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 develop means of measuring angiotensin converting enzyme of endothelial cells in culture, we have synthesized benzoyl-Phe-Ala-Pro-OH (I), benzoyl-Pro-Phe-Arg-OH (II) and benzoyl-Gly-His-Leu-OH (III), each bearing a 3H-atom on the para-position of its benzoyl moiety. All three of the acylated tripeptides are substrates for the enzyme. Substrate I exhibits the lowest Km (12.5 micrometer) and yields the most sensitive assay: the enzyme of 10(6) cells can be measured in a 30 min incubation at 37 degrees C. Radiolabelled reaction product is separated from substrate by extraction of acidified reaction mixture with an organic solvent, and the rate of formation of product can be quantified by liquid scintillation counting of the organic phase. Substrate III can also be used to measure angiotensin converting enzyme of cells but requires longer incubations (180--240 min) and high salt concentrations (0.75 M Na2SO4). Substrate II is not specific: it is hydrolyzed by more than one enzyme of endothelial cells.
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PMID:New substrates for the radioassay of angiotensin converting enzyme of endothelial cells in culture. 3 10

In chloralose-anesthetized dogs, we investigated the disappearance of bradykinin on passage across the renal circulation. The peptide was infused into a renal artery at various doses (5-200 ng/kg min-1); renal blood flow and the concentration of kinins in renal venous blood were then determined and the percent survival of bradykinin on passage through the kidney calculated. Bradykinin caused a dose-related increase in renal blood flow, urine flow, sodium excretion, and kinin content of renal venous blood. Intravenous administration of BPP9alpha (300 mug/kg), a peptide kininase II inhibitor, potentiated the renal vasodilator, diuretic, and natriuretic actions of bradykinin and augmented the survival of the kinin on passage through the kidney from 12.72 +/- 1.64% in control dogs to 53.92 +/- 7.48% (P less than 0.001). Furthermore, the values of peptide survival were positively correlated with the increases in renal blood flow (r = 0.92, P less than 0.01), urine flow (r = 0.75, P less than 0.01), and sodium excretion (r = 0.68, P less than 0.01) produced by bradykinin. In addition, BPP9alpha by itself increased renal blood flow (16%, P less than 0.01), urine flow (115%, P less than 0.005), and sodium excretion (167%, P less than 0.02). Similarly, the concentration of kinin in renal venous blood and the excretion of urinary kinins rose from 0.11 +/- 0.03 ng/ml and 4.1 +/- 1.1 ng/min to 0.24 +/- 0.05 ng/ml (P less than 0.005) and 38.5 +/- 12.2 ng/min (P less than 0.02). These studies suggest that kinins generated intrarenally play a role in the regulation of renal blood flow and salt-water excretion and that variations in the capacity of the kidney to inactivate kinins may be a determinant of the intrarenal activity of the kallikrein-kinin system.
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PMID:Disappearance of bradykinin in the renal circulation of dogs. Effects of kininase inhibition. 16 99

Urines and sera (human, guinea pig and rat) contain low molecular weight inhibitors of angiotensin converting enzyme (ACE). The urines contain ACE, but the enzyme is scarcely measurable without prior ultrafiltration or dialysis. The activity increases strikingly through three ultrafiltration steps using a membrane with a 10,000 MW retention limit. As implied, the ultrafiltrates contain inhibitory activity and can prevent the hydrolysis of [3H]benzoyl-Gly-His-Leu by ACE from any source, including lung and serum. Human urinary ultrafiltrate contains at least three inhibitors separable on Bio-Gel P-2. The inhibitors are acidic and can be partially purified on Bio-Rex 70 developed with an acetic acid gradient. The smallest of the inhibitors can be purified to apparent homogeneity by partition chromatography (sephadex G-25; butanol, acetic acid, H2O; 4:1:5). The excretion of inhibitory activity varies in response to dietary salt: Activity is low when rats are maintained on a high NaCl diet and is high (3 x's control) on a low NaCl diet. Thus, the activity of ACE may be modulated in vivo by naturally-occurring enzyme inhibitors. Whether some hypertensive patients are deficient in ACE inhibitory activity remains to be determined.
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PMID:Mammalian inhibitors of angiotensin converting enzyme (kininase II). 22 13

