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

The renin-angiotensin system (RAS) plays an important role in the maintenance of normal blood pressure and the etiology of hypertension; however, minimal attention has been paid to the degradation of the effector peptide, angiotensin II (AngII). Since aminopeptidase A (APA)-deficient mice develop hypertension APA appears to be an essential enzyme in the control of blood pressure via degradation of AngII. The robust hypertension seen in the spontaneously hypertensive rat (SHR) is due to activation of the RAS, and an accompanying decrease in kidney APA. Changes in APA have also been measured during the activation of the RAS in the Goldblatt hypertension model and Dahl salt-sensitive (DSS) rat. The DSS rat shows an elevation in renal APA activity at the onset of hypertension suggesting a protective role against elevations in circulating AngII, followed by decreased APA activity with advancing hypertension. Changes seen in human maternal serum APA activity during preeclampsia are similar to changes measured in renal APA in the DSS rat model. APA activity is higher than during normal pregnancy at the onset of preeclampsia, and with advancing preeclampsia (severe preeclampsia) declines below that seen during normal pregnancy. Serum APA activity is also increased during hormone replacement therapy (HRT), perhaps in reaction to elevated levels of AngII. Thus, it appears important to consider the relationship among activation of the RAS, circulating levels of AngII, and the availability of APA in hypertensive disorders.
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PMID:New insights into the importance of aminopeptidase A in hypertension. 1799 Jan 3

In the kidney, angiotensin II (Ang II) is metabolized to angiotensin III (Ang III) by aminopeptidase A (APA). In turn, Ang III is metabolized to angiotensin IV by aminopeptidase N (APN). Renal interstitial (RI) infusion of Ang III, but not Ang II, results in angiotensin type-2 receptor (AT(2)R)-mediated natriuresis. This response is augmented by coinfusion of PC-18, a specific inhibitor of APN. The present study addresses the hypotheses that Ang II conversion to Ang III is critical for the natriuretic response. Sprague-Dawley rats received systemic angiotensin type-1 receptor (AT(1)R) blockade with candesartan (CAND; 0.01 mg/kg/min) for 24 hours before and during the experiment. After a control period, rats received either RI infusion of Ang II or Ang II+PC-18. The contralateral kidney received a RI infusion of vehicle in all rats. Mean arterial pressure (MAP) was monitored, and urinary sodium excretion rate (U(Na)V) was calculated separately from experimental and control kidneys for each period. In contrast to Ang II-infused kidneys, U(Na)V from Ang II+PC-18-infused kidneys increased from a baseline of 0.03+/-0.01 to 0.09+/-0.02 micromol/min (P<0.05). MAP was unchanged by either infusion. RI addition of PD-123319, an AT(2)R antagonist, inhibited the natriuretic response. Furthermore, RI addition of EC-33, a selective APA inhibitor, abolished the natriuretic response to Ang II+PC-18. These data demonstrate that RI addition of PC-18 to Ang II enables natriuresis mediated by the AT(2)R, and that conversion of Ang II to Ang III is critical for this response.
Hypertension 2008 Feb
PMID:Conversion of renal angiotensin II to angiotensin III is critical for AT2 receptor-mediated natriuresis in rats. 1815 38

Among the main bioactive peptides of the brain renin-angiotensin system, angiotensin (Ang) II and AngIII exhibit the same affinity for the type 1 and type 2 Ang receptors. Both peptides, injected intracerebroventricularly, cause similar increase in blood pressure (BP). Because AngII is converted in vivo to AngIII, the identity of the true effector is unknown. This review summarized recent insights into the predominant role of brain AngIII in the central control of BP underlining the fact that brain aminopeptidase A (APA), the enzyme forming central AngIII, could constitute a putative central therapeutic target for the treatment of hypertension. This led to the development of potent, systematically active APA inhibitors, such as RB150, as a prototype of a new class of centrally acting antihypertensive agents for the treatment of certain forms of hypertension.
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PMID:Aminopeptidase A inhibitors as centrally acting antihypertensive agents. 1817 17

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 arginine vasopressin (AVP) release and blood pressure (BP); however, because Ang II is converted in vivo to Ang III, the identity of the true effector is unknown. 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 generating brain Ang III, may therefore be an interesting candidate 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. We also searched for a putative angiotensin receptor subtype specific for Ang III and isolated a seven transmembrane-domain G protein-coupled receptor corresponding to the receptor for apelin, a newly-discovered peptide isolated from bovine stomach. Apelin and its receptor are expressed in magnocellular vasopressinergic neurones in the hypothalamus. The central injection of apelin in lactating rats decreases the phasic electrical activity of vasopressinergic neurones and the systemic secretion of AVP, inducing water diuresis. Apelin is therefore a natural inhibitor of the antidiuretic effect of AVP. In addition, systemic administration of apelin decreases BP, improves cardiac contractility and reduces cardiac loading. The development of nonpeptide agonists of the apelin receptor may provide new therapeutic tools for treating water retention, hyponatraemia and cardiovascular diseases. Angiotensins and apelin thus exert opposing but complementary effects, and are thereby determinant for the maintenance of body fluid homeostasis and cardiovascular functions.
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PMID:Jacques Benoit lecture: the neuroendocrine view of the angiotensin and apelin systems. 1819 30

