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)

Captopril ((2S)-1-(3-mercapto-2-methyl-propionyl)-L-proline) inhibited the bifunctional, Zn(2+)-containing enzyme leukotriene A4 hydrolase/aminopeptidase reversibly and competitively with Ki = 6.0 microM for leukotriene B4 formation and Ki = 60 nM for L-lysine-p-nitroanilide hydrolysis at pH 8. Inhibition was independent of pH between pH 7 and 8, the optimum range for each catalytic activity. Half-maximal inhibition of leukotriene B4 formation by intact erythrocytes and neutrophils required 50 and 88 microM captopril, respectively. In neutrophils and platelets neither 5(S)-hydroxyeicosatetraenoic acid, 12(S)-hydroxyeicosatetraenoic acid, nor leukotriene C4 formation were reduced, indicating selective inhibition of leukotriene A4 hydrolase/aminopeptidase, not 5-lipoxygenase, 12-lipoxygenase, or leukotriene C4 synthase. In whole blood, captopril inhibited leukotriene B4 formation with an accompanying redistribution of substrate toward formation of cysteinyl leukotrienes. The decrease in leukotriene B4 was more substantial than the corresponding increase in cysteinyl leukotrienes suggesting that nonenzymatic hydration predominates over transcellular metabolism of leukotriene A4 by platelets during selective inhibition of leukotriene A4 hydrolase. Enalapril dicarboxylic acid and Glu-Trp-Pro-Arg-ProGln-Ile-Pro-Pro which inhibit angiotensin-converting enzyme: angiotensin I, bradykinin, and N-[3-(2-furyl)acryloyl]Phe-Gly-Gly which are substrates; and chloride ions which activate angiotensin-converting enzyme did not modulate leukotriene A4 hydrolase/aminopeptidase activity. The results indicate that: (i) the sulfhydryl group of captopril is an important determinant for inhibition of leukotriene A4 hydrolase/aminopeptidase, probably by binding to an active site Zn2+; (ii) aminopeptidase and leukotriene A4 hydrolase display differential susceptibility to inhibition; (iii) there is minimal functional similarity between angiotensin-converting enzyme (peptidyl dipeptidase) and leukotriene A4 hydrolase/aminopeptidase; (iv) captopril may be a useful prototype to identify more potent and selective leukotriene A4 hydrolase inhibitors.
J Biol Chem 1991 Sep 05
PMID:Inhibition of leukotriene A4 hydrolase/aminopeptidase by captopril. 188 82

Blockade of the renin-angiotensin system by an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II (Ang II) antagonist is accompanied by a reactive rise in renin release. This rise is generally attributed to interruption of the short feedback loop between Ang II and renin release. Similarly, after the administration of a renin inhibitor, the plasma concentrations of active and total renin are increased and plasma renin activity is suppressed. The aim of the present study was to investigate if a fall in the plasma Ang II level is the unique determinant of the rise in the active renin (AR) level that follows renin inhibition. Six normal male volunteers participated in three successive 240-minute experiments at weekly intervals according to a single-blind randomized Latin square design. For experiment 1, Ang II was infused at 2 ng/kg/min from 0 to 60 minutes and at 4 ng/kg/min from 60 to 120 minutes. For experiment 2, 0.3 mg/kg of the new potent renin inhibitor Ro 42-5892 was injected at 30 minutes followed by infusion at 0.1 mg/kg/hr from 30 to 240 minutes. For experiment 3, Ang II and Ro 42-5892 were administered simultaneously at the same doses as described above. The mean +/- SEM Ang II concentration increased from 10.2 +/- 1.6 to 33.7 +/- 11.2 pg/ml after infusion of exogenous peptide. It decreased from 9.5 +/- 0.9 to 1.4 +/- 0.3 pg/ml after the injection of Ro 42-5892 and increased from 15.6 +/- 2.9 to 37.1 +/- 11.8 pg/ml after the simultaneous infusion of both compounds.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension 1991 Sep
PMID:Renin release regulation during acute renin inhibition in normal volunteers. 188 41

Radioisotopic renal scanning after angiotensin converting enzyme inhibition (ACEI) has proven to be an exciting area for research. The biologic activity of markers such as DTPA and hippuran, when combined with the physiological effects of ACEI, may provide noninvasive methods of diagnosing both renal artery stenosis and renovascular hypertension. Recent investigators have demonstrated that the sensitivities and specificities of these tests may vary widely; these differences are probably due to variations in study design, patient population, diagnostic criteria, and outcome measurements. We have reviewed these studies and discuss these possible sources of variation and their impact on the clinical usefulness of these diagnostic tests, especially in relation to the prevalence of disease in the population. Current results suggest that the post-ACEI DTPA scan is relatively accurate in the diagnosis of renal artery stenosis, with sensitivity generally greater than 90% and specificity around 95%. However, the best results in predicting the response to angioplasty or surgery in patients with renal artery stenosis have been with the use of post-ACEI hippuran in combination with furosemide (sensitivity, 96%; specificity, 95%). With confirmation of these findings and continued investigation, it is expected that accurate noninvasive tests will be available for widespread clinical use in the near future.
Hypertension 1991 Sep
PMID:Diagnostic usefulness of renal scanning after angiotensin converting enzyme inhibitors. 188 44