1. Isoprenaline hydrochloride injected subcutaneously in rats given a choice test of 1.8% NaCl and water, first induced saline intake which started immediately and was almost concluded in 15 min, followed by a copious water intake. When either saline or water were given in a separate test, saline intake surpassed the water intake in the first 15 min.2. The delay of 15, 30 or 60 min after injection of isoprenaline, 100 mug/kg, before drinking was allowed, significantly reduced saline intake but did not modify the amount of water subsequently drunk.3. Isoprenaline caused a sudden drop in arterial blood pressure, the extent and duration depending on the dose. The time of maximum drop 3-4 min after injection coincided with the time the rat drank salt.4. Isoprenaline-induced saline drinking was significantly reduced after bilateral nephrectomy but water intake was unaffected.5. The beta-adrenoceptor blocking agent, propranolol, inhibited isoprenaline-induced NaCl and water intake, while the alpha-adrenoceptor antagonist phenoxybenzamine abolished isoprenaline-induced NaCl intake and enhanced water intake.6. Saralasin acetate (P-113), a competitive inhibitor of angiotensin II, given into the third brain ventricle, prevented the isoprenaline-induced NaCl and water intake as well as angiotensin II-induced drinking. The angiotensin converting enzyme inhibitor SQ-20881 reduced the isoprenaline-induced NaCl and water intake.7. In conclusion, hypotension might be a component of salt drinking evoked by isoprenaline although the dipsogenic action of beta-stimulation is mainly due to endogenous renin-angiotensin activation.
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PMID:Drinking behaviour in rats treated with isoprenaline, angiotensin II or angiotensin antagonists. 23 Nov

We assessed the role of the renin-angiotensin system in the response of the renal circulation to restriction of sodium intake in 38 normal patients. Both saralasin (10 to 30 ng/kg/min), an angiotensin antagonist, and SQ 20881 (30 to 300microgram/kg), a converting enzyme inhibitor, induced a dose-related increase in renal blood flow (xenon 133 washout) only when the resin-angiotension system was activated by restriction of sodium intake to 10 MEq/day. Increasing doses of saralasin (100 to 1,000 ng/kg/min) reduced renal blood flow, presumably due to the angiotensin-like action of this partial agonist. The renal vascular response to SQ 20881 paralleled the endocrine response: An identical threshold dose (30 microgram/kg) increased renal blood flow and reduced plasma angiotensin II concentration, which fell despite a progressive rise of plasma renin activity. Plasma bradykinin concentration did not change in response to SQ 20881, which also blocks kininase II. Both agents also induced a small but consistent and statistically significant reduction in arterial blood pressure, which will be important in assessing the pathogenetic significance of a blood pressure reduction in patients with hypertension. This study indicates that angiotensin mediates the renal vascular response to restriction of salt intake in normal man and provides an approach to assessing the role played by angiotensin in the pathogenesis of functional renal disease.
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PMID:Renal vascular response to interruption of the renin-angiotensin system in normal man. 59 39

The mechanism by which the angiotensin converting enzyme inhibitor, teprotide (SQ 20881), lowers blood pressure was assessed in anesthetized normotensive and spontaneously hypertensive (SHR) rats. Teprotide always was administered at a maximally effective dose of 1 mg/kg. In six normal Wistar rats, teprotide lowered blood pressure only after sodium depletion, an effect which was abolished by bilateral nephrectomy. Saralasin infusion (5 microgram/kg/min) into salt-depleted normal rats induced a blood pressure effect similar to that of teprotide. When administered in addition to saralasin infusion, teprotide did not reduce blood pressure further in normal rats or in SHR. When blood pressure of normal rats was raised by angiotensin II infusion (200 ng/kg/min), teprotide did not affect the induced blood pressure increase. In contrast, the pressure rise induced by angiotensin I infusion (230 ng/kg/min) was reversed by saralasin, but again concomitant administration of teprotide did not induce further blood pressure reduction. Thus, under the particular conditions of the present study, teprotide did not appear to exert its hypotensive effect by any mechanism other than inhibition of the renin-angiotensin system. Furthermore, given at a maximally effective dose to the rat, it produced no greater vasodepressor effect than did saralasin.
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PMID:Mechanism of blood pressure reduction by teprotide (SQ 20881) in rats. 65 Nov 28

