Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Aminopeptidase A (APA)- and aminopeptidase M (APM)-like activity were assayed in Moni-Trol ES with L-alpha-aspartyl-beta-naphthylamide and L-alanyl-beta-naphthylamide, respectively. Upon preincubation of the serum with 89.4, 223.5, and 447 mM acetaldehyde at room temperature for 30 min, a reduction in 26.8%, 55.3%, and 75.8% aminopeptidase A activity was observed. Similarly, aminopeptidase M activity was reduced by 26.5% and 53.1% upon preincubation with 223.5 and 447 mM acetaldehyde. Ethanol at 84.9, 212.3, and 427.9 mM did not significantly affect the enzymic activity. Because aminopeptidase A and aminopeptidase M also degrade the pressor substance, angiotensin II, it is suggested that inhibition of aminopeptidase A- and aminopeptidase M-like activity by acetaldehyde, the product of ethanol metabolism, may lead to higher levels of circulating angiotensin II and, consequently, hypertension, in alcoholics. The hydrolysis of lysine-p-nitroanilide, an aminopeptidase B substrate, was also inhibited upon addition of acetaldehyde to Moni-Trol ES serum.
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PMID:Acetaldehyde inhibits serum aminopeptidases. 881 45

The genetic mechanisms responsible for the formation of adrenocortical adenomas which autonomously produce aldosterone are largely unknown. The adrenal renin-angiotensin system has been implicated in the pathophysiology of these tumours. Angiotensin-converting enzyme (ACE) catalyses the generation of angiotensin II, and the insertion/deletion (I/D) polymorphism of the ACE gene regulates up to 50% of plasma and cellular ACE variability in humans. We therefore examined the genotypic and allelic frequency distributions of the ACE gene I/D polymorphism in 55 patients with aldosterone-producing adenoma, APA, (angiotensin-unresponsive APA n = 28, angiotensin-responsive APA n = 27), and 80 control subjects with no family history of hypertension. We also compared the ACE gene I/D polymorphism allelic pattern in matched tumour and peripheral blood DNA in the 55 patients with APA. The frequency of the D allele was 0.518 and 0.512 and the I allele was 0.482 and 0.488 in the APA and control subjects respectively. Genotypic and allelic frequency analysis found no significant differences between the groups. Examination of the matched tumour and peripheral blood DNA samples revealed the loss of the insertion allele in four of the 25 patients who were heterozygous for the ACE I/D genotype. The I/D polymorphism of the ACE gene does not appear to contribute to the biochemical and phenotypic characteristic of APA, however, the deletion of the insertion allele of the ACE gene I/D polymorphism in 16% of aldosterone-producing adenomas may represent the loss of a tumour suppressor gene/s or other genes on chromosome 17q which may contribute to tumorigenesis in APA.
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PMID:Insertion/deletion polymorphism of the angiotensin-converting enzyme gene and loss of the insertion allele in aldosterone-producing adenoma. 914 Jul 90