Vasoactive hormones acting as endocrine, neuroendocrine, or local hormonal systems (intracrine, autocrine, and paracrine) are an important component of the many factors that regulate blood pressure. Hypertension may be the result of an alteration in the balance between vasodepressor and vasopressor hormonal systems. Changes in this balance could be due to genetic factors such as mutations in one of the genes of the vasoactive system or environmental factors that alter the synthesis and release of one or more vasoactive hormones. Endocrine and neuroendocrine vasopressor hormonal systems, such as the renin-angiotensin system and catecholamines, play a well-established and important role in the regulation of blood pressure and the pathogenesis of some secondary forms of hypertension. The blockade of such systems has already resulted in effective antihypertensive treatment. The role of local hormonal systems is less well established; however, recent evidence suggests they also play an important role in the regulation of blood pressure and the pathogenesis of hypertension. Some vasopressor hormonal systems, such as the renin-angiotensin system, can act as both endocrine or local hormonal systems. Work using transgenic rats harboring the mouse Ren-2 gene has conclusively demonstrated that the renin-angiotensin system, acting as a local hormonal system, has the capability to cause severe hypertension. Whether this model of experimental hypertension mimics any type of human hypertension is not known. Vasodepressor hormones such as kinins, prostaglandins, and endothelium-derived relaxing factor (EDRF) act mainly as local hormonal systems, with the notable exception of atrial natriuretic factor, which may act as both an endocrine and a local hormone. The tissue kallikrein-kinin system, acting either directly or via paracrine eicosanoids or EDRF, participates in local regulation of the circulation, renal function, and the acute antihypertensive effect of angiotensin converting enzyme inhibitors. A restriction fragment length polymorphism (RFLP) that distinguishes the kallikrein gene family of a strain of spontaneously hypertensive rats (SHR) from normotensive Brown Norway rats has been identified. In a set of 32 recombinant inbred strains derived from these SHR and Brown Norway strains, the RFLP marking the kallikrein gene family of SHR cosegregated with an increase in blood pressure. Also, in a study of Utah families it was found that a dominant-allele kallikrein gene expressed as high urinary kallikrein excretion was associated with a decreased risk of essential hypertension. In conclusion, vasopressor and vasodepressor hormones, acting not only as endocrine but also as local hormones, play an important role in the regulation of blood pressure and the pathogenesis of hypertension.(ABSTRACT TRUNCATED AT 400 WORDS)
Hypertension 1991 Sep
PMID:Local hormonal factors (intracrine, autocrine, and paracrine) in hypertension. 188 59

Derangements of the peripheral circulation play a major role in the pathophysiology of congestive heart failure. Their appearance coincides with that of the symptoms and signs that characterize the full-blown clinical syndrome. Long-term therapy with ACE inhibitors partially reverses these abnormalities, but the pathologic mechanisms are still poorly understood.
Hosp Pract (Off Ed) 1991 Sep 15
PMID:Peripheral circulatory response in cardiac failure. 189 18

The effects of angiotensin converting enzyme inhibitors (ACEI) on proteinuria, renal function, and serum proteins were evaluated in six children with steroid-resistant nephrotic syndrome and proteinuria of 3-15 g/24 h (277 +/- 47 mg/m2 per hour). Following ACEI, proteinuria decreased from 7,408 +/- 2,385 (mean +/- SEM) to 3,746 +/- 1,395 mg/24 h (P less than 0.05). Creatinine clearance was 87.8 +/- 22.6 before and 96.4 +/- 23.6 ml/min per 1.73 m2 after ACEI. In two patients, inulin and para-aminohippuric acid clearances were normal before and after ACEI, together with parallel reductions of urine protein of 50% and 46%. Clearance of total protein was reduced by 56% following ACEI, compared with reduction in the clearance of gamma globulin by 58% and albumin by 39.5%. No significant change was seen in blood pressure, serum albumin, or total protein following ACEI. After ACEI, diuretic doses were able to be reduced or eliminated in three patients. Reduction of proteinuria was sustained during a followup period of 11-20 months in three patients. ACEI may be of benefit in the clinical management of children with steroid-resistant nephrotic syndromes, allowing reduction in diuretic requirements.
Pediatr Nephrol 1991 Sep
PMID:Angiotensin converting enzyme inhibitors for reduction of proteinuria in children with steroid-resistant nephrotic syndrome. 191 Nov 44

