AT1R antagonist (Alchemedicine)

Intracerebral renin-angiotensin system (RAS) activation in the forebrain nuclei, such as the subfornical organ (SFO) is among the important factors that increase sodium appetite in rats. Although an increased sodium appetite in congestive heart failure and spontaneously hypertensive rats was reported previously, few reports have shown an increased sodium appetite in chronic kidney disease (CKD) model rats, for which salt restriction is important. Here, we aimed to verify whether CKD model rats show increased sodium appetite and if therapeutic intervention reducing sodium appetite by suppressing the intracerebral RAS is possible. In this study, 5/6 nephrectomized (5/6Nx) and control rats were fed a high-salt (4% NaCl) or low-salt (0.04% NaCl) diet. Angiotensin II (AngII) levels in kidney and the SFO, renal injury, and sodium appetite were evaluated after 2 weeks of salt loading. The 5/6Nx high-salt diet (Nx-HS) group was further divided into subgroups receiving continuous intracerebroventricular (ICV) administration of the angiotensin II type 1 receptor (AT1R) antagonist ZD 7155 or saline. Compared with the control rats, the 5/6Nx rats exhibited significantly increased levels of AngII in kidney and the SFO, accompanied by elevated blood pressure and worsened renal injury, especially in the Nx-HS group. In the Nx-HS group, an increased sodium appetite was observed that was attenuated by the ICV administration of ZD 7155 but not by saline. In conclusion, a high-salt diet enhanced the sodium appetite of 5/6Nx rats via increased levels of AngII in the SFO, which was attenuated by continuous ICV administration of an AT1R antagonist.

Women with a history of preeclampsia (hxPE) have a ≥4-fold risk for developing cardiovascular disease (CVD) compared with women who had a healthy pregnancy (hxHC). HxPE have exaggerated vasoconstrictor sensitivity to angiotensin (ang) II after pregnancy, which likely contributes to CVD progression after preeclampsia. Ang II-mediated constriction via ang II type 1 receptors (AT1R) is countered by vasodilatory ang II type 2 receptors (AT2R); however, the extent to which reductions in AT2R-mediated responses contribute to exaggerated ang II-mediated constriction after preeclampsia remains unknown. We examined the balance of AT1R- and AT2R-mediated responses in hxPE and hxHC (n=12/group). We hypothesized that (1) attenuated AT2R-mediated dilation would be improved with AT1R inhibition in hxPE, and (2) AT2R inhibition would increase ang II-mediated constriction in hxHC but have no effect in hxPE. We measured cutaneous vascular conductance responses to compound 21 (AT2R agonist; 10-14–10-8mol/L) alone or with losartan (AT1R antagonist; 43 μmol/L) to assess AT2R-mediated dilation, and ang II (10−20–10−4 mol/L) alone or with PD-123319 (AT2R antagonist; 1 μmol/L) to assess the role of AT2R in vasoconstrictor sensitivity to ang II. Reduced AT2R-mediated dilation in hxPE (P=0.002) was improved with AT1R inhibition (P<0.001). Vasoconstrictor sensitivity to ang II was greater in hxPE compared with hxHC (P<0.001). Circulating AT1R agonistic autoantibodies (AT1-AA) were elevated in hxPE (P=0.015). AT2R inhibition increased the vasoconstrictor response to ang II in hxHC (P<0.001) but had no effect in hxPE (P=0.19). These data suggest that hxPE has reduced AT2R-mediated dilation that contributes to increased ang II vasoconstrictor sensitivity after preeclampsia.