The basic clinical pathophysiology of primary aldosteronism (PAL) was described by Conn in terms of autonomous production of aldosterone, secondary suppression of renin and development of hypertension with hypokalaemic alkalosis. Conn recognised a normokalaemic form of the syndrome and suggested that it might masquerade as essential hypertension and be not uncommon. This was hotly disputed at the time, and normokalaemic PAL considered rare until recently, and, as a consequence, overlooked. The advent of a simple screening test, the aldosterone-renin ratio, led to recognition that normokalaemic forms are not uncommon. In fact, PAL may be the commonest specifically treatable and potentially curable form of hypertension so far identified. In all patients with PAL confirmed by lack of suppressibility ("autonomy") of aldosterone production, Familial Hyperaldosteronism Type I (FH-I, glucocorticoid-remediable hyperaldosteronism, reviewed elsewhere in this issue) should first be excluded by dexamethasone suppression or genetic testing. Capable of causing fatal stroke in young people affected by this dominantly inherited disorder, it can be reversed by doses of glucocorticoids such as dexamethasone which partially suppress endogenous ACTH without producing "steroid" side-effects. The remaining varieties of PAL may eventually also be shown to have a genetic basis, but are currently treated either by excision of a solitary aldosterone-secreting tumour or by antagonism of aldosterone's action in the renal tubule. It is possible that both adrenal cortices are genetically predisposed to overproduction of aldosterone in all varieties of PAL, whether because of anomalous regulation of aldosterone secretion or because of a tendency towards hyperplasia and neoplasia. Aldosterone-producing adenomas (APA's) can be divided into two main subtypes based on morphology and biochemical behaviour. The first subtype to be morphologically and biochemically characterised is composed predominantly of fasciculata-like cells and is unresponsive to angiotensin II (ALL-U-APA). The more recently characterised subtype is composed predominantly of glomerulosa-like cells, is responsive to angiotensin II (AII-R-APA) and could previously have been misdiagnosed as bilateral hyperplasia. The renin gene is often overexpressed in the second variety of adenoma, and in surrounding non-tumorous cortex, and the two subgroups show different allelic frequencies for RFLP's of the constitutive renin gene and the constitutive ANP gene locus. Unilateral, solitary, benign adrenal cortical adenomas producing aldosterone (APA's) represent a potentially surgically curable form of hypertension. Adrenal venous sampling (AVS) should always be performed because APA's are biochemically recognisable by adrenal venous steroid measurement before they are identifiable by computerised tomography or scintigraphy, and adrenal masses seen on CT may not be responsible for PAL. The secretory activity of adrenal masses must therefore be established by AVS before surgical removal. Discovery of an adrenal mass on CT requires formulation of a plan, whether or not it is found to be secreting hormones in excess. Independently of the treatment of the patient's hypertension, an apparently nonfunctioning adrenal mass ("incidentaloma") should be removed if 2.5 cm or more in diameter, because of the risk of cancer. Smaller masses require long-term follow-up. Primary aldosteronism not lateralising on AVS should be treated with low dose spironolactone, or with amiloride. For any such patients intolerant of medical treatment, laparoscopic removal of the adrenal showing higher production of aldosterone on AVS is an option worthy of consideration.The resultant reduction in mass of tissue autonomously secreting aldosterone should improve hypertension, as aldosterone productions falls below a critical level, and may even be curative in the short, medium or long term, depending on the rate of growth and activity of au
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PMID:Primary aldosteronism. 922 Dec 68

We evaluated the endogenous action of angiotensin II (AII) and its active metabolite, angiotensin III (AIII), at the nucleus tractus solitarii (NTS) in the modulation of baroreceptor reflex (BRR) response, and the subtype(s) of angiotensin receptors involved in this process. Adult, male Sprague-Dawley rats that were anesthetized and maintained with pentobarbital sodium were used. Bilateral microinjection of AII or AIII (10, 20 or 40 pmol) into the NTS significantly and dose-dependently suppressed the BRR response, which was evoked by transient hypertension induced by phenylephrine (5 micrograms/kg, i.v.). The suppressive effect of AII (40 pmol) was reversed by co-administration of the non-peptide AT1 receptor antagonist, losartan (1.6 nmol), but only partially by the non-peptide AT2 receptor antagonist, PD-123319. On the other hand, both angiotensin receptor antagonists appreciably reversed the depressive action of AIII (40 pmol). Blocking the endogenous activity of the angiotensins by microinjection into the bilateral NTS of losartan (1.6 nmol) or PD-123319 (1.6 nmol) elicited a significant enhancement of the BRR response. An interruption of the conversion of AII to AIII with the aminopeptidase A inhibitor, amastatin (3.3 nmol), attenuated, but did not eliminate, the AII-induced inhibition of the BRR response. We conclude that whereas the endogenous AIII may exert a tonic inhibitory modulation on the BRR response by acting on both the AT1 and AT2 receptor subtypes, the same action of the endogenous AII engaged only the AT1 receptor subtype at the NTS. Furthermore, at least part of the suppressive action of AII may result from its metabolic conversion to AIII.
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PMID:Participation of AT1 and AT2 receptor subtypes in the tonic inhibitory modulation of baroreceptor reflex response by endogenous angiotensins at the nucleus tractus solitarii in the rat. 951 51

Aminopeptidase activity plays a role in the metabolism of several peptides that could be involved in blood pressure control. This activity has been implicated in the pathogenesis of hypertension, essentially in spontaneously hypertensive rats. However, few studies have examined aminopeptidase activities in animal models other than genetic hypertension. To analyze the aminopeptidase response to the specific conditions of the reduced renal mass saline model of arterial hypertension, aminopeptidase A activity (glutamyl- and aspartyl-aminopeptidase), aminopeptidase M activity (alanyl-aminopeptidase), aminopeptidase B activity (arginyl-aminopeptidase), pyroglutamyl-aminopeptidase and cystinyl-aminopeptidase were measured in the neurohypophysis, in the adrenal gland and in serum of this model of hypertension. In the neurohypophysis, there was a significant increase of soluble cystinyl-, alanyl-, arginyl-, pyroglutamyl- and membrane-bound aspartyl-aminopeptidase activities in hypertensive animals. In the adrenal gland, soluble cystinyl-, alanyl-, arginyl- and pyroglutamyl-aminopeptidase activities were also higher in hypertensive rats than in normotensive controls. No differences were found in serum levels of aminopeptidase activities between both groups of animals. A highly significant positive correlation between the neurohypophysis and the adrenal gland was observed for soluble cystinyl- and alanyl-aminopeptidase activities in the model of hypertension, whereas no correlation was observed in normotensive rats. Our results suggest that aminopeptidase activities could be involved in the regulatory response to the reduced renal mass hypertension and also suggest a coordinate response between the adrenal gland and the neurohypophysis, to the specific metabolic conditions of this model of hypertension.
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PMID:Activities of aminopeptidases in a rat saline model of volume hypertension. 966 82

