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Intrarenal aminopeptidase N inhibition restores defective angiontesin II type 2-mediated natriuresis in spontaneously hypertensive rats.
Hypertension. 2010 Feb; 55(2):474-80.H

Abstract

The preferred ligand of angiotensin (Ang) II type 2 (AT(2)R)-mediated natriuresis is Ang III. The major enzyme responsible for the metabolism of Ang III is aminopeptidase N, which is selectively inhibited by compound PC-18. In this study, urine sodium excretion rates (U(Na)V), fractional excretion of sodium, fractional excretion of lithium, glomerular filtration rate, and mean arterial pressures were studied in prehypertensive and hypertensive spontaneously hypertensive rats (SHRs) and compared with age-matched Wistar-Kyoto rats (WKYs). Although renal interstitial infusion of Ang II type 1 receptor blocker candesartan increased U(Na)V in WKYs from a baseline of 0.05+/-0.01 to 0.17+/-0.04 micromol/min (P<0.01), identical infusions failed to increase U(Na)V in hypertensive SHRs. Coinfusion of AT(2)R antagonist PD-123319 abolished the natriuretic responses to candesartan in WKYs, indicating an AT(2)R-mediated effect. AT(2)R-mediated natriuresis was enabled in hypertensive SHRs by inhibiting the metabolism of Ang III with PC-18 (0.05+/-0.01 to 0.11+/-0.03 micromol/min; P<0.05). The defects in sodium excretion were present before the onset of hypertension in SHRs, because young WKYs demonstrated double the U(Na)V of SHRs (0.04+/-0.006 versus 0.02+/-0.003 micromol/min; P<0.01) at baseline. The increased U(Na)V of young WKYs was attributed to reduced renal proximal tubule sodium reabsorption, because increases in fractional excretion of sodium were paralleled by increases in fractional excretion of lithium. Renal interstitial PC-18 infusion ameliorated defective AT(2)R-mediated natriuresis in young SHRs by increasing fractional excretion of sodium and fractional excretion of lithium without changing the glomerular filtration rate. Thus, increased renal proximal tubule sodium retention is observed before the onset of hypertension in SHRs, and inhibition of the metabolism of Ang III ameliorates this pathophysiologic defect in sodium excretion.

Authors+Show Affiliations

Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia Health System, Charlottesville, Va 22908-1414, USA. shp6a@virginia.eduNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

19996063

Citation

Padia, Shetal H., et al. "Intrarenal Aminopeptidase N Inhibition Restores Defective Angiontesin II Type 2-mediated Natriuresis in Spontaneously Hypertensive Rats." Hypertension (Dallas, Tex. : 1979), vol. 55, no. 2, 2010, pp. 474-80.
Padia SH, Howell NL, Kemp BA, et al. Intrarenal aminopeptidase N inhibition restores defective angiontesin II type 2-mediated natriuresis in spontaneously hypertensive rats. Hypertension. 2010;55(2):474-80.
Padia, S. H., Howell, N. L., Kemp, B. A., Fournie-Zaluski, M. C., Roques, B. P., & Carey, R. M. (2010). Intrarenal aminopeptidase N inhibition restores defective angiontesin II type 2-mediated natriuresis in spontaneously hypertensive rats. Hypertension (Dallas, Tex. : 1979), 55(2), 474-80. https://doi.org/10.1161/HYPERTENSIONAHA.109.144956
Padia SH, et al. Intrarenal Aminopeptidase N Inhibition Restores Defective Angiontesin II Type 2-mediated Natriuresis in Spontaneously Hypertensive Rats. Hypertension. 2010;55(2):474-80. PubMed PMID: 19996063.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Intrarenal aminopeptidase N inhibition restores defective angiontesin II type 2-mediated natriuresis in spontaneously hypertensive rats. AU - Padia,Shetal H, AU - Howell,Nancy L, AU - Kemp,Brandon A, AU - Fournie-Zaluski,Marie-Claude, AU - Roques,Bernard P, AU - Carey,Robert M, Y1 - 2009/12/07/ PY - 2009/12/10/entrez PY - 2009/12/10/pubmed PY - 2010/2/23/medline SP - 474 EP - 80 JF - Hypertension (Dallas, Tex. : 1979) JO - Hypertension VL - 55 IS - 2 N2 - The preferred ligand of angiotensin (Ang) II type 2 (AT(2)R)-mediated natriuresis is Ang III. The major enzyme responsible for the metabolism of Ang III is aminopeptidase N, which is selectively inhibited by compound PC-18. In this study, urine sodium excretion rates (U(Na)V), fractional excretion of sodium, fractional excretion of lithium, glomerular filtration rate, and mean arterial pressures were studied in prehypertensive and hypertensive spontaneously hypertensive rats (SHRs) and compared with age-matched Wistar-Kyoto rats (WKYs). Although renal interstitial infusion of Ang II type 1 receptor blocker candesartan increased U(Na)V in WKYs from a baseline of 0.05+/-0.01 to 0.17+/-0.04 micromol/min (P<0.01), identical infusions failed to increase U(Na)V in hypertensive SHRs. Coinfusion of AT(2)R antagonist PD-123319 abolished the natriuretic responses to candesartan in WKYs, indicating an AT(2)R-mediated effect. AT(2)R-mediated natriuresis was enabled in hypertensive SHRs by inhibiting the metabolism of Ang III with PC-18 (0.05+/-0.01 to 0.11+/-0.03 micromol/min; P<0.05). The defects in sodium excretion were present before the onset of hypertension in SHRs, because young WKYs demonstrated double the U(Na)V of SHRs (0.04+/-0.006 versus 0.02+/-0.003 micromol/min; P<0.01) at baseline. The increased U(Na)V of young WKYs was attributed to reduced renal proximal tubule sodium reabsorption, because increases in fractional excretion of sodium were paralleled by increases in fractional excretion of lithium. Renal interstitial PC-18 infusion ameliorated defective AT(2)R-mediated natriuresis in young SHRs by increasing fractional excretion of sodium and fractional excretion of lithium without changing the glomerular filtration rate. Thus, increased renal proximal tubule sodium retention is observed before the onset of hypertension in SHRs, and inhibition of the metabolism of Ang III ameliorates this pathophysiologic defect in sodium excretion. SN - 1524-4563 UR - https://www.unboundmedicine.com/medline/citation/19996063/Intrarenal_aminopeptidase_N_inhibition_restores_defective_angiontesin_II_type_2_mediated_natriuresis_in_spontaneously_hypertensive_rats_ L2 - https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.109.144956?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -