy and neuroeffector defects in TG(mREN2)27. 5. In conclusion, direct vasodilatation is not able to overcome the pathophysiological alterations in TG caused by transgene overexpression. In contrast, ACE-inhibitors and AT1-receptor antagonists, which inhibit the renin angiotensin system, equally exert beneficial effects on blood pressure, myocardial hypertrophy and neuroeffector mechanisms. Modulation of the sympathetic tone and resensitization of the beta-adrenergic signal transduction system may contribute to the special effectiveness of these drugs in the treatment of the hypertensive cardiomyopathy.
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PMID:Effects of quinapril, losartan and hydralazine on cardiac hypertrophy and beta-adrenergic neuroeffector mechanisms in transgenic (mREN2)27 rats. 950 80

The presence of components of the renin angiotensin system (RAS) and specific receptors of angiotensin II in the female and male reproductive tract supports the hypothesis that reproductive functions may be controlled by RAS. Therefore, the present study investigated the influence of ACE and angiotensins on sperm functions and the sperm-egg interaction. The experiments did not indicate direct effects of ACE on the capacitation process or acrosome reaction. Release of ACE from human spermatozoa during capacitation was not related to their ability to undergo acrosome reaction after stimulation with ionophore. Therefore, ACE release does not seem to be a useful clinical marker for human sperm capacitation. However, decreased binding of human spermatozoa to the oolemma of zonafree hamster oocytes after inhibition of ACE by captopril indicates that kininase II is involved in sperm-egg interactions. In contrast to other studies, incubation with captopril had no influence on sperm binding to the zona pellucida. Because effects of ACE on sperm-egg interactions but not on capacitation or acrosome reaction were observed, several experiments were performed to study the influence of substrates and products on the acrosome reaction. Angiotensin II induced the acrosome reaction dose-dependently, whereas angiotensin I had no effect on the acrosome reaction. The effect of angiotensin II on acrosome reaction seems to be calcium-dependent and mediated by protein kinases. Since a specific type 2 angiotensin II receptor inhibits the acrosome reaction induced by angiotensin II, this subtype of receptors may be present at the surface of sperm heads. Another clue for the presence of type 2 receptors on human spermatozoa is the finding that pertussis toxin did not inhibit the angiotensin II induced acrosome reaction. In contrast to type 1 angiotensin II receptors, type 2 receptors are known to be G-protein independent.
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PMID:Effect of angiotensin converting enzyme (ACE) and angiotensins on human sperm functions. 973 17

The cause can almost always be identified. Postnasal drip syndrome, asthma, or gastroesophageal reflux disease account for most cases. The differential diagnosis also includes ACE inhibitor therapy, pertussis, and, in up to 80% of patients, multiple causes. Response to treatment may offer diagnostic confirmation but can be slow in coming.
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PMID:Silencing chronic cough. 1023 42

Angiotensin I-converting enzyme (ACE, kininase II) has 2 active domains (N and C) in a single peptide chain. Because we found its N-domain more stable than its C-domain, we investigated the effect of the amino-terminus of human ACE on the C-domain with a molecular construct expressed in Chinese hamster ovary cells (CHO) cells and transiently in HEK293 cells. This active N-deleted ACE contained only the first 141 amino acids of the human N-domain but not its active center and was linked to the active C-domain containing the transmembrane and cytosolic portions of ACE. The CHO cells were also transfected with human B(2) bradykinin receptor. ACE inhibitors (5 nmol/L or 1 micromol/L) augmented bradykinin (100 nmol/L) effects, elevated B(2) receptor numbers, and resensitized the receptor desensitized by agonist as measured by arachidonic acid release or [Ca(2+)](i) mobilization. Arachidonic acid release was mediated by pertussis toxin-sensitive G alpha(i), and [Ca(2+)](i) mobilization was mediated by pertussis-insensitive G alpha(q) protein receptor complex. The properties of the construct were compared with wild-type ACE and separate N- and C-domains. The N-deleted ACE differed from wild-type in activation by Cl(-) and [SO(4)](2-) ions, hydrolysis ratios of substrates (both short synthetic and endogenous peptides) and heat stability. Thus, the N-terminal peptide of ACE affected the characteristics of the C-domain active center. ACE inhibitors acting on N-deleted ACE, which had only a single C-domain active center anchored to plasma membrane, induced cross-talk between the enzyme and the B(2) receptor (eg, the inhibitors resensitized the receptor) independent of blocking bradykinin inactivation.
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PMID:Effects of the N-terminal sequence of ACE on the properties of its C-domain. 1090 22