Tissue and plasma levels of aminopeptidase A (APA), the principal enzyme that hydrolyzes angiotensin II (Ang II) to angiotensin III, were measured in spontaneously hypertensive rats (SHR) and their normotensive control strain at 3 different ages corresponding to prehypertensive (4 weeks), developing (8 weeks), and established (16 weeks) phases of hypertension. Plasma APA activity was significantly but modestly elevated in SHR at all 3 ages compared with normotensive Wistar-Kyoto rats. Likewise, levels of APA in brain, heart, and adrenal gland were generally, but again only moderately, elevated in SHR at all ages. However, a large increase in APA activity was seen within the kidney in which APA levels were elevated 41%, 51%, and 68% in SHR at 4, 8, and 16 weeks of age, respectively. Kidney APA levels were also significantly increased in immunoblots from 8- and 16-week-old SHR. Glomeruli isolated from 16-week-old SHR had 57% higher APA activity and increased immunoreactivity compared with Wistar-Kyoto rats. To determine whether the increase in kidney APA activity in SHR was related to Ang II levels, SHR were treated for 2 weeks with the angiotensin-converting enzyme inhibitor captopril. Captopril treatment reduced blood pressure to normotensive values and resulted in a 25% reduction in kidney APA activity. These results suggest that APA expression in the kidney may be regulated by activity of the renin-angiotensin system. If so, this would further suggest that upregulation of APA during conditions in which Ang II levels were elevated would have a protective effect against Ang II-mediated cardiovascular diseases, whereas a decrease in APA expression or a failure to upregulate would exacerbate such conditions.
Hypertension 1999 Feb
PMID:Kidney aminopeptidase A and hypertension, part I: spontaneously hypertensive rats. 1002 38

Overactivity of the brain renin-angiotensin system (RAS) has been implicated in the development and maintenance of hypertension in several experimental models, such as spontaneously hypertensive rats and transgenic mice expressing both human renin and human angiotensinogen transgenes. We recently reported that, in the murine brain, angiotensin II (AngII) is converted to angiotensin III (AngIII) by aminopeptidase A (APA), whereas AngIII is inactivated by aminopeptidase N (APN). If injected into cerebral ventricles (ICV), AngII and AngIII cause similar pressor responses. Because AngII is metabolized in vivo into AngIII, the exact nature of the active peptide is not precisely determined. Here we report that, in rats, ICV injection of the selective APA inhibitor EC33 [(S)-3-amino-4-mercaptobutyl sulfonic acid] blocked the pressor response of exogenous AngII, suggesting that the conversion of AngII to AngIII is required to increase blood pressure (BP). Furthermore, ICV injection, but not i.v. injection, of EC33 alone caused a dose-dependent decrease in BP by blocking the formation of brain but not systemic AngIII. This is corroborated by the fact that the selective APN inhibitor, PC18 (2-amino-4-methylsulfonyl butane thiol), administered alone via the ICV route, increases BP. This pressor response was blocked by prior treatment with the angiotensin type 1 (AT(1)) receptor antagonist, losartan, showing that blocking the action of APN on AngIII metabolism leads to an increase in endogenous AngIII levels, resulting in BP increase, through interaction with AT(1) receptors. These data demonstrate that AngIII is a major effector peptide of the brain RAS, exerting tonic stimulatory control over BP. Thus, APA, the enzyme responsible for the formation of brain AngIII, represents a potential central therapeutic target that justifies the development of APA inhibitors as central antihypertensive agents.
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PMID:Aminopeptidase A inhibitors as potential central antihypertensive agents. 1055 35