Overactivity of the brain renin-angiotensin system has been implicated in the development and maintenance of hypertension. We reported previously that angiotensin II is converted to angiotensin III by aminopeptidase A in the mouse brain. We then used specific and selective aminopeptidase A inhibitors to show that angiotensin III is one of the main effector peptides of the brain renin-angiotensin system, exerting tonic stimulatory control over blood pressure in hypertensive rats. Aminopeptidase A, the enzyme generating brain angiotensin III, thus represents a potential candidate central nervous system target for the treatment of hypertension. Given this possible clinical use of aminopeptidase A inhibitors, it was, therefore, important to investigate their pharmacological activity after oral administration. We investigated RB150, a dimer of the selective aminopeptidase A inhibitor, EC33, generated by creating a disulfide bond. This chemical modification allows prodrug to cross the blood-brain barrier when administered by systemic route. Oral administration of RB150 in conscious DOCA-salt rats inhibited brain aminopeptidase A activity, resulting in values similar to those obtained with the brains of normotensive rats, demonstrating the central bioavailability of RB150. Oral RB150 treatment resulted in a marked dose-dependent reduction in blood pressure in DOCA-salt but not in normotensive rats, with an ED(50) in the 1-mg/kg range, achieved in <2 hours and lasting for several hours. This treatment also significantly decreased plasma arginine-vasopressin levels and increased diuresis, which may participate to the blood pressure decrease by reducing the size of fluid compartment. Thus, RB150 may be the prototype of a new class of centrally active antihypertensive agents.
Hypertension 2008 May
PMID:Orally active aminopeptidase A inhibitors reduce blood pressure: a new strategy for treating hypertension. 1836 27

An understanding of aminopeptidase A in hypertension is important, given its ability to cleave the N-terminal aspartic acid of potent vasoconstrictor angiotensin II. However, the role of aminopeptidase A in hypertension has received limited attention. Because we have succeeded in producing recombinant human aminopeptidase A, the effect of aminopeptidase A on systolic blood pressure in the spontaneously hypertensive rat was examined. Aminopeptidase A of 0.016 mg/kg was administrated intravenously to spontaneously hypertensive rats and blood pressure was monitored for 72 h. For repeated administration, aminopeptidase A doses of 0.016 mg/kg and 0.1-mg/kg doses of candesartan (an angiotensin II receptor 1 subtype blocker) were administrated daily in spontaneously hypertensive rats and blood pressure was monitored for 5 d. Bolus intravenous injection of aminopeptidase A at a dose of 0.016 mg/kg significantly decreased systolic blood pressure for 36 h in spontaneously hypertensive rats. A comparison of the antihypertensive effects of aminopeptidase A versus candesartan in spontaneously hypertensive rats showed that the effective dose of aminopeptidase A was about one-tenth that of candesartan. These results suggest the novel approach of utilizing aminopeptidase A to treat hypertension by degrading circulating angiotensin II before it binds to the receptor 1 subtype.
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PMID:The effect of recombinant aminopeptidase A on hypertension in spontaneously hypertensive rats: its effect in comparison with candesartan. 1872 31

Intraglomerular renin-angiotensin system enzyme activities have been examined previously using glomerular lysates and immune-based assays. However, preparation of glomerular extracts compromises the integrity of their anatomic architecture. In addition, antibody-based assays focus on angiotensin (Ang) II detection, ignoring the generation of other Ang I-derived metabolites, some of which may cross-react with Ang II. Therefore, our aim was to examine the metabolism of Ang I in freshly isolated intact glomeruli using matrix-assisted laser desorption ionization time of flight mass spectrometry as an analytic method. Glomeruli from male Sprague-Dawley rats were isolated by sieving and incubated in Krebs buffer in the presence of 1 micromol/L of Ang I for 15 to 90 minutes, with or without various peptidase inhibitors. Peptide sequences were confirmed by matrix-assisted laser desorption ionization time of flight tandem mass spectrometry or linear-trap-quadrupole mass spectrometry. Peaks were quantified using customized valine-(13)C(.15)N-labeled peptides as standards. The most prominent peaks resulting from Ang I cleavage were 899 and 1181 m/z, corresponding with Ang (1-7) and Ang (2-10), respectively. Smaller peaks for Ang II, Ang (1-9), and Ang (3-10) also were detected. The disappearance of Ang I was significantly reduced during inhibition of aminopeptidase A or neprilysin. In contrast, captopril did not alter Ang I degradation. Furthermore, during simultaneous inhibition of aminopeptidase A and neprilysin, the disappearance of Ang I was markedly attenuated compared with all of the other conditions. These results suggest that there is prominent intraglomerular conversion of Ang I to Ang (2-10) and Ang (1-7), mediated by aminopeptidase A and neprilysin, respectively. Formation of these alternative Ang peptides may be critical to counterbalance the local actions of Ang II. Enhancement of these enzymatic activities may constitute potential therapeutic targets for Ang II-mediated glomerular diseases.
Hypertension 2009 May
PMID:Angiotensin I is largely converted to angiotensin (1-7) and angiotensin (2-10) by isolated rat glomeruli. 1928 51

