Rationale Compound 21 (C-21) is a highly selective non-peptide AT2 receptor (AT2R) agonist. Objective To test the hypothesis that renal proximal tubule AT2Rs induce natriuresis and lower blood pressure (BP) in Sprague-Dawley rats and mice. Methods and Results In rats, AT2R activation with intravenous C-21 increased urinary sodium (Na+) excretion (UNaV) by 10-fold (P<0.0001); this natriuresis was abolished by direct renal interstitial (RI) infusion of specific AT2R antagonist PD-123319 (PD). C-21 increased fractional excretion of Na+ (FENa; P<0.05) and lithium (FELi; P<0.01) without altering renal hemodynamic function. AT2R activation increased renal proximal tubule cell (RPTC) apical membrane AT2R protein (P<0.001) without changing total AT2R expression and internalized/inactivated Na+- H+ exchanger-3 (NHE-3) and Na+/K+ATPase (NKA). C-21-induced natriuresis was accompanied by an increase in RI cyclic GMP (cGMP; P<0.01); C-21-induced increases in UNaV and RI cGMP were abolished by RI nitric oxide (NO) synthase inhibitor L-NAME or bradykinin (BK) B2 receptor antagonist icatibant. Renal AT2R activation with C-21 prevented Na+ retention and lowered BP in the angiotensin II (Ang II) infusion model of experimental hypertension. Conclusions AT2R activation initiates its translocation to the RPTC apical membrane and the internalization of NHE-3 and NKA inducing natriuresis in a BK-NO-cGMP-dependent manner. Intrarenal AT2R activation prevents Na+ retention and lowers BP in Ang II-dependent hypertension. AT2R activation holds promise as a RPT natriuretic/diuretic target for the treatment of fluid retaining states and hypertension.
In AT1 receptor (AT1R)-blocked rats, renal interstitial (RI) administration of des-aspartyl1-angiotensin II (Ang III), but not angiotensin II (Ang II), induces natriuresis via activation of angiotensin type-2 receptors (AT2R). In the present study, renal function was documented during systemic AT1R blockade with candesartan in Sprague-Dawley rats receiving unilateral RI infusion of Ang III. Ang III increased urine sodium excretion (UNaV), fractional excretion of sodium (FENa), and fractional excretion of lithium (FELi). RI co-infusion of specific AT2R antagonist PD-123319 (PD) abolished Ang III-induced natriuresis. The natriuretic response observed with RI Ang III was not reproducible with RI Ang (1–7) alone or together with angiotensin converting enzyme (ACE) inhibition. Similarly, neither RI Ang II alone nor in the presence of aminopeptidase A (APA) inhibitor to prevent degradation increased UNaV. In the absence of systemic AT1R blockade, Ang III alone did not increase UNaV, but natriuresis was enabled by the co-infusion of aminopeptidase N (APN) inhibitor and subsequently blocked by PD. In AT1R-blocked rats, RI administration of APN inhibitor alone also induced natriuresis that was abolished by PD. Ang III-induced natriuresis was accompanied by increased RI cyclic GMP 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 APN inhibition. These data demonstrate that endogenous intrarenal Ang III, but not Ang II or Ang (1–7), induces natriuresis via activation of AT2Rs in the proximal tubule via a cyclic GMP-dependent mechanism and suggest APN inhibition as a potential therapeutic target in hypertension.
Background Sustained pressure overload leads to changes in cardiac metabolism, function, and structure. Both time course and causal relationships between these changes are not fully understood. Therefore, we studied spontaneously hypertensive rats (SHR) during early hypertension development and compared them to control Wistar Kyoto rats. Methods and Results We serially evaluated myocardial glucose uptake rates (Ki) with dynamic 2‐[ 18 F] fluoro‐2‐deoxy‐D‐glucose positron emission tomography, and ejection fraction and left ventricular mass to body weight ratios with cardiac magnetic resonance imaging in vivo, determined glucose uptake and oxidation rates in isolated perfused hearts, and analyzed metabolites, mammalian target of rapamycin activity and endoplasmic reticulum stress in dissected hearts. When compared with Wistar Kyoto rats, SHR demonstrated increased glucose uptake rates (Ki) in vivo, and reduced ejection fraction as early as 2 months of age when hypertension was established. Isolated perfused SHR hearts showed increased glucose uptake and oxidation rates starting at 1 month. Cardiac metabolite analysis at 2 months of age revealed elevated pyruvate, fatty acyl‐ and branched chain amino acid‐derived carnitines, oxidative stress, and inflammation. Mammalian target of rapamycin activity increased in SHR beginning at 2 months. Left ventricular mass to body weight ratios and endoplasmic reticulum stress were elevated in 5 month‐old SHR. Conclusions Thus, in a genetic hypertension model, chronic cardiac pressure overload promptly leads to increased myocardial glucose uptake and oxidation, and to metabolite abnormalities. These coincide with, or precede, cardiac dysfunction while left ventricular hypertrophy develops only later. Myocardial metabolic changes may thus serve as early diagnostic markers for hypertension‐induced left ventricular hypertrophy.
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