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)

The role of the renin-angiotensin system in the control of blood pressure in normal rodents, primates and man has been evaluated using inhibitors which block the system at various stages. Renin plays a major role in the maintenance of blood pressure under volume depletion. In subjects with a normal salt intake, the contribution of the renin-angiotensin system in maintaining blood pressure levels can be evaluated using angiotensin converting enzyme (ACE) inhibitors. The contribution of the renin-angiotensin system can now be evaluated more closely following the development of new substances which block the renin-angiotensinogen reaction. Available data strongly suggest that renin contributes to the maintenance of blood pressure levels in subjects with a normal salt intake, although to a lesser degree than in subjects on a low sodium intake. The renin-angiotensin system plays a role in the regulation of blood pressure levels in normal experimental animals and man--its importance depending on the state of sodium balance.
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PMID:The role of the renin-angiotensin system in blood pressure regulation in normotensive animals and man. 610 Aug 73

The proteolytic enzyme renin (EC3.4.99.19) cleaves the protein substrate angiotensinogen to yield angiotensin I, the decapeptide substrate transformed by converting enzyme into the pressor substance angiotensin II. Although the contribution of this pathway to the maintenance of normal blood pressure is unclear, it seems to be a major factor in various hypertensive states. Important progress in the control of hypertension has been achieved by development of the potent inhibitors SQ-14,225 (captopril) and MK-421 (enalapril maleate), which block the generation of angiotensin II by the inhibition of angiotensin converting enzyme. An attractive alternative to the inhibition of converting enzyme would be the blockade of the preceding step in the cascade, the renin reaction. We report here new highly potent (IC50 = 10(-9)-10(-8) M) competitive inhibitors of renin in which statine, (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, is incorporated into analogues of the pig renin substrate (Fig. 1).
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PMID:Novel renin inhibitors containing the amino acid statine. 634 56

Direct effects of captopril on renal function were examined in isolated perfused rat kidneys. Captopril induced a significant increase in urinary volume and urinary sodium excretion (1.8- and 1.7-fold, respectively; both p less than 0.005), whereas urinary potassium excretion and renovascular resistance were not significantly changed. Because the perfusion medium lacks angiotensinogen, kininogen and aldosterone, the natriuretic action in perfused kidneys may not be related to its inhibitory action on angiotensin I converting enzyme or kininase II. Because the natriuresis was not accompanied by changes in renovascular resistance, it is suggested that captopril possesses a direct natriuretic action and that this property may partly explain the mechanism of captopril-induced natriuresis clinically observed.
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PMID:Direct renal action of captopril (SQ 14225): dissociation of natriuretic and vascular actions in isolated perfused rat kidney. 704 88

The kidney has been traditionally considered to be one the pivotal organs involved in the systemic actions of the renin-angiotensin system (RAS) with renin produced in the juxtaglomerular apparatus and angiotensin II (ANG II) as a key player in the regulation of glomerular hemodynamics. However, many studies in the last decade, facilitated by a throughout molecular characterization of all elements of the RAS, have provided convincing evidence that the kidney exhibits a local RAS which may independently function from the systemic actions of the endocrine RAS. Moreover, even local distinct cell populations along the nephron possess all components of a functioning RAS. For example, proximal tubular cells express mRNA and protein for angiotensinogen, renin, and angiotensin converting enzyme (ACE). They bear different types of ANG II receptors with the appropriate signal transduction systems, and these cells also exhibit surface proteases like angiotensinase A which are required for the inactivation of ANG II. Moreover, recent studies in the isolated perfused kidney have clearly shown that proximal tubular cells produce considerable amounts of ANG II and these concentrations exceed approximately hundred times the systemic concentration of the peptide. Besides the well-known regulation of glomerular hemodynamics by contraction of the efferent glomerular arteriole and mesangium cells, ANG II influences transport and acidification processes in proximal and distal tubules. In addition, the octapeptide stimulates metabolic pathways like tubular gluconeogenesis and ammoniagenesis. Accumulating data over the last years derived from in vivo and in vitro studies have demonstrated that ANG II is also a growth factor for renal cells. For example, cell culture experiments have shown that the octapeptide stimulates proliferation or hypertrophy of mesangial cells. In contrast, proliferation of cultured proximal tubular cells is inhibited by ANG II and cellular hypertrophy of these cells is induced. Many studies have provided evidence that early mesangial proliferation/hypertrophy and tubular hypertrophy is a predecessor of the subsequent development of glomerulosclerosis and interstitial fibrosis, situations with irreversible morphological changes of the kidney's architecture leading finally to end-stage renal disease. Therefore, the identification of ANG II as a renal growth factor and a better understanding of its local intrarenal synthesis and growth stimulating effects on different cell types along the nephron may help to develop rational therapeutic interventions to prevent the progression of renal disease.
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PMID:Angiotensin as a renal growth promoting factor. 748 25

