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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

Although hypercholesterolemia and hypertension have been extensively associated, the regulatory mechanism underlying this relationship is poorly understood. Systemic and local renin-angiotensin systems are involved in the control of blood-pressure. Angiotensin II has been considered as the main effector peptide of renin-angiotensin system. However, other peptides derived from the metabolism of angiotensin II, as angiotensins III and IV have been shown to play significant roles. The aim of this study is to analyse the effect of dietary cholesterol on the activity of the enzymes involved in the metabolism of angiotensins II and III. Soluble and membrane-bound aminopeptidase A (aspartyl- and glutamyl-aminopeptidases), B (arginyl-aminopeptidase) and M (alanyl-aminopeptidase) activities were measured in the frontal cortex of male and female mice fed a cholesterol enriched-diet (1% cholesterol; 0.5 cholic acid). Soluble and membrane-bound aminopeptidases B and M did not change in male or female cholesterol groups. Significant increases were observed in membrane-bound aspartyl- and glutamyl-aminopeptidase activities in both cholesterol groups. Soluble aspartyl- and glutamylaminopeptidases did not change in male cholesterol group, but significant decreases were detected in female cholesterol group. Our results may indicate that the metabolism of angiotensin II to angiotensin III by aminopeptidase A is increased, but angiotensin III metabolism by aminopeptidases B and M is not modified after cholesterol intake; so cholesterol may enhance the effects of angiotensin III, at least, at the cortical level.
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PMID:Differential effects of dietary cholesterol on aminopeptidase A, B and M in the frontal cortex of male and female mice. 1184 65

Angiotensin-II-cleaving angiotensinase A (aminopeptidase A, E.C. 3.4.11.7, ATA) plays an important role in glomerular haemodynamics. the pathophysiology of essential arterial hypertension and the induction of vascular disorders. In order to study biochemical and immunological properties of ATA, two isoforms (I and II) of the glycoprotein were isolated for the first time from human kidney cortex. Kidney cortex homogenate, digested with bromelain, was fractionated by ammonium sulphate precipitation and subsequent hydrophobic interaction chromatography, using a fast protein liquid chromatographic (FPLC) system. By anion-exchange FPLC (Mono Q column), the isoforms of ATA were eluted in two distinct peaks and were further purified by size-exclusion FPLC and preparative polyacrylamide gel electrophoresis. Biochemical, immunological and immunohistological characterization disclosed differences in the intrarenal localization, glycosylation Michaelis constant and apparent molecular mass (native and sodium dodecyl sulphate gel electrophoresis) but similar properties in the double-immunodiffusion technique. Polyclonal rabbit antibodies, raised against ATA isoforms I and II, precipitated an analogous antigen in urine from patients with renal tubular damage.
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PMID:Angiotensinase A (aminopeptidase A): properties of chromatographically purified isoforms from human kidney. 1212 12

Local concentrations of the vasopressor peptide, angiotensin II (AngII), depend upon the balance between synthesis and degradation. Previous studies of blood pressure (BP) regulation have focused primarily on the generation of AngII and its receptors, and less attention has been devoted to angiotensin degradation. Aminopeptidase A (APA, EC 3.4.11.7) is responsible for the N-terminal cleavage of AngII, a hydrolytic event that serves as a rate-limiting step in angiotensin degradation. To evaluate the physiological role of APA, we examined BP homeostasis in APA-deficient mice. We measured basal BP and BP with continuous infusion of AngII in APA mutant mice by tail-cuff method. We also evaluated the development and histology of AngII-targeted organs as well as urine excretion in these mice. Homozygous APA mutant mice were found to have elevated basal systolic BP when compared with heterozygous mutant and wild-type littermate mice. Infusion of AngII led to an enhanced systolic BP response in the APA-deficient mice. Despite the sustained elevation of BP in APA knockout mice, neither their renal and cardiac sizes nor their histological appearances were not different from control mice. Moreover, the volume, osmolality, and electrolyte content of the urine were normal in APA-deficient mice. APA deficiency increased baseline BP and enhanced the hypertensive response to increased levels of AngII. These findings indicate a physiological role for APA in lowering BP and offer novel insight into the mechanisms for developing hypertension.
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PMID:Hypertension and angiotensin II hypersensitivity in aminopeptidase A-deficient mice. 1276 41

Chronic inhibition of nitric oxide synthase promotes renin-dependent hypertension and renal injury. The present study examines how renal angiotensin II receptors are expressed in this model. N(G)-nitro-L-arginine methyl ester (L-NAME) was given orally to rats for 1 month and was associated or not with captopril during the 4 last days of the administration. 125I-[Sar1, Ile8]-Ang II binding, AT1)mRNA and cytosolic calcium were studied in isolated glomeruli from L-NAME and control rats and in cultured mesangial cells from normal rats. Renal injury was marked in rats receiving L-NAME. Type I angiotensin II (AT1) receptor number and mRNA expression were decreased (p < 0.05) in glomeruli isolated from L-NAME-treated rats compared with controls, unless they received captopril in combination. The low level of AT1 receptor expression was associated with an attenuated rise of cytosolic calcium in response to angiotensin II. Angiotensin-converting enzyme activity in glomeruli and angiotensin II concentration in renal cortex were increased (p < 0.05) in rats receiving L-NAME alone, whereas aminopeptidase A activity was not modified. To better discriminate between the direct and indirect effects of nitric oxide deficiency, rat mesangial cells were exposed or not for 24 h to S-nitroso-N-acetyl penicillamine, a nitric oxide donor. Angiotensin II binding, AT1 mRNA expression and calcium response to angiotensin II were decreased in presence of the nitric oxide donor (p < 0.01). These results suggest that the decrease of AT1 receptor expression after 1 month of L-NAME treatment does not depend on a direct effect of nitric oxide deficiency but results from the high local angiotensin II concentration due to the stimulated angiotensin-converting enzyme activity. They also show that the renin-angiotensin dependence of this model of hypertension does not result from the overexpression of AT1 receptors.
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PMID:AT1 receptor expression in glomeruli from NO-deficient rats. 1464 64

The hyperactivity of the brain renin-angiotensin system (RAS) has been implicated in the development and maintenance of hypertension in several types of experimental and genetic hypertension animal models. We previously reported that in the murine brain, aminopeptidase A (APA) is involved in the conversion of angiotensin II (AngII) to AngIII and that AngIII is one of the main effector peptides of the brain RAS in the control of vasopressin release. Here we report that brain AngIII exerts a tonic stimulatory effect on blood pressure in a model of salt-dependent hypertension, the DOCA-salt rat, characterized by a depressed systemic but a hyperactive brain RAS. Similar high blood pressure accompanied by a low systemic renin state was described in some patients, especially in hypertensive African Americans who are resistant to treatment by blockers of the systemic RAS. We developed RB150, a prodrug of the specific and selective APA inhibitor, EC33. RB150 given i.v. is able to cross the blood-brain barrier, to inhibit brain APA, and to block the formation of central AngIII. A single dose of systemic RB150 (15 mg/kg, i.v.) in conscious DOCA-salt rats inhibited brain APA activity and markedly reduced blood pressure for up to 24 h. These results demonstrate the crucial role of brain APA as a candidate target for the treatment of hypertension and suggest that RB150, a potent systemically active APA inhibitor, could be the prototype of a new class of antihypertensive agents for the treatment of certain forms of hypertension.
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PMID:Brain renin-angiotensin system blockade by systemically active aminopeptidase A inhibitors: a potential treatment of salt-dependent hypertension. 1513 30


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