In a detailed study focused on the methodological problems in dehydrogenase histochemistry [e.g., fixation, diffusion of enzymes and of reduced inermediates, conversion of NADPH and NADP to NADH and NAD, respectively, penetration of tetrazolium salt and formazan substantivity, 'nothing dehydrogenase' reaction, use of exogenous CoQ10 and of flavoprotein substitute (PMS)], the distribution and activity of succinate dehydrogenase, NAD(P)H-tetrazolium reductase, glucose-6-phosphate dehydrogenase, lactate dehydrogenase (H and M types), and of L-glutamate dehydrogenase (E.C.1.4.1.2 and E.C.1.4.1.3) have been investigated in the rat cerebellum. It was evident from the study that reliable results could only be obtained if all the aforementioned factors had been considered. The image of actual concentration of SDH in the neuropil of the molecular layer could only be recorded by adding CoQ10, while other structures exhibited greater balance between SDH and endogenous mitochondrial CoQ. Contrary to previous studies, a reversed localization of the activity of G-6-PDH and LDH was noticed. The elements of molecular and Purkinje layers were rich in G-6-PDH, while the granular layer was nearly depleted. The actual level of LDH could only be recorded if NADH-tetrazolium reductase was bypassed with PMS. The H and M types of LDH coexisted in the three cortical layers, the H type being prevalent and the M type attaining its highest level in synaptic glomeruli followed by the structures of the molecular layer and the Purkinje cells. High activity of GDH was noticed in Bergmann glia followed by synaptic glomeruli, while most other structures showed weak to moderate activity. The two GDH types coexisted in all structures showing activity, except for Bergmann cells, which only showed presence of the E.C. 1.4.1.3 type. Furthermore, Bergmann glia was exceptional by showing no activity of SDH and LDH, but strong activity of G-6-PDH and NADPH-tetrazolium reductase. The granular cells were exceptional by showing weak or no activity of all enzymes in question.
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PMID:Methodological aspects of the histochemical localization and activity of some cerebellar dehydrogenases. 66 87

Kinins and prostaglandins of the E series (PGE) have the capacity to influence renal hemodynamic and excretory events and may interact intrarenally so as to reinforce one another. Thus, in the isolated Krebs-perfused rabbit kidney we showed that addition of either bradykinin or kininogen to the perfusing fluid augments the release of a PGE-like substance and that aprotinin, a kallikrein inhibitor, reduces the release of prostaglandins evoked by kininogen but not by bradykinin. Moreover, we have observed that deoxycorticosterone, an agent which increases urinary kallikrein, enhances the urinary excretion of PGE-like substance, and that this effect is prevented by simultaneous treatment with aprotinin. These observations and our demonstration that enhanced intrarenal activity of the kallikrein-kinin system, consequent to kininase II inhibition, is associated with renal vasodilation, diuresis, and natriuresis, suggest that a coupling of kinins and prostaglandins intrarenally may be directed towards the facilitation of salt-water excretion. The interdigitation of prostaglandins and the kallikrein-kinin system may thereby constitute the essential operation of a regulatory system in which the complementary actions of these hormones antagonize the sodium retaining effect of mineralocorticoids in those states in which salt-water balance is positive.
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PMID:Interaction of mineralocorticoids, renal prostaglandins and the renal kallikrein-kinin system. 76 63