Recent evidence in rats has indicated that angiotensinogen may be synthesised in adipose tissue surrounding blood vessels and that a local renin-angiotensin system may regulate adipose tissue blood supply and the efflux of fatty acids from fat in that species. This hypothesis is critically dependent on the local expression of the angiotensin converting enzyme gene in adipocytes. Thus the current study set out to examine whether the angiotensin converting enzyme gene was expressed in human adipose tissue and, if it was present, to localise the individual sites of that expression. Northern analysis indicated the presence of mRNA for angiotensin converting enzyme in both subcutaneous and extraperitoneal adipose tissue. In situ hybridisation showed that the gene was expressed in adipocytes. The foregoing results therefore suggest that components of the renin-angiotensin cascade are also present in human adipose tissue and support the hypothesis that adipose tissue may play a role in the local production of Angiotensin II and hence participate in vascular function and blood pressure control in the human.
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PMID:The expression and localisation of the angiotensin-converting enzyme mRNA in human adipose tissue. 751 11

On the basis of recent advances in molecular biology and statistical genetics, it has become possible to search for chromosome regions that contain genes predisposing to hypertension and to directly link specific mutations on candidate genes to hypertension. As the human genome has been extensively mapped, highly informative, polymorphic markers are available, which can be used to detect genes in their proximity with 'hypertensinogenic' alleles. Some of these markers have been shown to be tightly linked to the genes of the renin-angiotensin system. Furthermore, the coding and regulatory regions of the genes encoding for renin, ACE, angiotensinogen and the AT1 receptor have been partially characterized. This provides a basis for further definition of specific polymorphisms within these genes that are of functional importance and that can be used to examine their contribution to the inheritance of primary hypertension. The first studies of these links have already emerged and have been reviewed in this article. Several problems arise in performing such linkage studies in human primary hypertension, however. It is difficult to define the genetic background of heterogeneous, multigenetic and multifactorial diseases such as human hypertension. Extensive studies of population genetics, including the analysis of large numbers of generations and controlled breeding experiments, cannot be performed, for obvious reasons. Blood pressure is not a convenient study trait, because it exhibits great intraindividual variance and also because of the relatively low reliability of just a few indirect measurements obtained under loosely controlled environmental conditions. Twenty-four-hour ambulatory blood pressure measurements may improve such investigations in the near future. Ravogli et al (1990) reported that the 24-hour ambulatory systolic blood pressure is higher in normotensive subjects of hypertensive parents than in normotensive subjects of normotensive parents--a finding that had not been previously reported using the conventional method of measurement. Hypertension as a trait per se is also problematic: its classification (above 140/90 mmHg) is purely artefactual, and its aetiology is highly heterogeneous. Thus, we have to keep in mind that even strong gene effects, if present in only a small subgroup of hypertensives, may not be detected in these studies. Attempts are being made to strengthen the analysis by characterizing physiologically distinct subgroups. In addition, the investigation of intermediate phenotypes, such as plasma parameters, which are more reliable and less subject to variations, may be helpful.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Molecular basis of human hypertension: the role of angiotensin. 757 36

Previous studies have indicated that the hypertension that develops after unilateral arterial constriction (2 kidney, 1 clip) involves an active participation by the non-clipped contralateral kidney. Even though the non-clipped kidney is not the initial causative factors, and despite the progressive renin depletion during the early weeks following clipping, the non-clipped kidney is highly responsive to angiotensin blockers. Furthermore, the non-clipped kidney has augmented tissue ANG II levels and ACE activity suggesting that some renin-independent mechanism may be stimulating intrarenal ANG II formation. This model has been simulated by infusing ANG II at low subpressor doses (40 ng/min) to uninephrectomized rats for 14 days. With this model, plasma and renal renin levels are markedly suppressed; however, the renal ANG II levels are increased to levels above those that can be explained on the basis of circulating ANG II. In agreement with the responses observed in the non-clipped kidney of 2K1C rats, there is also an increased renal ACE activity. In contrast to the marked suppression of renin gene expression and renin activity, angiotensinogen gene expression is not suppressed. These results support the hypothesis that small elevations in circulating ANG II stimulate intrarenal ANG II production through a renin-independent mechanism.
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PMID:Enhancement of intrarenal angiotensin II levels in 2 kidney 1 clip and angiotensin II induced hypertension. 758 82

