Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.24.11 (CD10)
 9,792 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In this paper, we present the amino-terminal sequence of rat tonin, an endopeptidase responsible for the conversion of angiotensinogen, the tetradecapeptide renin substrate, or angiotensin I to angiotensin II. It is shown that isoleucine and proline occupy the amino- and carboxy-terminal residues respectively. The N-terminal sequence analysis permitted the identification of 34 out of the first 40 residues of the single polypeptide chain composed of 272 amino acids. These results showed an extensive homology with the sequence of many serine proteases of the trypsin-chymotrypsin family. This information, coupled with the slow inhibition of tonin by diisopropylfluorophosphate, classified this enzyme as a selective endopeptidase of the active serine protease family.
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PMID:N-Terminal amino acid sequence of rat tonin: homology with serine proteases. 21 93

Inactive human renin is found in amniotic fluid, plasma, and kidney and may be a renin precursor ("prorenin"). The mechanism of activation of inactive renin in vivo is not known. The present study examined the hypothesis that cathepsin D, a lysosomal pepsin-like endopeptidase may be capable of eliciting activation. Cathepsin D was incubated with inactive renin in human amniotic fluid at pH 4.8 and 22 C for 0-5 h. Marked activation occurred and the reaction displayed first order kinetics with respect to the concentration of cathepsin D. The initial velocity of conversion of inactive renin to active renin by cathepsin D was 0.007%/min/microgram cathepsin D. Under identical conditions, the initial velocity of conversion by pepsin was 0.18%/min/microgram pepsin. The 25-fold higher potency of pepsin compared with cathepsin D is in accordance with the recognized relative substrate affinities and catalytic efficiencies of the two enzymes. Inactive renin in human amniotic fluid seems to be similar to that found in human kidney and since cathepsin D is present in juxtaglomerular cells, this activation process may have physiological importance.
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PMID:Activation of human inactive ("pro-") renin by cathepsin D and pepsin. 37 40

Despite the availability of numerous antihypertensive agents, a concerted research effort to develop new approaches to hypertension treatment is necessary. Published results of large multicenter trials emphasize the benefits of available treatments in highly selected patients. A critical look at the results shows that treatment failure is frequent and side effects are common. In the Systolic Hypertension in the Elderly Program, 28 to 35% of patients did not reach the goal blood pressure, 13% stopped treatment because of side effects, and 21% required medication other than a diuretic and a beta-blocker. Basic research may bring forth novel concepts of treatment, such as neutral endopeptidase inhibition, renin inhibition, or new techniques such as gene therapy. In the meantime, among many other lines of research, type 1 angiotensin II-receptor antagonists represent a promising new group of agents for the vast majority of hypertensive patients who are renin-dependent. A different global approach to hypertension management is also needed. Because hypertension is a heterogeneous disease, individual sequential monotherapy or the "N of 1" trial aim to select the most effective drug for each patient. To achieve the accurate assessment of drug efficacy that is a prerequisite for this approach, the number of blood pressure measurements before and during drug administration must be increased. For this purpose, self-blood pressure measurement and teletransmission of results to the physician will provide a major treatment advance.
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PMID:Improving hypertension treatment. Where should we put our efforts: new drugs, new concepts, or new management? 129 Jun 21

Atrial stretch causes the release of atriopeptin (AP, ANF) from preformed vesicular storage sites. The circulating hormone acts on unique receptor sites (containing guanylate cyclase) to release guanosine 3',5'-cyclic monophosphate (cGMP) that mediates the natriuresis and vasodilation and probably the suppression of renin, aldosterone, and vasopressin. The biological effects of atriopeptin are transient because of the rapid inactivation of the circulating hormone (by neutral endopeptidase or clearance receptors) or the second messenger (by cGMP-phosphodiesterase). Heart failure due to chronic cardiac volume overload [aortovenocaval (A-V) fistula] exhibits markedly elevated circulating AP blood levels and urinary cGMP levels, accompanied by induction of ventricular AP gene and protein expression and release. Pharmacological manipulation of endogenous AP, either by inhibiting cGMP phosphodiesterase (i.e., mediator prolongation) or neutral endopeptidase (i.e., prolongation of hormone half-life) in A-V fistula animals results in profound natriuresis and diuresis without hypotension. These pharmacological maneuvers bypass the suppressed renal response to exogenous AP seen in heart failure and provide a rational therapeutic strategy based on our understanding of the underlying physiological and pathological mechanisms.
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PMID:Effect of pharmacological manipulation of endogenous atriopeptin activity on renal function. 131 20