With the availability of a wide selection of antihypertensive drugs acting by different mechanisms, it should be possible to match the requirement of individual patients with the pharmacological and clinical properties of an appropriate agent. Although the concept of stepped-care therapy is now largely outdated, therapy must be initiated with one agent. Diuretics remain a first-choice option in the elderly and in Black patients, as do calcium antagonists. In patients with ischaemic heart disease or enhanced adrenergic drive, beta-blockers are preferred. Calcium antagonists or ACE inhibitors are finding increasing use as initial therapy when quality of life is important and metabolic neutrality is required. The choice of antihypertensive agent may be limited by adverse effects, e.g. pedal oedema with nifedipine, constipation with verapamil, and cough with ACE inhibitors. Certain advantages are evident for both calcium antagonists and ACE inhibitors. Calcium antagonists are more likely to be effective first-line therapy than ACE inhibitors in Black patients, in those with a high salt intake, in patients with Raynaud's disease, and when angina pectoris is present. ACE inhibitors are preferred for use in combination with diuretic agents, and in the presence of congestive heart failure or low salt intake. Combination therapy between these 2 drug classes is finding increasing acceptance because of its many theoretical advantages, and may provide a means of maximising benefit.
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PMID:Choosing the correct drug for the individual hypertensive patient. 128 79

Diabetes mellitus (DM)-linked metabolic alterations and hypertension concomitantly accelerate or precipitate cerebrovascular and coronary heart disease, nephropathy, retinopathy and widespread macroangiopathy, thereby conferring to diabetic patients a very high risk of morbidity, disability and early death. Therefore, the long-term care for diabetic patients should be aimed at concomitant metabolic and blood pressure (BP) control. Dietary measures are indispensable; a high fibre, low fat, low salt diet is recommended, complemented with caloric restriction and physical exercise when body weight is above the ideal. Antidiabetic pharmacotherapy involves an unresolved dilemma. The desired achievement of euglycemia necessitates effective levels of insulin, but hyperinsulinemia (due to parenteral [over]treatment in insulin-dependent DM) is suspected to promote atherogenesis and represents a coronary risk factor and perhaps even facilitates hypertension. Considering antihypertensive pharmacotherapy, thiazide-type or loop diuretics are problematic drugs in DM because they can aggravate metabolic alterations. These agents also seem to exert only a limited preventive or regressive effect on left ventricular hypertrophy (LVH); beta-blockers are also not considered ideal, since they decrease the awareness of hypoglycemia and tend to promote glucose intolerance. Unselective beta-blockers in particular promote peripheral ischemia and insulin-induced hypoglycemia, while beta-blockers without intrinsic sympathomimetic activity lower serum HDL-cholesterol. Calcium antagonists and ACE inhibitors have equivalent antihypertensive efficacy, do not impair carbohydrate and lipid homeostasis or peripheral perfusion and can effectively improve LVH. Certain ACE inhibitors may even slightly ameliorate abnormal insulin sensitivity and plasma glucose levels. While alpha-blockers share most of these desirable properties, these agents are more prone to precipitate orthostatic hypotension in the diabetic patient. The non-thiazide diuretic indapamide and the serotonin2-antagonist ketanserin also combine antihypertensive efficacy with metabolic neutrality. The ultimate goal of therapy is to improve life prognosis. In essential hypertension, conventional drug treatment based on diuretics in high dosage satisfactorily reduced cerebrovascular but not coronary complications or sudden death. In diabetic patients, the influence of antihypertensive therapy on prognosis has not been assessed prospectively. Based on retrospective analyses, Warram et al reported a 3.8 times higher mortality in diabetics treated with diuretics alone, than in diabetics with untreated hypertension (Arch Intern Med. 1991;151:1350). H. H. Parving calculated that effective BP control in patients with diabetic nephropathy might reduce 10 year-mortality from about 65 to 20 percent (J Hypertension. 1990; 8[Suppl 7]:187).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Antihypertensive therapy in diabetic patients. 128 10


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