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)

An extracellular protease derived from the culture broth of a microorganism, a Streptomyces species, produced Boc-Pro-Pro and diproline from Boc-Pro-Pro-Pro-Pro. The enzyme was purified 726-fold, with a yield of 2.6%, by ammonium sulfate fractionation, ion-exchange chromatography, and gel filtration chromatography. The molecular weight of the enzyme was determined to be 65,000 by gel filtration and 70,000 by SDS-PAGE. The enzyme released a C-terminal dipeptide from peptide substrates having a C-terminal proline and a penultimate proline or alanine residue, but did not hydrolyze angiotensin I or bradykinin. When the enzyme hydrolyzed Leu-Pro-Pro-Pro-Pro-Pro, it produced Leu-Pro-Pro-Pro and Pro-Pro before producing Leu-Pro. The enzyme thus seems to be a kind of dipeptidyl carboxypeptidase, its substrate specificity being very different from that of the well known dipeptidyl carboxypeptidases [EC 3.4.15.1] such as the angiotensin-converting enzyme.
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PMID:Purification and characterization of a novel dipeptidyl carboxypeptidase from a Streptomyces species. 140 Feb 66

The role of angiotensin receptor subtypes 1 and 2 was assessed on neointima formation after injury in rat carotid artery. The effects of angiotensin converting enzyme inhibition by perindopril (3 mg.kg-1 x day-1 p.o.) and selective blockade of angiotensin subtype 1 receptors by DuP 753 (5 and 30 mg.kg-1 x day-1 p.o.) were compared on proliferative response to balloon injury. In rats treated 6 days before and for 14 days after injury, perindopril significantly reduced (-76%, p < 0.01) myointimal hyperplasia. In contrast, DuP 753 at 5 mg.kg-1 x day-1 did not modify the hyperplastic response to balloon catheterization. Only at 30 mg.kg-1 x day-1 was DuP 753 able to reduce neointima formation (-47%, p < 0.05). This dose was equipotent to perindopril on the renin-angiotensin system as assessed by the pressor response to angiotensin II and angiotensin I. Therefore, blockade of subtype 1 receptors was a less effective means of suppression of myointimal growth than angiotensin converting enzyme inhibition, suggesting that another angiotensin receptor subtype or converting enzyme substrates are involved in this process. For the determination of whether angiotensin subtype 2 receptors were implicated, the specific subtype 2 receptor antagonist CGP 42112A (1 mg.kg-1 x day-1) was continuously infused perivascularly for 14 days in the vicinity of the injured carotid artery. CGP 42112A was as effective in preventing neointima formation as perindopril (-73%, p < 0.01, versus -76%, p < 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Role of angiotensin subtype 2 receptor in neointima formation after vascular injury. 145 89

Since converting enzyme and kininase II are identical enzymes and probably influences both, the biosynthesis of Ang II and the metabolism of bradykinin we investigated the effects of bradykinin, desArg-bradykinin and some bradykinin antagonists (desArg[9]-Leu[8]-bradykinin, HOE S 890307) on the sympathetic outflow of pithed SHR or Brown-Norway-Rats before and after acute or chronic inhibition of the converting enzyme by ramipril. bradykinin increased dose dependently the noradrenaline and adrenaline release in particular when the converting enzyme was inhibited. DesArg-bradykinin caused a dose-dependent increase in adrenaline release only after converting enzyme inhibition. The bradykinin-antagonists led to an increase in adrenaline release during ramipril administration. The weak but significant stimulation of adrenaline release by the bradykinin antagonists after converting enzyme inhibition might be due to unspecific actions on the adrenal medulla possibly induced by histamine release from mast cells.
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PMID:Modulation of presynaptic sympathetic activity by kinins and related compounds: influence of converting enzyme inhibition. 146 84