We investigated the processing enzymes involved in the formation of circulating angiotensin-(1-7) after intravenous administration of angiotensin I to conscious spontaneously hypertensive and Wistar-Kyoto rats. Immunoreactive products, including angiotensin I, angiotensin II, and angiotensin-(1-7), were measured in arterial blood by three specific radioimmunoassays. Angiotensin I infusion (2 nmol) induced a rapid increase in immunoreactive angiotensin II and angiotensin-(1-7). Pretreatment with the angiotensin converting enzyme inhibitor enalaprilat (2 mg/kg) eliminated angiotensin II formation and augmented circulating levels of angiotensin I and angiotensin-(1-7) in spontaneously hypertensive and Wistar-Kyoto rats. The elevated levels of angiotensin-(1-7) in enalaprilat-treated rats were blocked by concurrent treatment with the neutral endopeptidase (EC 3.4.24.11) inhibitor SCH 39,370 (15 mg/kg) in both strains. Administration of SCH 39,370 alone decreased angiotensin-(1-7) levels in spontaneously hypertensive rats, whereas angiotensin II levels increased in both strains (p less than 0.01). Comparisons of the metabolism of angiotensin I in the two rat strains showed increased formation of angiotensin-(1-7) in spontaneously hypertensive rats not given any of the enzyme inhibitors. In addition, levels of angiotensin I were higher after administration of SCH 39,370 in hypertensive rats. These novel findings reveal that neutral endopeptidase EC 3.4.24.11 participates in the conversion of angiotensin I to angiotensin-(1-7) and in the metabolism of angiotensin II in the circulation of both spontaneously hypertensive and Wistar-Kyoto rats. Our results suggest that neutral endopeptidase EC 3.4.24.11 is a major enzymatic constituent of the circulating renin-angiotensin system.
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PMID:In vivo metabolism of angiotensin I by neutral endopeptidase (EC 3.4.24.11) in spontaneously hypertensive rats. 131 52

All four components of the kallikrein-kinin system--kininogens, tissue kallikreins, kinins, and kininases--have been found in human male genital secretions. Kinins are continuously released from seminal plasma kininogens through limited proteolysis by kininogenases like tissue kallikrein from prostate and sperm acrosin. Kinins are the terminal effectors of the kallikrein-kinin system and increase sperm motility and sperm metabolism at nanomolar concentrations. Recent investigations indicate that these effects are possibly mediated by a specific sperm membrane integrated bradykinin receptor, subtype B2. The two major kininase that are present in seminal plasma are kininase II and neutral metallo-endopeptidase. Kininase II, which is identical with angiotensin-converting enzyme, is also involved in the renin-angiotensin system as it converts angiotensin I into angiotensin II and thus is the connecting enzyme of both systems. Apart from the observed effects of kinins on sperm motility, the kallikrein-kinin system is thought to be involved in the regulation of spermatogenic functions of the testis: in the rat, kallikrein activates Sertoli cell function, increases the relative number of spermatocytes and the [3H] thymidine incorporation of testicular tissue, enhances glucose-intake, and increases testicular blood flow. Clinical trials showed that systemic administration of kallikrein may be particularly useful for treatment of infertile men suffering from asthenozoospermia and/or oligozoospermia. During kallikrein therapy, the number of spermatozoa and both quantitative and qualitative sperm motility increased, and a significant improvement of the conception rate was achieved. An increased sperm number was also observed after application of the specific kininase II inhibitor captopril.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Possible effects of the kallikrein-kinin system on male reproductive functions. 131 46

Diuretics have long been used to lower blood pressure in hypertensive patients or to control body fluid and electrolyte homeostasis in diseases such as congestive heart failure, chronic renal failure or cirrhosis. The initial response to diuretics is a negative sodium and fluid balance. The diuretic-induced loss of salt and water activates several hormonal systems such as vasopressin, the renin-angiotensin-aldosterone system or the sympathetic nervous system which tend to compensate for the changes in sodium and water balance. This neurohormonal response may have important clinical implications. Thus, the activation of the renin-angiotensin-aldosterone cascade appears to be partially responsible for the flat dose-blood pressure response curve of thiazides in hypertensive patients. It may also be responsible for the difference between responders and non-responders to diuretic therapy and for the development of side-effects such as hypokalaemia, metabolic alkalosis or hyponatraemia. There are several ways to prevent the undesirable consequences of the neurohormonal responses to diuretics. The first is to use low doses of these agents. It is also possible to combine them with agents that block the activity of the renin-angiotensin-aldosterone system such as ACE inhibitors or in combination with drugs that reduce aldosterone secretion such as calcium antagonists. The development of drugs able to enhance urinary sodium excretion and to reduce simultaneously the activity of the renin-angiotensin-aldosterone system may offer a new interesting alternative. This might perhaps be achieved in the future with the administration of neutral endopeptidase inhibitors which interfere with the enzymatic degradation of atrial natriuretic peptide.
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PMID:Neurohormonal consequences of diuretics in different cardiovascular syndromes. 136 43

