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 determine the mechanism of endothelium-dependent relaxation by bradykinin, we simultaneously measured changes in cytosolic calcium concentrations ([Ca2+]i) and force of fura-2-loaded strips of porcine coronary artery. We also examined effects of captopril, an angiotensin converting enzyme inhibitor, on bradykinin-induced relaxation. Bradykinin, in a concentration-dependent manner (10(-10) to 10(-7) M), decreased both [Ca2+]i and force to resting levels, during 10(-5) M prostaglandin F2 alpha-induced contractions, only when endothelium was intact. Treatment with 10(-5) M captopril enhanced the bradykinin-induced decreases in [Ca2+]i and force and shifted the concentration-response curve to the left. During 118 mM K+ depolarization, bradykinin induced a greater relaxation than that expected from the reduction in [Ca2+]i. Captopril had no effects on the relationship between reduction in [Ca2+]i and relaxation induced by bradykinin. Bradykinin relaxes porcine coronary artery in an endothelium-dependent manner, by decreasing [Ca2+]i and also by controlling the Ca2+ sensitivity of the contractile apparatus of smooth muscle. Captopril enhanced the bradykinin-induced relaxation, with no apparent direct effect on Ca2+ sensitivity of the contractile apparatus.
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PMID:Cytosolic Ca2+ transients in endothelium-dependent relaxation of pig coronary artery, and effects of captopril. 811 4

Isolated rat left atria or right ventricular strips were electrically stimulated at a constant frequency. The amplitude of twitch contractions, thus elicited, rose as a function of stimulation intensity because of increases in the evoked release of sympathetic catecholamines. Bradykinin had no effect on contractile force in preparations paced at a minimal intensity (threshold). By contrast, bradykinin (1 nmol/L to 1 mumol/L) markedly increased twitch contractile force when the preparations were paced at a high intensity (two to three times threshold). The EC50 for the positive inotropic action of bradykinin averaged 42 nmol/L. Ramiprilat (1 mumol/L), an angiotensin I-converting enzyme/kinase II inhibitor, shifted the EC50 for bradykinin to approximately 2 nmol/L. Ramiprilat (1 mumol/L) per se also produced a modest positive inotropic effect. The effects of bradykinin and/or ramiprilate were inhibited by HOE 140 (300 nmol/L), a bradykinin B2-receptor antagonist. Propranolol (1 mumol/L), a beta-adrenoceptor blocker, abolished the effects of bradykinin. After the destruction of sympathetic nerve endings by use of 6-hydroxydopamine, bradykinin no longer exerted a positive inotropic action. Cocaine (10 micrograms/mL), an inhibitor of catecholamine reuptake, potentiated the effect of bradykinin. Bradykinin did not affect the positive inotropic response to tyramine (10 mumol/L), whereas cocaine blocked it. Furthermore, bradykinin did not modify the dose-response curves for added norepinephrine. omega-Conotoxin (100 nmol/L) inhibited the positive inotropic effect of intensified stimulation and bradykinin potentiation. Bradykinin is suggested to facilitate the evoked release of sympathetic catecholamines and thereby cause a positive inotropic effect.
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PMID:Importance of sympathetic innervation in the positive inotropic effects of bradykinin and ramiprilat. 811 52

Bradykinin B2 receptor-like binding activity was solubilized from guinea pig lung using the zwitterionic detergent 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulphonate (Chaps). The binding of [3H]bradykinin to the soluble fraction was time-dependent and saturable. Scatchard analysis of equilibrium binding data indicated that the soluble extract contained a single class of binding sites with a Kd of 696 pM and a Bmax of 57 fmol/mg protein. Unlabelled bradykinin and B2 antagonists inhibited the binding of [3H]bradykinin to Chaps-solubilized extracts with relative potencies similar to those observed with the low-affinity membrane-bound binding sites. Following partial purification of the soluble preparation, using anion exchange (DEAE-Sephacel) and gel filtration (Aca 34) column chromatography steps, two peaks eluted off the column were able to bind [3H]bradykinin and have molecular masses of 168 and 98.5 kDa. The former seems to represent binding of bradykinin to angiotensin converting enzyme (ACE, EC 3.4.15.1) and the latter binding to bradykinin receptor. Using purified commercial ACE, we show that the binding of [3H]bradykinin to ACE can easily be distinguished from that of the bradykinin receptor, since both B1 and B2 ligands were able to inhibit bradykinin binding with affinities clearly different from that expected for a bradykinin receptor.
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PMID:Co-solubilization of bradykinin B2 receptors and angiotensin-converting enzyme from guinea pig lung membranes. 815 65