The angiotensin II (AII) receptor antagonist, DuP 753 (10 mg/kg intraduodenal), produced a sustained and long-lasting antihypertensive effect in conscious renin-dependent hypertensive rats. Blood pressures were still reduced markedly 24 to 72 hr after administration of a single dose of DuP 753. However, pressor responses elicited by either angiotensin I or AII were not blocked at these times despite the continued antihypertensive effect of DuP 753. In a model of orthostatic hypotension, DuP 753 and the selective alpha-1 adrenoceptor antagonist prazosin produced a marked orthostatic hypotension response in renin-dependent hypertensive rats as demonstrated by potentiation of the decrease in blood pressure induced by a 90 degrees tilt. The nonpeptide AII receptor antagonist SK&F 108566 (10 mg/kg intraduodenal) did not produce orthostatic hypotension and the angiotensin converting enzyme inhibitor enalapril produced only a slight orthostatic response to tilting. In conscious spontaneously hypertensive rats (SHR), allowed 3 to 4 days to recover from surgery, administration of either enalapril (1 mg/kg i.v.) or SK&F 108566 (10 mg/kg i.v.) did not significantly effect blood pressure. In SHR tested within 24 hr of surgery, enalapril was effective in lowering blood pressure. In contrast, in surgically recovered SHR, DuP 753 (10 mg/kg i.v.) produced an antihypertensive effect that was slow in onset, sustained and extremely long in duration. Blood pressures did not return to predrug levels until 48 hr after administration of DuP 753. Stimulation of the thoracolumbar sympathetic outflow in pithed rats produced frequency-dependent pressor responses that were significantly potentiated by continuous infusion of a subpressor dose of AII.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The antihypertensive effect of the angiotensin II receptor antagonist DuP 753 may not be due solely to angiotensin II receptor antagonism. 150 Nov 14

Felodipine induces natriuresis, possibly by renal hemodynamic and/or tubular effects. Theoretically, reversal of the sodium-retaining effect of angiotensin II (Ang II) could be involved. Therefore, we administered felodipine during Ang II infusion and during suppression of endogenous Ang II production in two double-blind studies in healthy volunteers. First, a gradually increasing dose of Ang II was infused during felodipine or solvent infusion. Before starting Ang II, felodipine had lowered renal vascular resistance (RVR) and filtration fraction (FF), and simultaneously increased CNa. The Ang II induced rise of mean arterial pressure (MAP) and renal vasoconstriction was partly antagonized and the falls in glomerular filtration rate (GFR) and CNa completely abolished by felodipine. The combination of felodipine and 3.0 ng/kg/min Ang II even enhanced natriuresis. Second, felodipine or solvent was infused after one week of pretreatment with placebo or the angiotensin converting enzyme (ACE) inhibitor ramipril, which reduced MAP and induced renal vasodilatation. Ramipril pretreatment did not influence significantly the blood pressure reduction, renal vasodilatation, and natriuresis caused by felodipine. In conclusion, it seems unlikely that the natriuretic effect of felodipine is due to interference with renal effects of endogenous Ang II. The fact that felodipine reverses sodium retention on exogenous Ang II may be explained by interference with systemic and renal hemodynamic effects of exogenous Ang II.
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PMID:Is natriuresis on felodipine due to reversal of the renal effects of angiotensin II? 153

The response of the human detrusor muscle to angiotensins and the difference in contractility between neurogenic and control bladders were examined. Both angiotensin I and II induced potent contraction of the human detrusor muscle. In Ca-free Krebs' solution the contractile response to angiotensin II was abolished. However, verapamil and indomethacin suppressed it only slightly. Captopril blocked completely the response to angiotensin I, and saralasin inhibited completely the response to both angiotensin I and II. The contraction strength in response to both angiotensin I and II was significantly weaker in the neurogenic bladder than in the control. However, there was no difference in the value of ED50 between the two groups. These findings suggest that angiotensin I is converted to angiotensin II by angiotensin converting enzyme at the detrusor, and that angiotensin II subsequently contracts the detrusor muscle through angiotensin II receptors. The contractility of the neurogenic bladder in response to angiotensin was significantly lower compared to that of the control.
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PMID:[Response of human urinary bladders to angiotensins: comparison between neurogenic and control bladders]. 160 59

The demonstration of all components of the renin-angiotensin system in vascular tissue has raised questions as to the precise location of the local angiotensin II generation within the vascular wall. We investigated the metabolism of angiotensin I to angiotensin II in the vascular wall in the isolated rabbit thoracic aorta. Angiotensin I (3 x 10(-9) M) applied into the aortic lumen was partially converted to angiotensin II (14% after 60 minutes), but most of the luminal angiotensin I was degraded to peptide fragments or diffused as intact angiotensin I, peptide fragments, or both, into the vessel wall. Incubation studies with [3H]angiotensin I revealed that angiotensin I or angiotensin I fragments mainly diffused into the medial layer of the aorta and to a lesser degree into the adventitia and the endothelium. After removal of the endothelium, angiotensin II generation could no longer be detected. Addition of the angiotensin converting enzyme inhibitor ramiprilat (10(-7) M) to the incubation medium led to a complete blockade of angiotensin II generation by endothelial angiotensin converting enzyme. Our results underline the importance of the endothelium for conversion of angiotensin I to angiotensin II and provide evidence that conversion of angiotensin I to angiotensin II is predominantly achieved by endothelial cells. They also support the concept of an endocrine versus autocrine/paracrine renin-angiotensin system where the endothelium of the vasculature is the critical target site for angiotensin II production by both systems and, thus, the most important site for the actions of angiotensin converting enzyme inhibitors.
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PMID:Distribution and metabolism of angiotensin I and II in the blood vessel wall. 163 56