A few simple rules can allow physicians to successfully identify many patients with arterial hypertension caused by PA among the so-called essential hypertensive patients. The hyperaldosteronism and the hypokalemia can be cured with adrenalectomy in practically all of these patients. Moreover, in a substantial proportion of them, the blood pressure can be normalized or markedly lowered if a unilateral cause of PA is discovered. Hence, the screening for PA can be rewarding both for the patient and for the clinician, particularly in those cases where hypertension is severe and/or resistant to treatment, in which the removal of an APA can allow blood pressure to be brought under control despite withdrawal of, or a prominent reduction in, the number and doses of antihypertensive medications.
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PMID:Diagnosis and treatment of primary aldosteronism. 2156 69

Hypertension affects 26% of adults and is in constant progress related to increased incidence of obesity and diabetes. One-third of hypertensive patients may be successfully treated with one antihypertensive agent, one-third may require two agents and in the remaining patients will need three agents for effective blood pressure (BP) control. The development of new classes of antihypertensive agents with different mechanisms of action therefore remains an important goal. Brain renin-angiotensin system (RAS) hyperactivity has been implicated in hypertension development and maintenance 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 have similar affinities for type 1 (AT1) and type 2 (AT2) Ang II receptors. Following intracerebroventricular (i.c.v.) injection, Ang II and Ang III similarly increase arginine-vasopressin (AVP) release and BP. Blocking the brain RAS may be advantageous as it simultaneously (1) decreases sympathetic tone and consequently vascular resistance, (2) decreases AVP release, reducing blood volume and vascular resistance and (3) blocks angiotensin-induced baroreflex inhibition, decreasing both vascular resistance and cardiac output. However, as Ang II is converted to Ang III in vivo, the exact nature of the active peptide is not precisely determined. We summarize here the main findings identifying AngIII as one of the major effector peptides of the brain RAS in the control of AVP release and BP. Brain AngIII exerts a tonic stimulatory effect on BP in hypertensive rats, identifying brain aminopeptidase A (APA), the enzyme generating brain Ang III, as a potentially candidate target for hypertension treatment. This has led to the development of potent orally active APA inhibitors, such as RB150--the prototype of a new class of centrally acting antihypertensive agents.
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PMID:The role of the brain renin-angiotensin system in hypertension: implications for new treatment. 2176 94

In angiotensin type 1 receptor-blocked rats, renal interstitial (RI) administration of des-aspartyl(1)-angiotensin II (Ang III) but not angiotensin II induces natriuresis via activation of angiotensin type 2 receptors. In the present study, renal function was documented during systemic angiotensin type 1 receptor blockade with candesartan in Sprague-Dawley rats receiving unilateral RI infusion of Ang III. Ang III increased urine sodium excretion, fractional sodium, and lithium excretion. RI coinfusion of specific angiotensin type 2 receptor antagonist PD-123319 abolished Ang III-induced natriuresis. The natriuretic response observed with RI Ang III was not reproducible with RI angiotensin (1-7) alone or together with angiotensin-converting enzyme inhibition. Similarly, neither RI angiotensin II alone or in the presence of aminopeptidase A inhibitor increased urine sodium excretion. In the absence of systemic angiotensin type 1 receptor blockade, Ang III alone did not increase urine sodium excretion, but natriuresis was enabled by the coinfusion of aminopeptidase N inhibitor and subsequently blocked by PD-123319. In angiotensin type 1 receptor-blocked rats, RI administration of aminopeptidase N inhibitor alone also induced natriuresis that was abolished by PD-123319. Ang III-induced natriuresis was accompanied by increased RI cGMP levels and was abolished by inhibition of soluble guanylyl cyclase. RI and renal tissue Ang III levels increased in response to Ang III infusion and were augmented by aminopeptidase N inhibition. These data demonstrate that endogenous intrarenal Ang III but not angiotensin II or angiotensin (1-7) induces natriuresis via activation of angiotensin type 2 receptors in the proximal tubule via a cGMP-dependent mechanism and suggest aminopeptidase N inhibition as a potential therapeutic target in hypertension.
Hypertension 2012 Aug
PMID:Intrarenal angiotensin III is the predominant agonist for proximal tubule angiotensin type 2 receptors. 2268 43


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