In non-smokers the underlying causes for chronic persistent cough (CPC) e.g. chronic cough without diagnostic chest X-ray or pulmonary function test--are usually as follows: several common upper airways diseases, bronchial (cough type) asthma, gastrooesophageal reflux or treatment with an ACE (angiotensin converting enzyme)--inhibitor. In 10% of CPC however the cause remains uncertain. We report a 30 year old non-smoker with severe coughing and repeated vomiting for two months. No laboratory or technical data could be collected suggestive of a common cause of CPC: Upper airways disease, bronchial flow limitation or hyperresponsiveness, ACE inhibitor medication, B. pertussis infection, gastrooesophageal reflux disease (by 24 hours pH-probe) were ruled out. Fiberbronchoscopic findings remained unremarkable, except for the bronchial biopsy specimen, which showed moderate eosinophilic inflammation of the mucosa and marked thickening of the subepithelial layer. Since the cough was non-productive, sputum induction with 3 ml nebulised 3% NaCl solution was performed. 28% of the granulocytes were eosinophil stained. A low quality morning sputum (< 1 ml) showed 21% eosinophilia. Thus, the diagnosis of eosinophilic bronchitis was established. 400 micrograms budesonide dry powder inhalations b.i.d. for one week resolved the cough, treatment was stopped after three weeks. No recurrence was seen two months later. Both the cough type asthma and the eosinophilic bronchitis could represent a form fruste of classical bronchial asthma beyond wheezing or dyspnoea, but with the common main symptom: cough. Since hyperresponsiveness and cough are phenotypic hallmarks of cough variant asthma, in eosinophilic bronchitis--beside cough--another two features of asthma are present: eosinophilic inflammation of the mucosa along with sputum eosinophilia and subepithelial layer thickening. Not surprisingly, eosinophilic bronchial inflammation could be shown in patients with cough variant asthma as well, who--up to 56% during a four year-period--develop classic asthma. The long-term outcome of eosinophilic bronchitis is not known, however. Thus, asthma, cough variant asthma and cough due to eosinophilic bronchitis can mirror different phenotypes or phases of the same entity. CPC due to either the cough type asthma or the eosinophilic bronchitis is like asthma fast responding to inhalative steroids. (Induced) sputum staining should be added to the diagnostic armamentarium of CPC.
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PMID:[Eosinophilic bronchitis without asthma--an additional rare cause for chronic persistent cough (CPC)? A 30-year old patient with severe CPC due to eosinophilic bronchitis without asthma or hyperreactivity]. 1144 11

Cardiac dysfunction in animals with congestive heart failure due to myocardial infarction (MI) is known to be associated with a wide variety of defects in receptor and post-receptor mechanisms. Since the heart function have been shown to be improved by treatment with different angiotensin converting enzyme (ACE) inhibitors, we examined the effects of imidapril, an ACE inhibitor, on changes in post-receptor mechanisms involving adenylyl cyclase (AC) and G proteins in the failing heart. Heart failure in rats was induced by occluding the coronary artery and 3 weeks later the animals were treated daily with 1 mg/kg (orally) imidapril for 5 weeks. The animals were assessed for their left ventricular function and crude membranes were isolated from the viable left ventricle and examined for AC activities as well as G-protein activities and expression. Animals with heart failure exhibited depressions in ventricular function and AC activities in the absence or presence of forskolin, NaF and Gpp(NH)p. The AC activity in the presence of pertussis toxin was increased whereas that in the presence of cholera toxin was decreased in the failing heart. Protein contents and mRNA levels for G(i)-proteins were increased whereas those for G(s)-proteins were unaltered in the infarcted heart. All these changes due to MI were prevented by imidapril treatment. The results indicate that the depressed cardiac function in the failing heart may partly be due to the direct effects of changes in AC and G(i) proteins.
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PMID:Attenuation of changes in G(i)-proteins and adenylyl cyclase in heart failure by an ACE inhibitor, imidapril. 1459 52