Effects of imidapril hydrochloride ((-)-(4S)-3-[(2S)-2-[[(1S)-1- ethoxycarbonyl-3-phenylpropyl]amino]propionyl]-1-methyl-2- oxoimidazolidine-4-carboxylic acid hydrochloride, imidapril, TA-6366, CAS 89396-94-1), a new prodrug type angiotensin converting enzyme (ACE) inhibitor, and 6366 A (CAS 89371-44-8), an active metabolite of imidapril, on isolated vascular preparations were studied. 6366 A inhibited angiotensin I (AT-I)-induced contraction of the rabbit thoracic aorta at 3 x 10(-10) mol/l or more and augmented bradykinin (BK)-induced relaxation of the dog renal artery precontracted with prostaglandin F2 alpha PGF2 alpha at 10(-9) mol/l or more, whereas imidapril at 10(-7) mol/l did not affect these responses. However, 6366 A, like imidapril, had no effect on angiotensin II (AT-II), norepinephrine, serotonin-, KCl- and PGF2 alpha-induced contractions. The inhibitory effect of 6366 A on AT-I-induced contraction was attenuated by denudation of the endothelium, but it was still maintained even after washing out the aorta that had been previously exposed to the medium containing 6366 A. This suggests that 6366 A persistently inhibits the angiotensin I converting enzyme located preferentially in the endothelium. Therefore, the antihypertensive action of imidapril is mainly attributable to the vasodilation through the inhibitory effects of 6366 A on AT-II synthesis and BK degradation in the vasculature.
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PMID:Effects of the new angiotensin-I-converting enzyme inhibitor imidapril on the responses of isolated vascular preparations to various agonists. 164 67

Activity of prolyl endopeptidase (EC 3.4.21.26) which hydrolyses the Pro7-Phe8 bond in angiotensin II has been found to elevate in experimentally produced granulomatous inflammation in liver and skin. We purified the enzyme 1,536-fold by 6 steps from murine hepatic granulomas. The purified enzyme has a molecular weight of 79 kDa and physicochemical properties equivalent to those previously reported for prolyl endopeptidase purified from other sources. By HPLC analysis, the cleavage of Phe8-Leu10 and Phe8 from angiotensin I and II, respectively, was detected and quantified. Monospecific IgG was prepared from serum of rabbits injected with purified enzyme. Concentration of the enzyme was immunohistochemically detected in cells which form granulomatous organization, but not in inflammatory cells surrounding the foci. The antibody, however, cross reacted with the enzyme in adjacent liver cells and weakly stained their cytoplasm. The findings indicate that this enzyme, in addition to angiotensin converting enzyme, may serve as a useful biochemical marker for granulomatous tissue reactions.
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PMID:Prolyl endopeptidase purified from granulomatous inflammation in mice. 164 66

The pattern of inhibition of tissue angiotensin converting enzyme (ACE) was studied in rats after acute and chronic (14 days) oral administration of perindopril. Free and total tissue ACE were measured by quantitative in vitro autoradiography using [125I]-351A as a radioligand and compared with plasma ACE and pressor responses to angiotensin I. Following oral perindopril, plasma perindoprilic acid and the pattern of inhibition of plasma ACE activity were maximal at 1 to 2 h, but recovered over 24 h. However, inhibition of the pressor response to angiotensin I was more prolonged, being 95% at 4 h, but had not fully recovered by 24 h. Acutely, ACE was markedly inhibited in renal proximal tubules, lung parenchyma, and aortic wall. At 24 h, ACE in these tissues had only partially recovered. Angiotensin converting enzyme in vascular endothelium of other organs showed a similar pattern of inhibition. In contrast, ACE in testicular seminiferous tubules was unaffected by perindopril. After chronic (14 days) administration of perindopril, total plasma ACE increased 3-fold, of which 49% was occupied by the inhibitor. Total tissue ACE in kidney and aorta did not change, and the pattern of inhibition observed acutely was maintained during chronic treatment. These results demonstrate a prolonged effect of ACE inhibitors on tissue ACE that may better explain the time course of these drugs than the changes in plasma ACE or plasma levels of the drugs.
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PMID:Acute and chronic effects of perindopril on tissue angiotensin converting enzyme activity. 164 81


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