Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

To investigate the role of kinins in augmentation of insulin sensitivity by angiotensin converting enzyme inhibitor (ACEI), the effects of ACEI (delapril) on the insulin resistance in fructose-fed rats (FFR) were evaluated with or without the administration of bradykinin receptor antagonist (Hoe 140). Male Sprague-Dawley rats were fed on fructose rich chow (FFR) or standard chow (control) for 4 weeks and treated with 10 mg/kg/day of delapril with or without Hoe 140 (0.5 mg/kg/day) for an additional 2 weeks. Steady state plasma glucose (SSPG) and steady state plasma insulin (SSPI) were determined while the rats were conscious. Insulin (2.5 mU/kg/min) and glucose (8 mg/kg/min) were simultaneously infused to determine insulin sensitivity in each group. Mean blood pressure (MBP), SSPG and SSPI were significantly higher in FFR than in control, and were significantly lower in the FFR+delapril than in FFR+vehicle. There were no difference in MBP, SSPG and SSPI between FFR+delapril+vehicle and FFR+delapril+Hoe 140. We concluded that the main mechanisms of improving the insulin sensitivity by ACEI may not be the enhancement of kinins but the suppression of angiotensin II in FFR.
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PMID:The mechanisms of the improvement of insulin sensitivity by angiotensin converting enzyme inhibitor. 886 4

The purpose of this study was to determine whether an aqueous extract of smokeless tobacco (moist snuff) increases clearance of macromolecules from postcapillary venules in the in situ oral mucosa and, if so, whether bradykinin mediated this response. Using intravital microscopy, we found that 20-min suffusion of the extract elicited significant concentration-dependent leaky site formation and increase in clearance of FITC-dextran (molecular mass, 70 kDa) from the hamster cheek pouch (p < 0.05). These responses were associated with a significant increase in bradykinin-like immunoreactivity in the suffusate. Smokeless tobacco extract-induced leaky site formation and increase in clearance of FITC-dextran were significantly attenuated by NPC 17647 and Hoe 140 (p < 0.05), two bradykinin B2 receptor antagonists, but not by desArg9,[Leu8]bradykinin, a bradykinin B1 receptor antagonist. Both bradykinin B2 receptor antagonists had no significant effects on adenosine-induced responses. Indomethacin had no significant effects on smokeless tobacco extract-induced responses. Exposure to smokeless tobacco extract was associated with a significant decrease in angiotensin I-converting enzyme activity and a small, but significant, increase in neutral endopeptidase 24.11 activity in the cheek pouch, two peptidases widely distributed in the microcirculation that cleave and inactivate bradykinin (p < 0.05). Overall, these data suggest that smokeless tobacco elicits plasma exudation in the oral mucosa in vivo in a specific fashion, and that this response is mediated by bradykinin.
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PMID:Mechanisms of smokeless tobacco-induced oral mucosa inflammation: role of bradykinin. 890 42

We studied the effects of angiotensin-converting enzyme (ACE)/kininase II inhibition selectively in the ischemic zone on reperfusion arrhythmias, and the role of bradykinin versus angiotensin II (produced locally in this zone) in modulating the severity of such arrhythmias. Isolated rat hearts (n = 12 per group) were subjected to independent perfusion of left and right coronary beds. The left coronary bed received the ACE/kininase II inhibitor ramiprilat, alone or in combination with either HOE140 (bradykinin B2 receptor antagonist) or angiotensin II, before induction of regional ischemia (10 min) by discontinuation of flow to the bed. Ramiprilat (1, 10, or 100 nM) did not significantly alter the incidence of reperfusion-induced ventricular tachycardia (VT) or fibrillation (VF), but reduced the incidence of sustained VF from 83% in controls to 75, 50, and 25% (p < 0.05). The protective effects of 100 nM ramiprilat were abolished by coinfusion of HOE140 (10 or 100 nM) but not affected by coinfusion of angiotensin II (1 nM). HOE140 (10 nM), when infused alone into the left coronary bed before 7-min ischemia, increased the incidence of sustained VF from 42 to 100% (p < 0.05). Although HOE140 caused vasoconstriction in the left coronary bed when given alone or in combination with ramiprilat, its proarrhythmic effects were not due to a reduction of flow to the bed. We conclude that selective inhibition of ACE/kininase II in the ischemic zone moderately attenuates reperfusion arrhythmias and that enhanced bradykinin availability rather than reduced angiotensin II in synthesis contributes to such an effect.
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PMID:Attenuation of reperfusion arrhythmias by selective inhibition of angiotensin-converting enzyme/kininase II in the ischemic zone: mediated by endogenous bradykinin? 890 6