Overactivity of the brain renin-angiotensin system (RAS) has been implicated in the development and maintenance of hypertension in several experimental animal models. We have recently reported that, in the murine brain RAS, angiotensin II (AngII) is converted by aminopeptidase A (APA) into angiotensin III (AngIII),which is itself degraded by aminopeptidase N (APN), both peptides being equipotent to increase vasopressin release and arterial blood pressure when injected by the intracerebroventricular (i.c.v.) route. Because AngII is converted in vivo into AngIII, the exact nature of the active peptide is not precisely known. To delineate their respective roles in the central control of cardiovascular functions, specific and selective APA and APN inhibitors are needed to block the metabolic pathways of AngII and AngIII respectively. In the absence of such compounds for APA, we first explored the organization of the APA active site by site-directed mutagenesis. This led us to propose a molecular mechanism of action for APA similar to that proposed for the bacterial enzyme thermolysin deduced from X-ray diffraction studies. Secondly, we developed a specific and selective APA inhibitor, compound EC33 [(S)-3-amino-4-mercaptobutylsulphonic acid], as well as a potent and selective APN inhibitor, PC18 (2-amino-4-methylsulphonylbutane thiol). With these new tools we examined the respective roles of AngII and AngIII in the central control of arterial blood pressure. A central blockade of APA with the APA inhibitor EC33 suppressed the pressor effect of exogenous AngII, suggesting that brain AngII must be converted into AngIII to increase arterial blood pressure. Furthermore, EC33, injected alone i.c.v. but not intravenously, caused a dose-dependent decrease in arterial blood pressure by blocking the formation of brain AngIII but not systemic AngIII. This is corroborated by the fact that the selective APN inhibitor PC18 administered alone via the i.c.v. route increased arterial blood pressure. This pressor response was blocked by prior treatment with the angiotensin type 1 receptor antagonist losartan, showing that blocking the action of APN on AngIII metabolism leads to an increase in endogenous AngIII levels, resulting in arterial blood pressure increase through an interaction with angiotensin type 1 receptors. These results demonstrate that AngIII is a major effector peptide of the brain RAS, exerting a tonic stimulatory control over arterial blood pressure. Thus APA, the enzyme responsible for the formation of brain AngIII, represents a potential central therapeutic target that justifies the development of APA inhibitors, crossing the blood-brain barrier, as central anti-hypertensive agents.
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PMID:Aminopeptidase A, which generates one of the main effector peptides of the brain renin-angiotensin system, angiotensin III, has a key role in central control of arterial blood pressure. 1096 35

A high intake of monounsaturated fat has been proposed to be a dietary factor that can decrease the incidence of cardiovascular disease and hypertension. In addition, increasing dietary fat saturation has been shown to increase plasma total cholesterol and elevate systolic and diastolic blood pressures. We demonstrated previously that cholesterol selectively increases in vitro aminopeptidase A activity, which is related to angiotensin metabolism. In this study, we investigated the effect of different degrees of dietary fatty acid saturation on serum aminopeptidase activities in vivo. Serum total cholesterol concentrations were also measured. Five groups of male Balb/C mice were fed for 10 wk diets containing 2.4 g/100 g of sunflower oil, fish oil, olive oil, lard or coconut oil. We measured alanyl-, arginyl-, cystinyl-, pyroglutamyl-, aspartyl- and glutamyl-specific aminopeptidase activities using arylamides as substrates. Serum total cholesterol levels were higher in mice fed diets containing saturated oils (lard and coconut) than in those consuming sunflower oil, which is unsaturated. Two of the serum aminopeptidase A activities (aspartyl and glutamyl aminopeptidase) increased progressively with the degree of saturation of the dietary fatty acids; activities were significantly greater in mice fed coconut oil than in those fed sunflower or fish oil. Therefore, the substrates hydrolyzed by this activity as well as their functions may be similarly affected. These results may have some implication for the treatment of cardiovascular disease.
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PMID:Serum aminopeptidase A activity of mice is related to dietary fat saturation. 1128 22

Among the main bioactive peptides of the brain renin-angiotensin system, angiotensin (Ang) II and AngIII exhibit the same affinity for type 1 and type 2 AngII receptors. Both peptides, injected intracerebroventricularly, cause similar increases in vasopressin release and blood pressure. Because AngII is converted in vivo to AngIII, the identity of the true effector is unknown. This review summarizes new insights into the predominant role of brain AngIII in the control of vasopressin release and blood pressure and underlines the fact that brain aminopeptidase A, the enzyme forming central AngIII, could constitute a putative central therapeutic target for the treatment of hypertension.
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PMID:Angiotensin III: a central regulator of vasopressin release and blood pressure. 1129 71


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