Bradykinin is known to stimulate neurons in rat sympathetic ganglia and to enhance transmitter release from their axons by interfering with the autoinhibitory feedback, actions that involve protein kinase C. Here, bradykinin caused a transient increase in the release of previously incorporated [3H] noradrenaline from primary cultures of dissociated rat sympathetic neurons. When this effect was abolished by tetrodotoxin, bradykinin caused an inhibition of tritium overflow triggered by depolarizing K+ concentrations. This inhibition was additive to that caused by the alpha2-adrenergic agonist UK 14304, desensitized within 12 min, was insensitive to pertussis toxin, and was enhanced when protein kinase C was inactivated. The effect was half maximal at 4 nm and antagonized competitively by the B2 receptor antagonist Hoe 140. The cyclooxygenase inhibitor indomethacin and the angiotensin converting enzyme inhibitor captopril did not alter the inhibition by bradykinin. The M-type K+ channel opener retigabine attenuated the secretagogue action of bradykinin, but left its inhibitory action unaltered. In whole-cell patch-clamp recordings, bradykinin reduced voltage-activated Ca2+ currents in a pertussis toxin-insensitive manner, and this action was additive to the inhibition by UK 14304. These results demonstrate that bradykinin inhibits noradrenaline release from rat sympathetic neurons via presynaptic B2 receptors. This effect does not involve cyclooxygenase products, M-type K+ channels, or protein kinase C, but rather an inhibition of voltage-gated Ca2+ channels.
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PMID:Presynaptic inhibition of transmitter release from rat sympathetic neurons by bradykinin. 1593 32

Pyroglutamyl proline-rich oligopeptides, present in the venom of the pit viper Bothrops jararaca (Bj-PROs), are the first described naturally occurring inhibitors of the angiotensin I-converting enzyme (ACE). The inhibition of ACE by the decapeptide Bj-PRO-10c (<ENWPHPQIPP) and other Bj-PROs was classically used to explain the pharmacological effects of these venom peptides in mammals resulting in a decrease of blood pressure. Recent studies, however, suggest that ACE inhibition alone is not sufficient for explaining the antihypertensive actions exerted by these peptides. In this study, we show that intracerebroventricular injection of Bj-PRO-10c induced a significant reduction of mean arterial pressure (MAP) together with a decrease of heart rate (HR) in spontaneously hypertensive rats, indicating that Bj-PRO-10c may act on the central nervous system. In agreement with its supposed neuronal action, this peptide dose-dependently evoked elevations of intracellular calcium concentration ([Ca(2+)](i)) in primary culture from postnatal rat brain. The N-terminal sequence of the peptide was not essential for induction of calcium fluxes, while any changes of C-terminal Pro or Ile residues affected Bj-PRO-10c's activity. Using calcium imaging by confocal microscopy and fluorescence imaging plate reader analysis, we have characterized Bj-PRO-10c-induced [Ca(2+)](i) transients in rat brain cells as being independent from bradykinin-mediated effects and ACE inhibition. Bj-PRO-10c induced pertussis toxin-sensitive G(i/o)-protein activity mediated through a yet unknown receptor, influx and liberation ofcalcium from intracellular stores, as well as reduction of intracellular cAMP levels. Bj-PRO-10c promoted glutamate and GABA release that may be responsible for its antihypertensive activity and its effect on HR.
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PMID:The central nervous system as target for antihypertensive actions of a proline-rich peptide from Bothrops jararaca venom. 2009 50


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