Rapid growth of the left ventricle of the newborn pig heart can be restrained by treating piglets with the angiotensin converting enzyme inhibitor, enalapril maleate. This reduced rate of growth is reflected in vitro by reduced rates of ribosome formation and protein synthesis, and may be due to decreased availability of angiotensin II (AII), a potentially hypertrophic agent; decreased numbers of AII receptors; increased availability of bradykinin, a potentially antihypertrophic agent; or reduced hemodynamic load on the left ventricle. Because enalapril decreases degradation of bradykinin, the role of bradykinin as an inhibitor of cardiac growth in the newborn heart was investigated. Addition of 1 x 10(-5) M bradykinin and 1 x 10(-6) M enalapril to the perfusate of isolated hearts from 2 day old piglets did not significantly alter heart rate, contents of ATP or creatine phosphate or rates of ribosome formation or protein synthesis during 1 h of perfusion. Similarly, exposure of myocytes isolated from the left ventricular free wall of piglets to 5 x 10(-6) M bradykinin for 72 h did not alter the rate of [3H]-phenylalanine incorporation into total protein. The reduced rate of left ventricular growth in vivo caused by enalapril administration was not reversed by simultaneous treatment with the specific bradykinin receptor antagonist, HOE 140. HOE 140 alone did not alter ventricular growth as compared to hearts from untreated piglets. In summary, these results demonstrate that the reduced rate of left ventricular growth in vivo and the reduced rate of ribosome formation and protein synthesis in the left ventricle in vitro after enalapril treatment of piglets is not the result of an inhibitory effect of bradykinin on cardiac growth.
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PMID:Role of bradykinin in the antihypertrophic effects of enalapril in the newborn pig heart. 897 42

A local renin-angiotensin system (RAS) is present in the vasculature and might have an important role in the control of vascular resistance. In order to assess its functional role in the control of vasomotor tone, we investigated the effect of the RAS of a donor vessel (rat carotid artery) on the diameter of a recipient rat mesenteric resistance artery. Arteries were perfused in series in an arteriograph at a rate of 100 microL/min, under a pressure of 100 mm Hg. The two vessels were superfused in separate organ chambers to which drugs were added. Recipient artery internal diameter was measured continuously. Phenylephrine (0.1 mumol/L) was present in the organ baths throughout the experiments, ensuring a preconstriction of the recipient artery (236 +/- 4 to 174 +/- 3 microns, n = 65 arterial segments from 34 rats). The angiotensin I-converting enzyme inhibitors (ACEIs) cilazapril (1 mumol/L) and captopril (10 mumol/L) inhibited phenylephrine-induced constriction by 30 +/- 12% (n = 7, P < .001) and 20 +/- 8% (n = 5, P < .01), respectively. Addition of cilazapril (1 mumol/L) or captopril (10 mumol/L) to the donor vessel chamber further inhibited the constriction by 8 +/- 3% (n = 7, P < .01) and 31 +/- 10% (n = 5, P < .05), respectively. The angiotensin II receptor (AT1) antagonist losartan (10 mumol/L) prevented, in part, the relaxation due to the ACEI. The association of losartan (10 mumol/L) with the bradykinin B2 receptor antagonist HOE 140 (1 mumol/L) totally prevented the relaxation due to the ACEI. Finally, angiotensin II was measured in the perfusate of the carotid artery and was found to be released at a rate of 11.9 +/- 2.2 pg in 60 minutes (n = 8), which was significantly decreased to 1.4 +/- 0.4 pg in 60 minutes (n = 4) by cilazapril (1 mumol/L). This study provides functional evidence that tissue-generated angiotensin II and bradykinin, produced locally and in upstream arteries, control the diameter of a resistance mesenteric artery.
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PMID:In vitro modulation of a resistance artery diameter by the tissue renin-angiotensin system of a large donor artery. 901 41