The successful introduction of angiotensin converting enzyme (ACE) inhibitors in the treatment of patients with essential hypertension or heart failure has increased interest in the (patho)physiological role of the renin-angiotensin system (RAS). ACE is not only involved in the formation of angiotensin II from angiotensin I, but also inactivates vasoactive substances such as bradykinin and substance P. Accumulation of these substances during treatment with ACE inhibitors may contribute to both their therapeutic action and certain adverse effects associated with their use, such as cough and angioneurotic oedema. Renin inhibitors offer an alternative approach to inhibit the RAS. The major advantage of these, still experimental, drugs is their high specificity for the RAS since angiotensinogen is the only known substrate of renin. The currently available renin inhibitors are pseudopeptides that are rapidly taken up by the liver and excreted in the bile. Consequently, these drugs are subjected to a considerable first pass effect which limits their oral bioavailability. Additionally, plasma elimination half-life times are short and the duration of action is limited. Despite these shortcomings, single oral or intravenous administration results in a 80 to 90% inhibition of plasma renin activity and a slight reduction in blood pressure in patients with hypertension. The extent of blood pressure reduction is dependent on the patient's salt balance. After 1 week of oral treatment with the renin inhibitor remikiren, the antihypertensive effect was reduced in salt-repleted hypertensive patients. Subsequent intravenous administration of the drug did not further affect blood pressure, indicating that it was not the first pass effect that was limiting the efficacy of remikiren.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Clinical pharmacokinetics and efficacy of renin inhibitors. 758 99

The concept of classical endocrine control of ovarian function has now been extended to a more complex regulator system, including paracrine and autocrine modulating mechanisms. Among many factors, locally produced intraovarian insulin-like growth factors (IGFs) and the binding proteins (IGFBPs) and renin-angiotensin system (RAS) have been shown to play an important role in the control of folliculogenesis and ovulation. Growth hormone (GH) amplified gonadotropin actions in the process of follicular development and ovulation, at least in part, stimulating ovarian IGF-I production. IGF-I as well as IGFBPs were produced by ovarian granulosa cells. IGF-I acted synergistically with gonadotropins in the stimulation of a variety of granulosa cell functions, including estradiol (E2) and progesterone production and plasminogen activator (PA) activity. Furthermore, rabbit ovarian cells and rat granulosa cells possessed specific IGF type I receptors. The biological effects of IGF-I, including intrafollicular PA activities and ovarian steroidogenesis, were modulated by a family of IGFBPs in a complex manner. In the ovary IGFBP-3 appeared to neutralize the actions of gonadotropin and IGF-I, probably via its ability to sequester IGF-I, in the process of follicular growth, oocyte maturation, and ovulation. A functional local RAS is also known to exist in the ovary. Angiotensin II (Ang II) at 2-h intervals induced oocyte maturation, ovulation, and the production of E2 and prostaglandins (PGs) in the in vitro perfused rabbit ovaries in the absence of gonadotropin. In addition, the intrafollicular Ang II content and renin-like activity were enhanced during the ovulatory process by exposure to hCG, and the concomitant addition of saralasin inhibited hCG-induced ovulation in a dose-dependent manner. Captopril, an inhibitor of angiotensin converting enzyme, significantly inhibited the resumption of meiosis in the ovulated ova and follicular oocytes stimulated by hCG. Autoradiographic study revealed that AT2 receptors were predominantly located in granulosa cells, whereas AT1 receptors were more concentrated in the stroma and the thecal layers. Ang II-stimulated production of E2 and PGs and ovulation were significantly blocked by PD123319, a selective nonpeptide antagonist for AT2 receptors. The increase in ovarian IGF-I synthesis by exposure to hCG or GH induced the stimulation of intrafollicular PA activities. IGFBP-3 blocked the stimulatory effects of gonadotropin in the ovulatory process by neutralizing endogenously produced IGF-I, resulting in reduced intrafollicular PA activities. The increase in intrafollicular PA activities significantly stimulated the generation of Ang II in the preovulatory follicles by an activation of prorenin to renin and/or by the direct cleavage of angiotensinogen.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:[Regulatory system and physiological significance of local factors in the ovary during follicular development and maturation]. 759 85

Plasma renin-angiotensin parameters were measured before and 24h after binephrectomy (BNx) in male Swiss (Ren-1, Ren-2) and BALB/c (Ren-1) female mice (representing the extremes of differences in tissue renin expression), together with in vivo inhibition of residual renin. Plasma Ang II increased from 18.9 +/- 7.3 to 48.1 +/- 16.9 pg/ml after BNx in conscious Swiss mice (+/- sd, p < 0.001, n = 11&12), renin activity (PRA) increased 2.76 times, angiotensinogen (aogen) increased 4.57 times and renin concentration (PRC) fell by 65%. In BALB/c, Ang II+Ang III decreased slightly (56.6 +/- 11 to 37.7 +/- 14.7, p < 0.05, n = 5&6), PRA was unchanged, aogen increased 12 times and PRC fell by 93%. Plasma ACE decreased by 26% and 28% respectively. Aogen did not increase further when post BNx plasma renin was inhibited with antirenin in vivo during 20h. Thus plasma angiotensin is maintained or considerably increased following BNx in mice and the change is consistent with first-order kinetics with respect to renin and aogen in the circulation. Whether the strain carries one or two renin genes, high renal and extrarenal renin production combined with a low plasma aogen phenotype yields resting angiotensin levels similar to other mammals. A kinetic regulation of aogen levels is proposed in mice wherein Ang II production is limited by low substrate concentration thereby ensuring normotension in the face of abundant extrarenal renin secretion.
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PMID:Plasma angiotensin in binephrectomised mice. 765 52


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