Angiotensin converting enzyme active sites from rat plasma, lung, kidney and testis were assessed by comparative radioligand binding studies under physiological chloride conditions. Displacement of [125I]Ro 31-8472 from somatic and plasma angiotensin converting enzyme by angiotensin converting enzyme inhibitors of different structure indicated two binding sites (perindoprilat: high affinity carboxyl site, KDC 18 +/- 6 pM), and a single high affinity binding site on testis angiotensin converting enzyme (KDC 20 +/- 1 pM). Displacement of [125I]351A from plasma, somatic and testis angiotensin converting enzyme occurred at a single high affinity binding site. Reduction in affinity at the amino binding site of somatic angiotensin converting enzyme was related to an increased side chain size (lung KDA (pM): Ro 31-8472 175 +/- 38, lisinopril 2205 +/- 1832, and 351A 2271 +/- 489), or hydrophobicity of the competing unlabelled angiotensin converting enzyme inhibitor (lung KDA (pM): quinaprilat 1267 +/- 629 and perindoprilat 824 +/- 6). This trend was reversed at the carboxyl binding site of plasma, somatic and testis angiotensin converting enzyme. Bradykinin hydrolysis by lung angiotensin converting enzyme was inhibited in a similar manner by cilazaprilat or quinaprilat (F = 0.64, F-test based on the extra sum-of-squares principle; P > 0.05), indicating the angiotensin converting enzyme carboxyl active site predominates in bradykinin cleavage. The data demonstrate that the two binding sites on native plasma and somatic angiotensin converting enzyme are of potentially different functional and structural nature, suggesting they may have different substrate specificities.
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PMID:Structural constraints of inhibitors for binding at two active sites on somatic angiotensin converting enzyme. 817 3

The angiotensin converting enzyme (ACE) inhibitors, moexiprilat and ramiprilat, relaxed preconstricted endothelium-intact bovine coronary artery rings and enhanced the relaxant response to bradykinin. The relaxation was observed in the presence of a cyclooxygenase inhibitor and without previous exposure to bradykinin. ACE inhibitor-dependent relaxation was attenuated by the selective B2-kinin receptor antagonist, Hoe 140, and completely abolished by removal of the endothelium. Bradykinin or moexiprilat also significantly increased the cyclic guanosine monophosphate (cGMP) content of these coronary segments, an effect which was abolished by the nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine (NNA), or by removal of the endothelium. NNA also diminished the relaxant response to moexiprilat, but only partially inhibited that to bradykinin, suggesting that the ACE inhibitor-induced relaxation was predominantly mediated by endothelial NO release, whereas bradykinin acted in part by another endothelium-dependent mechanism. These findings indicate that ACE inhibitors can elicit endothelium-dependent relaxations presumably by facilitating the accumulation of endothelium-derived kinins in or at the vessel wall. This local mechanism may significantly contribute to the antihypertensive action of these compounds in vivo.
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PMID:Angiotensin-converting enzyme inhibitors unmask endogenous kinin production by bovine coronary artery endothelium. 829 68