Using indomethacin (2.5 mg/kg/day, i.m.) in rats, we confirmed the well-known interaction of NSAID's and the urinary elimination of lithium. This is due to an increase in the tubular reabsorption of lithium, probably associated with an increase in the reabsorption of sodium in the ascending limb of the loop of Henle, following inhibition of the synthesis of prostaglandins. With ramipril (1 mg/kg/day, p.o.), we confirmed an interaction with lithium pharmacokinetics in rats, also associated with an increase in the tubular reabsorption of sodium. In contrast, the angiotensin receptor antagonist losartan (10 mg/kg/day, p.o.) had no effect in this paradigm. Since the effects of ramipril were partially inhibited by an i.v. infusion of an antagonist of the bradykinin B2 receptor icatibant (0.1 mg/kg/day), we suggest that bradykinin contributes to the interaction between angiotensin converting enzyme inhibitors and renal excretion of lithium.
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PMID:[Mechanisms of drug interactions with renal elimination of lithium]. 931 48

Bradykinin exerts important influences on renal hemodynamics and tubular function by acting on renal bradykinin B2 receptors. However, the precise sites and mechanisms of its actions on the kidney are not known. To help elucidate the mechanisms of renal actions of bradykinin in vivo, we have employed high resolution electron microscopic autoradiography to localize bradykinin B2 binding sites in the rat kidney following intravenous administration of a radiolabeled ligand, 125I-HPP-Hoe140 (3-4-Hydroxyphenyl-propionyl-DArg0-[Hyp3-Thi5-D-Tic 7-Oic8]-bradykinin), a derivative of the highly selective bradykinin B2 receptor antagonist, Hoe140. In non-treated rats, bradykinin B2 binding sites were localized to the cell bodies and the luminal brush border of the proximal convoluted tubules in the cortex. In the medulla (except for the outer stripe of the outer medulla), binding occurred in the distal tubules, thin limbs of the loop of Henle, collecting ducts, peritubular capillary endothelium and renomedullary interstitial cells. To exclude the possibility that the radioligand may bind to angiotensin converting enzyme, rats were pretreated with the angiotensin converting enzyme inhibitor, perindopril. In these rats, binding to the cell bodies and the luminal brush border of the proximal convoluted tubules in the cortex was completely abolished, while binding remained unaltered in the medulla. Further studies using high performance liquid chromatography revealed that while the radioligand was degraded following systemic administration in nontreated rats, the degradation was significantly reduced in the rats pretreated chronically with perindopril. These results indicate that binding detected in the proximal tubules in the normal rats is due primarily to the tubular uptake of the degraded radioligand, and that bradykinin B2 binding sites occur predominantly in the renal tubules, vascular endothelium, and renomedullary interstitial cells of the renal medulla.
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PMID:Localization of bradykinin B2 binding sites in rat kidney following chronic ACE inhibitor treatment. 935 Jun 49

We used the isolated N- and C-domains of the angiotensin 1-converting enzyme (N-ACE and C-ACE; ACE; kininase II) to investigate the hydrolysis of the active 1-7 derivative of angiotensin (Ang) II and inhibition by 5-S-5-benzamido-4-oxo-6-phenylhexanoyl-L-proline (keto-ACE). Ang-(1-7) is both a substrate and an inhibitor; it is cleaved by N-ACE at approximately one half the rate of bradykinin but negligibly by C-ACE. It inhibits C-ACE, however, at an order of magnitude lower concentration than N-ACE; the IC50 of C-ACE with 100 micromol/L Ang I substrate was 1.2 micromol/L and the Ki was 0.13. While searching for a specific inhibitor of a single active site of ACE, we found that keto-ACE inhibited bradykinin and Ang I hydrolysis by C-ACE in approximately a 38- to 47-times lower concentration than by N-ACE; IC50 values with C-ACE were 0.5 and 0.04 micromol/L. Furthermore, we investigated how Ang-(1-7) acts via bradykinin and the involvement of its B2 receptor. Ang-(1-7) was ineffective directly on the human bradykinin B2 receptor transfected and expressed in Chinese hamster ovary cells. However, Ang-(1-7) potentiated arachidonic acid release by an ACE-resistant bradykinin analogue (1 micromol/L), acting on the B2 receptor when the cells were cotransfected with cDNAs of both B2 receptor and ACE and the proteins were expressed on the plasma membrane of Chinese hamster ovary cells. Thus like other ACE inhibitors, Ang-(1-7) can potentiate the actions of a ligand of the B2 receptor indirectly by binding to the active site of ACE and independent of blocking ligand hydrolysis. This potentiation of kinins at the receptor level can explain some of the well-documented kininlike actions of Ang-(1-7).
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PMID:N-domain-specific substrate and C-domain inhibitors of angiotensin-converting enzyme: angiotensin-(1-7) and keto-ACE. 953 14

