We appreciate Dr Zhuo's 1 interest in our work on PET imaging of the renal AT 1 receptor (AT 1 R) in a swine model of renal artery stenosis. One of the challenges of PET receptor studies is separation of signals representing nonspecific and receptor-specific radioligand accumulation. We had performed 3 measurements to support our concept that retention of In our study AT 1 R binding was markedly increased in pig kidneys with renal artery stenosis. Dr Amiri's group 3 cited by Dr Zhuo used binding assays to study the 2K1C rat model of renovascular hypertension and found increased angiotensin II (Ang II) production with a negative correlation between Ang II and AT 1 R. However, a positive correlation was described by Dr Zhuo's group in Hypertension 4 : during Ang II hypertension, increased Ang II levels in renal cortical endosomes were associated with enhanced expression of the AT 1 R in endosomes and intermicrovillar clefts. Multiple factors are likely involved in the regulation of the AT 1 R, which include not only altered renal perfusion pressure but also the local release of Ang II and other tissue hormones. Thus, different regulation patterns observed in different animal models of hypertension were in part caused by comparison of in vitro and in vivo measurements or 2 in vitro techniques. Another important observation by Dr Zhuo states that lisinopril treatment is expected to increase rather than abolish intrarenal AT 1 R binding. 5 We documented increased AT 1 R binding in the hypoperfused kidney, an effect that was not further affected by an oral ACE inhibitor at a dose high enough to attenuate hypertension. There is no simple explanation for the difference between effect on blood pressure without effect on the AT 1 R. ACE inhibitors not only affect the RAS but also reduce the degradation of bradykinin, another modulator of AT 1 R expression. Tokuyama et al 6 reported that in clipped kidneys, elevated Ang II is not suppressed by ACE inhibitors and disclose a novel mechanism that in the kidneys, Ang II may be generated through ACE-independent pathways, resulting in an "ACE-escape" phenomenon. Although the sample size in our article may not be sufficient to demonstrate differences between the untreated and treated subgroups, the results are assuring that, if the test becomes applicable in human renovascular hypertension, its sensitivity will not be affected by ACE inhibitor therapy at doses typically taken by human subjects.
Sources of FundingThis study was supported by National Institute of Diabetes and Digestive and Kidney Diseases grant RO1 DK50183, Interdisciplinary Small Animal Imaging grant 5R24CA092871.
DisclosuresNone.
Jinsong Xia Zsolt Szabo
Department of Radiology The Johns Hopkins Medical InstitutionsBaltimore, Md