The possible role of the endogenous kinins in the control of alcohol intake was assessed in two experiments. In Experiment 1, naive rats, maintained on ad lib food and water, were given daily 40-min access to a 6% (w/v) alcohol solution and water. Daily intraperitoneal (IP) injections of captopril (20 mg/kg) significantly reduced alcohol intake, while pretreatment with subcutaneous (SC) injections of the bradykinin antagonist [D-Phe7]-bradykinin (100-300 micrograms/kg) attenuated the suppressive effect of captopril on alcohol intake. The saline vehicle or the bradykinin antagonist alone did not alter alcohol intake. In Experiment 2, bradykinin was administered daily at 100, 200, and 400 micrograms/kg doses SC either alone or in combination with captopril 10 mg/kg IP. Neither bradykinin nor captopril by themselves changed alcohol or water intake. Bradykinin combined with captopril stimulated water intake and reduced alcohol intake by up to 70%. This effect was not due to drug-induced changes in the pharmacokinetics of alcohol. The angiotensin II receptor antagonist [Sar1,Thr8]-angiotensin II at 250 and 500 micrograms/kg SC attenuated the stimulation of water intake but not the reduction in alcohol intake. It is suggested that by inhibiting kininase II, ACE inhibitors extend the duration of action of bradykinin and thereby unmask a potent inhibition of alcohol intake mediated by kinins--an effect that is dissociable from the accompanying stimulation of water intake. Taken together, these results point to an involvement of the kinin system in the regulation of alcohol intake and in particular to a role of bradykinin in the suppressive effect of ACE inhibitors on alcohol intake.
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PMID:Bradykinin suppresses alcohol intake and plays a role in the suppression produced by an ACE inhibitor. 830 51

The renin angiotensin system and endothelium-derived vasoactive substances are both important regulators of vascular tone. Recent evidence suggests that the two systems may be tightly interconnected and drugs interfering with one system may also affect the other. Beside the circulating renin angiotensin system, a vascular wall renin angiotensin system has been postulated and various components of it have been demonstrated in endothelial and vascular smooth muscle cells. Of particular importance is the angiotensin converting enzyme (ACE) which is identical to kininase II, which breaks down bradykinin into inactive components. Bradykinin is a potent activator of the L-arginine nitric oxide system (endothelium-derived relaxing factor). Hence, ACE-inhibitors not only deactivate the pressor system, but increase the local concentrations of bradykinin and thereby stimulate a potent endothelium-derived vasodilator system. Angiotensin II not only can activate vascular smooth muscle cells (where it causes contraction and proliferation), but also endothelial cells. In certain blood vessels, angiotensin II can stimulate prostacyclin production; in addition, angiotensin II activates endothelin messenger RNA in endothelial cells. This activation of the endothelin vasopressor system increases vascular tone and enhances the local vasoconstrictor responses (due to the amplifying effects of endothelin on noradrenaline- and serotonin-induced contractions). Although the acute effects of ACE-inhibitors in isolated blood vessels are restricted to inhibition of angiotensin I-induced contractions and augmentation of bradykinin-induced endothelium-dependent relaxations, chronic therapy with the drugs appears to enhance endothelium-dependent responses to several agonists, particularly in hypertensive animals. Hence, this mechanism of action of ACE-inhibitors may account for an important vascular protective effect of the drugs. Thus, in summary, the renin angiotensin system and endothelium-derived vasoactive substances are tightly interconnected. This may be important under physiological and pathophysiological conditions, and is of importance for the action of currently available cardiovascular drugs, in particular, ACE-inhibitors.
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PMID:Angiotensin, ACE-inhibitors and endothelial control of vasomotor tone. 835 30

Bradykinin (BK) affects a variety of smooth muscle types, including uterus. These effects are generally short-lived due to metabolism by a variety of enzymes including angiotensin converting enzyme (ACE), endopeptidase 24.11 (EP-24.11) and endopeptidase 24.15 (EP-24.15). The uterotonic action of BK and the limitation of that action by peptidases were examined using isolated rat uterus. BK contracted the estrus, diestrus and day 22 pregnant rat uterus. N-[1(R,S)-carboxy-3-phenylpropyl]-Phe-p-aminobenzoate (10(-7) M), a specific inhibitor of EP-24.11, and N-[1(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate (10(-6) M), a specific inhibitor of EP-24.15, enhanced BK-induced contraction in the estrus and pregnant uterus. Enalaprilat (6 x 10(-8) M), an inhibitor of ACE, also enhanced BK-induced contraction. The enzyme inhibitors alone did not contract the uterus. Bradykinin B2 receptor antagonism blocked the effects of the inhibitors. ACE is present in the rat uterus, but there are no reports of EP-24.11 or EP-24.15. Here we report that EP-24.11 and EP-24.15 activities are present in the estrus and pregnant rat uterus. Partially purified uterine homogenates metabolized specific model substrates for EP-24.11 and EP-24.15. The enzyme activities were inhibited by N-[1(R,S)-carboxy-3-phenylpropyl]-Phe-p-aminobenzoate and N-[1(R,S)-carboxy-3-phenylpropyl]-Ala-Ala-Phe-p-aminobenzoate, respectively, and increased 5- to 8-fold at term pregnancy as compared to estrus.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Modulatory effect of endopeptidase inhibitors on bradykinin-induced contraction of rat uterus. 839 14

