Conversion of brain angiotensin II to angiotensin III is critical for pressor response in rats

Wright, John W.; Tamura-Myers, Elizabeth; Wilson, William S.; Roques, Bernárd P.; Llorens-Cortes, Catherine; Speth, Robert C.; Harding, Joseph W.

doi:10.1152/ajpregu.00326.2002

Cited by 77 publications

(52 citation statements)

References 51 publications

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“…These findings are somewhat unexpected, because increased levels of ang III alter water balance and blood pressure (31)(32)(33). One possible reason why hemodynamics and electrolyte homeostasis remain normal with no APN activity may be that a mouse homologue of the human adipocyte-derived leucine aminopeptidase (A-LAP) can directly cleaves ang II to produce ang IV (34).…”

Section: Discussionmentioning

confidence: 99%

Impaired angiogenesis in aminopeptidase N-null mice

Rangel

Sun

Guzman-Rojas

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

114

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Aminopeptidase N (APN, CD13; EC 3.4.11.2) is a transmembrane metalloprotease with several functions, depending on the cell type and tissue environment. In tumor vasculature, APN is overexpressed in the endothelium and promotes angiogenesis. However, there have been no reports of in vivo inactivation of the APN gene to validate these findings. Here we evaluated, by targeted disruption of the APN gene, whether APN participates in blood vessel formation and function under normal conditions. Surprisingly, APN-null mice developed with no gross or histological abnormalities. Standard neurological, cardiovascular, metabolic, locomotor, and hematological studies revealed no alterations. Nonetheless, in oxygen-induced retinopathy experiments, APN-deficient mice had a marked and dose-dependent deficiency of the expected retinal neovascularization. Moreover, gelfoams embedded with growth factors failed to induce functional blood vessel formation in APNnull mice. These findings establish that APN-null mice develop normally without physiological alterations and can undergo physiological angiogenesis but show a severely impaired angiogenic response under pathological conditions. Finally, in addition to vascular biology research, APN-null mice may be useful reagents in other medical fields such as malignant, cardiovascular, immunological, or infectious diseases.CD13 ͉ knockout mice ͉ retinopathy ͉ vasculogenesis T he aminopeptidases are a large family of proteolytic enzymes that affect protein maturation, degradation, and regulation (1, 2). Aminopeptidase N (APN) is a membrane-bound zincdependent metalloprotease originally identified as a surface marker in myeloid cells (3,4). APN is widely distributed in many cell types, and its role in hydrolyzing unsubstituted N-terminal residues with neutral side chains varies in different locations. In the epithelium of the renal proximal tubule, APN cleaves its only known natural substrate, angiotensin (ang) III, to ang IV; in synaptic membranes, APN metabolizes enkephalins and endorphins; in the heart, it is an integral component of cardiac remodeling postmyocardial infarction (5-10); and in the respiratory system, APN is the cell surface receptor for certain human coronaviruses and potentially for the severe acute respiratory syndrome (SARS) virus (11-13). Additionally, APN functions in signal transduction, cell cycle control, and differentiation (14, 15).We have developed an in vivo system by using ligand peptides displayed on the surface of phage to study organ-and tumorspecific vascular homing; this methodology enables the identification of vascular markers (16,17). We have isolated phage displaying an asparagine-glycine-arginine (NGR)-containing peptide in a tumor-homing selection and have shown that these phage bind selectively to angiogenic blood vessels. When coupled to a cytotoxic drug (18) or fused to a proapoptotic peptide (19) or to tumor necrosis factor (20), NGR-targeted compounds were more effective and less toxic than the respective controls. The cell surface receptor fo...