The renal natriuretic actions of endogenous atrial natriuretic factor are enhanced by neutral endopeptidase inhibition (NEP-I). Recognizing that activation of the renin-angiotensin-aldosterone system in congestive heart failure (CHF) antagonizes the renal actions of atrial natriuretic factor, we hypothesized that angiotensin II antagonism with converting enzyme inhibition would potentiate the renal actions of NEP-I in CHF. To test this hypothesis, the renal responses to a specific NEP-I (SQ 28,603) were assessed in dogs with eight days of experimental CHF produced by rapid ventricular pacing. The renal natriuretic responses to NEP-I in experimental CHF were significant. In the same model of CHF, chronic angiotensin antagonism with converting enzyme inhibition potentiated both renal hemodynamic and excretory responses to NEP-I. The potentiated renal hemodynamic response included significant increases in glomerular filtration rate and filtration fraction. In the CHF group with angiotensin antagonism, an intrarenal infusion of low-dose angiotensin abolished the potentiated renal responses to NEP-I, supporting the concept that intrarenal angiotensin antagonism, rather than improved systemic hemodynamics or potentiation of other peptide systems, mediated the enhanced renal responses to NEP-I in the presence of converting enzyme inhibition.
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PMID:Angiotensin inhibition potentiates the renal responses to neutral endopeptidase inhibition in dogs with congestive heart failure. 165 47

The renal, hormonal and haemodynamic effects of chronic (4 days) dosing with an inhibitor of endopeptidase EC 3.4.24.11 (UK 79300) were assessed in two groups, each of eight normal volunteers, receiving 25 mg every 12 h (group 1) or 100 mg every 12 h (group 2) of UK 79300 in double-blind, balanced-randomized, placebo-controlled, crossover studies. Group 2 (but not group 1) exhibited a significant transient natriuresis (P less than 0.01) and a consequent sustained negative cumulative sodium balance (70 +/- 21 mmol) which was established within 48 h and remained for the duration of dosing with UK 79300. Urine and plasma cyclic guanosine monophosphate (cGMP) levels rose significantly above placebo values (P less than 0.01 and P less than 0.001, respectively) in both groups and the effect was sustained throughout the dosing period. Plasma atrial natriuretic factor (ANF) was slightly enhanced by UK 79300 in group 1 (P less than 0.05) but not significantly increased in group 2. Despite a significant increase in heart rate in both groups (P less than 0.001) and of natriuresis in group 2, there was minimal evidence of renin-aldosterone activation in either group. Trends towards lower systolic pressures, observed in both groups, did not attain statistical significance. These findings suggest chronic treatment with UK 79300 induces an increase in tissue ANF levels, with sustained enhancement of plasma and urine concentrations of ANF second messenger (cGMP) and increased heart rate.
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PMID:Prolonged inhibition of endopeptidase 24.11 in normal man: renal, endocrine and haemodynamic effects. 165 38

We have demonstrated that the isolated perfused rat mesenteric arterial bed (MAB) secretes peptidases capable of metabolizing bradykinin and angiotensin I. The major degradative pathway of bradykinin by enzymes found in the rat MAB perfusate was mediated by carboxypeptidase A-like activity, whereas angiotensin 1 degradation followed two main routes, one attributable to a carboxypeptidase A-like enzyme and the other to an endopeptidase. This latter enzyme seems to be a novel serine peptidase capable of releasing angiotensin II directly from both angiotensin I and renin substrate tetradecapeptide. The rat MAB perfusate was also shown to contain additional endo- and exopeptidases that might play a role in the metabolism of other vasoactive peptides. Our finding that isolated rat MAB secretes peptidases into the perfusion medium indicates that peptide processing within the microvasculature environment may be effected by enzymes besides those normally found in plasma or associated with cell membranes.
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PMID:A survey of vasoactive peptide metabolizing enzymes in the rat mesenteric arterial bed perfusate. 174 67


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