The modulatory effect of bradykinin on electrically-induced noradrenaline release was assessed in isolated atria from normal and B2 knockout transgenic mice preincubated with [3H]noradrenaline. Concentrations of 1, 3 and 10 nM of bradykinin did not significantly alter the outflow of radioactivity whereas higher concentrations of bradykinin (30 and 100 nM) enhanced it. The facilitatory effect of 30 nM bradykinin was inhibited by a selective bradykinin B2 receptor antagonist. Hoe 140 (D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]bradykinin, 30 nM), and by a protein kinase C inhibitor, bisindolylmaleimide (1 microM). The co-administration of bradykinin (1 to 100 nM) with either [Leu8]des-Arg9-bradykinin (100 nM), AcLys[DbetaNal7,Ile8]des-Arg9-bradykinin (30 nM) (bradykinin B1 receptor antagonists) or diclofenac (1 microM) (a cyclooxygenase inhibitor), shifted the facilitatory effect of bradykinin to lower concentrations. The facilitatory effect of bradykinin also was enhanced by enalaprilat (1 microM) and mergetpa (1 microM), inhibitors of angiotensin-converting enzyme (kininase II) and kininase I, respectively. In contrast, selective bradykinin B1 receptor agonists, des-Arg9-bradykinin (1 to 100 nM) and Sar[D-Phe8]des-Arg7-bradykinin (1 to 100 nM), did not significantly affect the stimulation-induced outflow of radioactivity. Neither bradykinin (100 nM) nor des-Arg9-bradykinin (100 nM) had any modulatory effect in B2 knockout transgenic mice. These findings suggest that the facilitatory effect of bradykinin on noradrenaline release in the mouse atria is mediated exclusively by presynaptic bradykinin B2 receptors which are linked to protein kinase C. The greater release of noradrenaline with bradykinin under inhibition of prostaglandins production and kininases I and II activity might be of importance in pharmacotherapies.
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PMID:Modulatory effect of bradykinin on noradrenaline release in isolated atria from normal and B2 knockout transgenic mice. 965 56

Kinins have been shown to play an important role in the cardioprotective effect of ACE inhibitors (ACEi) during heart failure and ischemia-reperfusion. However, it is controversial as to whether kinins oppose the hypertensinogenic effect of deoxycorticosterone acetate plus salt (DOCA-salt) or aortic coarctation and whether they mediate both chronic antihypertensive and cardiac antihypertrophic effects of ACEi in hypertension. Using normal 129/SvEvTac mice and mice lacking the bradykinin B2 receptor gene (B2-KO), we investigated whether (1) the hypertensinogenic effect of DOCA-salt or aortic coarctation is enhanced in B2-KO mice and (2) the chronic antihypertensive and antihypertrophic effects of an ACEi (ramipril, 4 mg. kg-1. d-1) are mediated by B2 receptors in aortic coarctation (6 weeks)- and DOCA-salt (4 weeks)-induced hypertension. Before surgery, there was no difference between 129/SvEvTac and B2-KO mice in terms of blood pressure and heart weight, suggesting that kinins are not essential to maintaining normal blood pressure. DOCA-salt (volume expansion) or aortic coarctation (renin-dependent) induced similar hypertension and left ventricular hypertrophy (LVH) in 129/SvEvTac and B2-KO mice, suggesting that kinins do not play an essential role in the development of DOCA-salt- or aortic coarctation-induced hypertension. We found that B2 receptors mediate only the early (1 week) but not the late phase (4 weeks) of the chronic hypotensive effect of ACEi in DOCA-salt hypertension. On the other hand, chronic ACE inhibition prevented the development of hypertension and LVH in both 129/SvEvTac and B2-KO mice given DOCA-salt or subjected to aortic coarctation, suggesting that kinins do not participate in the chronic antihypertensive and antihypertrophic effects of ACEi in these 2 models of hypertension. Thus, in mice, kinins acting via B2 receptors do not participate in (1) maintenance of normal basal blood pressure, (2) establishment and maintenance of hypertension induced by DOCA-salt or aortic coarctation, and (3) chronic antihypertensive and cardiac antihypertrophic effects of ACEi in DOCA-salt and aortic coarctation hypertension.
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PMID:Effect of ACE inhibitor on DOCA-salt- and aortic coarctation-induced hypertension in mice: do kinin B2 receptors play a role? 1060 Nov 37


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