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Section: Discussionmentioning

confidence: 99%

Impaired angiogenesis in aminopeptidase N-null mice

Rangel

Sun

Guzman-Rojas

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

114

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“…For example, in the brain RAS, Ang III, instead of Ang II, was shown to mediate the pressor response by AT 1 receptors, because selective blockade of the formation of brain Ang III resulted in a decrease in BP. 20 In the kidney, we know that Ang II is converted to Ang III in vivo via aminopeptidase A, which is present in both glomeruli and renal tubules. 4 Ang III is converted to Ang IV via aminopeptidase N. In the lumen of proximal tubule cells, the concentration of Ang II is 1000-fold higher than in plasma, but, because of the high density of peptidases, Ang II only represents Ϸ5% to 15% of total renal Angs.…”

Section: Discussionmentioning

confidence: 99%

“…In the second group, this study was repeated in the presence of a systemic CAND (0.01 mg/kg per minute) infusion 24 hours before and during the experiment. Lastly, the entire experiment was repeated (nϭ17) using higher infusion rates of Ang II (20,40, 80 nmol/kg per minute) in the presence of systemic CAND. Ϫ8 mol/L and Ͼ1ϫ10 Ϫ4 mol/L for AT 2 and AT 1 receptors, respectively), was used interstitially to block the AT 2 receptor.…”

Section: Receptor Blockadementioning

confidence: 99%

Renal Angiotensin Type 2 Receptors Mediate Natriuresis Via Angiotensin III in the Angiotensin II Type 1 Receptor–Blocked Rat

et al. 2006

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Abstract-Whereas angiotensin (Ang) II is the major effector peptide of the renin-angiotensin system, its metabolite, des-aspartyl 1 -Ang II (Ang III), may also have biologic activity. We investigated the effects of renal interstitial (RI) administration of candesartan (CAND), a specific Ang II type 1 receptor (AT 1 ) blocker, with and without coinfusion of PD-123319 (PD), a specific Ang II type 2 receptor (AT 2 ) blocker, on Na ϩ excretion (U Na V) in uninephrectomized rats. We also studied the effects of unilateral RI infusion of Ang II or Ang III on U Na V with and without systemic infusion of CAND with the noninfused kidney as control. In rats receiving normal Na ϩ intake, RI CAND increased U Na V from 0.07Ϯ0.08 to 0.82Ϯ0.17 mol/min (PϽ0.01); this response was abolished by PD. During Na ϩ restriction, CAND increased U Na V from 0.06Ϯ0.02 to 0.1Ϯ0.02 mol/min (PϽ0.05); this response also was blocked by PD. In rats with both kidneys intact, in the absence of CAND, unilateral RI infusion of Ang III did not significantly alter U Na V. However, with systemic CAND infusion, RI Ang III increased U Na V from 0.08Ϯ0.01 mol/min to 0.18Ϯ0.04 mol/min (PϽ0.01) at 3.5 nmol/kg per minute, and U Na V remained elevated throughout the infusion; this response was abolished by PD. However, RI infusion of Ang II did not significantly alter U Na V at any infusion rate (3.5 to 80 nmol/kg per minute) with or without systemic CAND infusion. These results suggest that intrarenal AT 1 receptor blockade engenders natriuresis by activation of AT 2 receptors. AT 2 receptor activation via Ang III, but not via Ang II, mediates the natriuretic response in the presence of systemic AT 1 receptor blockade. Key Words: angiotensin Ⅲ sodium Ⅲ natriuresis Ⅲ angiotensin Ⅲ receptors, angiotensin II A ngiotensin (Ang) II, the primary transducer peptide of the renin-Ang system (RAS), acts at 2 major Ang II receptors, type 1 (AT 1 ) and type 2 (AT 2 ). 1 The majority of Ang II actions are believed to occur via the AT 1 receptor, including antinatriuresis. 2 The role of the AT 2 receptor is less clearly understood. 3 Furthermore, whereas Ang II has been considered the major effector peptide of the RAS, its direct metabolite, des-aspartyl 1 -Ang II (Ang III) also has biologic activity. 4 Indeed, some actions originally attributable to Ang II, such as vasopressin release, are mediated at least in part by Ang III. 5 Recent reports suggest that Ang III could be involved in renal physiological processes as well. 6 -8 Studies involving AT 2 receptors and the regulation of sodium (Na ϩ ) excretion have been limited. In vitro studies have demonstrated that the AT 2 receptor may decrease renal proximal tubule bicarbonate reabsorption via phospholipase A 2 and arachidonic acid release. 9 In vivo studies in mice lacking the AT 2 receptor (AT 2 -null), have demonstrated a shift to the right (less sensitive) in the pressure-natriuresis curve. 10 In addition, antinatriuretic and pressor hypersensitivity to Ang II has been documented in AT 2 -null mice. 11 However, th...

