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)

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

In addition to the neural and autoregulatory factors, blood pressure (BP) is regulated by humoral factors including vasoactive peptides. When evaluating the peptide actions, degradation by proteases should be also considered in addition to the generation of peptides and their receptors. This review describes the roles of aminopeptidase A, placental leucine aminopeptidase and kininase I, which are enzymes responsible for hydrolyzing angiotensin II (AngII), vasopressin (AVP) and bradykinin (BK), respectively, in BP regulation. Especially, we focus on the association of the proteases with preeclampsia, hypertensive disorder peculiar to pregnancy, since one of the representative organs that are rich in theses proteases is placenta. Although the physiological roles of the placental proteases have not been fully understood, several lines of evidence suggest that the proteases are involved in the maintenance of pregnancy homeostasis including fetal and maternal BP regulation through the metabolism of bioactive peptides at the interface between mother and fetus.
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PMID:Role of aminopeptidases in the blood pressure regulation. 1518 14

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. Among the main bioactive peptides of the brain RAS, angiotensin (Ang) II and Ang III display the same affinity for type 1 and type 2 Ang II receptors. Both peptides, injected intracerebroventricularly, similarly increase blood pressure (BP); however, because Ang II is converted in vivo to Ang III, the identity of the true effector is unknown. In this article, we review new insights into the predominant role of brain Ang III in the control of BP, underlining the fact that brain aminopeptidase A (APA), the enzyme-forming central Ang III, could constitute a putative central therapeutic target for the treatment of hypertension. This justifies the development of potent systemically active APA inhibitors, such as RB150, as prototypes of a new class of antihypertensive agents for the treatment of certain forms of hypertension.
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PMID:Role of angiotensin III in hypertension. 1574 38

Preeclampsia is characterized by pregnancy-induced hypertension accompanied with protein urea and generalized edema. Preeclampsia develops during the second half of pregnancy and resolves postpartum promptly, implicating the placenta as a primary cause in the disorder. Normal pregnancy is associated with reductions in arterial pressure and attenuated pressor response to exogenous infused angiotensin II (ANG II). In contrast, women with preeclampsia show the similar sensitivity to the pressor effect of ANG II as do non-pregnant women. To elucidate the involvement of placental peptidases associated with renin-angiotensin systems, we determined the localization of angiotensin-converting enzyme (ACE) and aminopeptidase A (AP-A), ANG II degrading enzyme, in the placenta and compared the expression of mRNA and protein in uncomplicated and preeclamptic placenta. In addition, AP-A expression in trophoblastic cells treated with ANG II and ACE expression in HUVECs under hypoxic condition were analyzed, respectively. The expression of both peptidases in the preeclamptic placenta was significantly higher than those from uncomplicated. ACE was primarily localized to venous endothelial cells of stem villous whereas AP-A expression was recognized in the trophoblast and pericytes of fetal arterioles and venules within stem villous. Hypoxia induced ACE expression in HUVECs while both hypoxia and ANG II evoked AP-A expression in trophoblast. These results suggested that hypoxic condition in preeclampsia induces ACE activation in feto-placental unit to maintain the fetal hemodynamics and placental AP-A plays a role as a component of the barrier of ANG II between mother and fetus.
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PMID:Involvement of placental peptidases associated with renin-angiotensin systems in preeclampsia. 1589 65

The purpose of this study was to examine the prevalence, risk factors, and consequences of obesity in borderline patients 6 years after an index admission for psychiatric reasons. Two hundred and sixty-four borderline patients who met Revised Diagnostic Interview for Borderlines (DIB-R; Zanarini, Gunderson, Frankenburg, & Chauncy, 1989) and Diagnostic and Statistical Manual of Mental Disorders (3rd ed. ref.) (DSM-III-R; APA, 1987) criteria for BPD were interviewed concerning their body mass index (BMI) and related medical problems. Seventy-four of the 264 borderline patients at 6-year follow up were obese, having a BMI > or = 30 kg/m2. They were significantly more likely than the nonobese patients to report suffering from diabetes, hypertension, osteoarthritis, chronic back pain, carpal tunnel syndrome, urinary incontinence, gastroesophageal reflux disorder, gallstones, and asthma. Four significant risk factors were found: chronic PTSD, lack of exercise, a family history of obesity, and a recent history of psychotropic polypharmacy. These results suggest that obesity is common among heavily treated borderline patients and is associated with a number of chronic medical disorders.
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PMID:Obesity and obesity-related illnesses in borderline patients. 1656 80

The brain aminopeptidases that participate in the enzymatic cascade of the renin-angiotensin system play a major role in blood pressure (BP) control, and their study offers new perspectives for the understanding of central BP control and the treatment of hypertension. In this system, angiotensin II is converted to angiotensin III (Ang III) by glutamyl aminopeptidase (GluAP) and Ang III is further metabolised to angiotensin IV by alanyl aminopeptidase or arginine-aminopeptidase. It is now clear that Ang III is the key active form of the central angiotensins, exerting tonic stimulatory control over BP. Therefore, the development of GluAP inhibitors as potential antihypertensive agents offers new perspectives for therapy. Brain aspartyl aminopeptidase, which converts angiotensin I to angiotensin 2-10, is also a possible target for antihypertensive therapy because of its potential role in BP control. Finally, since changes in BP levels, that paralleled changes in brain and plasma aminopeptidase activities, were observed after unilateral lesions of the nigrostriatal system, brain asymmetry, aminopeptidase activities and BP control appear to be related, resulting their interplay in an asymmetrical neuroendocrine response that differentially affect BP control. The study of this interaction may contribute to our understanding of how the brain controls BP.
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PMID:Brain aminopeptidases and hypertension. 1709 48


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