Using microscopic fluorometry and fura-2-loaded cultured bovine aortic endothelial cells, we determined the effects of captopril, an angiotensin converting enzyme (ACE) inhibitor, on bradykinin-induced Ca2+ transients in endothelial cells. In the presence of extracellular Ca2+, 10(-9) M bradykinin induced an early rise in the transients followed by sustained elevations of cytosolic calcium concentration ([Ca2+]i). Bradykinin concentration-dependently increased [Ca2+]i (EC50 6.7 x 10(-9) M). Captopril, 10(-5) M, enhanced and prolonged the bradykinin-induced Ca2+ transients and shifted the concentration-response curve to the left (EC50 8.5 x 10(-10) M). In porcine coronary aterial strips with intact endothelium, cumulative applications of bradykinin induced an endothelium-dependent relaxation during prostaglandin F2 alpha-induced contraction (EC50 = 2.0 x 10(-9) M). Treatment with 10(-5) M captopril enhanced the bradykinin-induced relaxation and shifted the concentration-response curve to the left (EC50 = 7.6 x 10(-10) M). Thus, captopril enhances the bradykinin-induced relaxation by mechanisms mainly dependent on the endothelium, namely the inhibition of ACE.
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PMID:Enhancement by captopril of bradykinin-induced calcium transients in cultured endothelial cells of the bovine aorta. 843 10

1. Conscious, Long Evans rats were chronically instrumented with pulsed Doppler flow probes and intravascular catheters to allow regional haemodynamic (coeliac, mesenteric and hindquarters vascular beds) responses to i.v. bradykinin to be assessed in the absence and presence of captopril and of ganglion blockade (with mecamylamine). 2. Bradykinin (3 nmol kg-1, i.v. bolus) had no effect on mean arterial blood pressure, although it caused hyperaemic vasodilatation in the coeliac, mesenteric and hindquarters vascular beds. Following administration of captopril at a dose (28 nmol kg-1) which had no effect on responses to angiotensin I, the hypotensive and coeliac and mesenteric vasodilator responses to bradykinin were enhanced. However, there was a temporal dissociation between these events indicating that changes in cardiac output must have been contributing to the changes in mean arterial blood pressure. 3. Captopril at a higher dose (280 nmol kg-1) caused reversible inhibition of the pressor and coeliac and mesenteric vasoconstrictor effects of angiotensin I, but the inhibition of the mesenteric vascular responses was significantly less than that of the coeliac vascular responses. Under the same conditions, the mesenteric vasodilator effects of bradykinin were less enhanced than the coeliac vasodilator effects, consistent with greater inhibition of angiotensin-converting enzyme (i.e., kininase II) in the coeliac than in the mesenteric vascular bed. But, since the hypotensive action of bradykinin was markedly enhanced in these circumstances, the possibility existed that baroreflex responses influenced the haemodynamic effects of bradykinin. However, assessment of the haemodynamic changes following bradykinin administration(bolus or infusion) in the presence of ganglion blockade showed that only the hindquarters vasodilator response to bradykinin was enhanced, while the coeliac and mesenteric vasodilator responses were diminished. Thus, additional factors must have been influencing the latter responses.4. The results show that inhibition of angiotensin-converting enzyme (kininase II) can have differential effects on the regional haemodynamic responses to angiotensin I and bradykinin. The results provide a striking illustration of our previous assertion that the measurement of arterial blood pressure alone cannot provide sufficient information to allow interpretation either of the effects of vasoactive substances,or of the influence of drugs thereupon.
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PMID:Differential effects of captopril on regional haemodynamic responses to angiotensin I and bradykinin in conscious rats. 846 63


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