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“…However, the pressor response to ICV administered D-Asp 1 Ang II in rats after administration of PC18 was not prolonged. 46 Recently, we reported that PC18 and EC33 inhibited the dipsogenic and saline intake responses of rats to an aminopeptidase-resistant Ang II given ICV, and that PC18 delayed the dipsogenic and saline intake responses of rats to an aminopeptidase-resistant Ang III given ICV. 47 This again suggests possible adverse effects of these inhibitors on AT 1 receptor function in the rat brain.…”

Section: Central Effects Of Ang II and Its Aminopeptidase-resistant Amentioning

confidence: 94%

Central Pressor Actions of Aminopeptidase-Resistant Angiotensin II Analogs

Kokje

Wilson²,

Brown³

et al. 2007

Hypertension

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Abstract-Intracerebroventricular administration of angiotensins causes pronounced pressor and dipsogenic responses. The suggestion that angiotensin III rather than angiotensin II is the active peptide in the brain spawned what we call The Angiotensin III Hypothesis. To test this hypothesis, 5 angiotensin II analogs containing zero or one position substitutions conferring resistance to aminopeptidases were administered intracerebroventricularly to determine their pressor and dipsogenic efficacies. Two aminopeptidase-resistant analogs caused significantly greater pressor responses than angiotensin II, whereas 3 analogs caused pressor responses similar to angiotensin II. Latency to cause a pressor response for 4 of the 5 aminopeptidase-resistant angiotensin II analogs was the same as for angiotensin II. There was no detectable formation of 125 I-angiotensin III from 1 of the intracerebroventricularly administered analogs, 125 I-N-Methyl-L-Asp 1 -angiotensin II, indicating its aminopeptidase resistance. Latency to drink also did not differ between the angiotensins. After the initial dipsogenic response, water was removed until 25 minutes after angiotensin administration to avoid interfering with the pressor response. The dipsogenic stimulus was sustained 25 minutes after intracerebroventricular injection of angiotensin II and its aminopeptidase-resistant analogs. Comparison of angiotensin III and angiotensin II showed equivalent pressor responses with similar latencies and durations. The latency to drink was similar for angiotensin III and angiotensin II. However, there was no dipsogenic response to angiotensin III 25 minutes after intracerebroventricular injection. These data do not support The Angiotensin III Hypothesis and suggest that conversion of exogenously applied angiotensin II to angiotensin III is not necessary to cause brain-mediated pressor or dipsogenic responses. Key Words: brain angiotensin receptors Ⅲ intracerebroventricular Ⅲ dipsogenesis Ⅲ metabolism T he brain rennin-angiotensin system (RAS) is distinct from the peripheral RAS and regulated independently. [1][2][3] Hyperactivity of the brain RAS is known to cause hypertension. 4 Angiotensin II (Ang II) receptors in circumventricular organs (which respond to both blood-borne and centrally produced Ang II), as well as in the hypothalamus and brain stem, cause cardiovascular, endocrine, and behavioral effects. 5 Centrally administered angiotensins stimulate both angiotension II type 1 (AT 1 ) and type 2 (AT 2 ) receptor subtypes in the brain, but the cardiovascular effects arise from AT 1 receptor-mediated vasopressin, oxytocin and aldosterone release, activation of sympathetic neuronal activity, and enhanced thirst and salt appetite. 6,7 Fitzsimons demonstrated that angiotensin III (Ang III) which is des Asp 1 Ang II also acts in the brain, to cause thirst. 8 Subsequent studies demonstrated that intracerebroventricular (ICV) Ang II and Ang III were equipotent at causing dipsogenic and pressor responses. 9 Harding and Felix 10 were able to increas...

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Conversion of brain angiotensin II to angiotensin III is critical for pressor response in rats

Cited by 77 publications

References 51 publications

Impaired angiogenesis in aminopeptidase N-null mice

Impaired angiogenesis in aminopeptidase N-null mice

Renal Angiotensin Type 2 Receptors Mediate Natriuresis Via Angiotensin III in the Angiotensin II Type 1 Receptor–Blocked Rat

Central Pressor Actions of Aminopeptidase-Resistant Angiotensin II Analogs

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