A major issue in the study of the pathogenesis of primary biliary cirrhosis is whether the E2 subunit of the pyruvate dehydrogenase complex (PDH-E2), the major autoantigen in the disease, exists as a tissue-specific isoform. cDNA clones spanning a segment of the 3'-catalytic region of PDH-E2 (nt 1158-1361) have been isolated from human kidney, placenta and bile epithelium cells. Nucleotide sequence analysis of the clones showed differences consistent with the presence of normal variants of PDH-E2 in the human population. However, the existence of tissue-specific isoforms of PDH-E2 cannot yet be discounted.
Biochim Biophys Acta 1991 Sep 23
PMID:The human pyruvate dehydrogenase complex: a polymorphic region of the lipoate acetyl transferase (E2) subunit gene. 191 85

Arteriosclerosis is the hallmark of hypertension and of its complications, namely stroke, coronary artery disease and ischaemic renal failure. The earliest morphological change in the arteriosclerotic process is vascular smooth muscle hypertrophy and hyperplasia. Angiotensin II is an important growth factor in vascular smooth muscle cells. The chronic administration of ACE inhibitors will reverse many of the changes of vascular hypertrophy in experimental animal models, and will improve vascular compliance in hypertensive patients. Some differences have been reported between different ACE inhibitors with respect to blood pressure-lowering effect and regression of medial hypertrophy in spontaneously hypertensive rats.
S Afr Med J 1991 Sep 21
PMID:Reversal of structural changes in hypertensive arteries--a major prospect for the future. 192 14

Nitroglycerin and the organic nitrates (RONO2) can be considered prodrugs that require conversion to an active intracellular moiety that initiates vascular smooth muscle relaxation. Vasodilation of veins and arteries occurs when the enzyme guanylate cyclase (GC) is activated, initiating the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP); this is the final pathway for vascular dilation caused by the nitrovasodilators (organic nitrates, sodium nitroprusside, and molsidomine) as well as endothelium-derived relaxing factor (EDRF). The common denominator appears to be the intracellular production of nitric oxide (NO), which is the activated product of organic nitrate denitration. Nitrate tolerance has been associated with a relative depletion or unavailability of thiol groups that are involved in the initial step of denitration of RONO2. Sulfhydryl groups (SH) are oxidized during this process; with continuous nitrate exposure, decreased nitrate metabolism within the vascular smooth muscle cell occurs as a direct result of the depletion of reduced SH groups. Thus, less NO is formed and cGMP production is diminished, with a subsequent decrease or absence of vasodilation. In addition, SH groups or thiols are required for the production of S-nitrosothiols (RSNO). These short-lived compounds have been identified as an end product of organic nitrate metabolism and as possibly obligatory for the induction of GC. It is unclear, however, as to whether S-nitrosothiols are a necessary by-product of NO production from organic nitrates. It appears that RSNO can be formed outside the cell membrane and may be able to induce vasorelaxation after penetrating the cell and initiating GC activation. Exogenous SH donors, particularly N-acetylcysteine (NAC), have been employed to provide intracellular thiols in efforts to prevent or reverse nitrate tolerance. Nitrate physiologic actions are accentuated following NAC administration in the absence of tolerance. Although controversial, the concept that NAC or other thiols might be able to prevent the development of nitrate tolerance is being actively studied in laboratories around the world. Methionine has also been utilized as an SH donor with some success. Not all data are consistent, however, and the ultimate role of thiol donors for the prevention or reversal of nitrate tolerance remains uncertain. Finally, there has been considerable interest in supplying thiols by use of the SH-containing angiotensin converting enzyme inhibitors, such as captopril. This approach does not seem promising, probably because insufficient thiol can be supplied by therapeutic dosages of these drugs.
Am J Med 1991 Sep 30
PMID:Interactions between organic nitrates and thiol groups. 192

The major differences that have been recognized between black and white hypertensives are primarily epidemiologic, with hypertension being more prevalent, having an earlier onset, and having more severe sequelae in the black population. The cause of the problem in both black and white people remains obscure, but it appears that a difference in sodium handling may contribute to the particular hemodynamic and hormonal profile of black hypertensives. Salt sensitivity, expanded plasma volume and low renin levels have been the hallmark of the black hypertensive. Complications such as stroke and left ventricular hypertrophy remain the major sequelae of this disease in blacks. Finally, a current study confirmed the improved efficacy of antihypertensive therapy in blacks to diuretics and calcium channel blockers and a somewhat lower efficacy profile to angiotensin converting enzyme inhibitors and beta blockers, although the latter classes of agents have shown better response in blacks than previously thought.
Prim Care 1991 Sep
PMID:Hypertension in blacks. 194 90


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