Use of the AT1R ligand C-11 KR31173 for monitoring of the myocardial effect of drugs inhibiting the renin-angiotensin system after myocardial infarction

Objectives After myocardial infarction (MI), the renin-angiotensin system is activated globally and on the myocardial tissue level. This may initialize and promote cardiac remodeling. Using a rodent model of MI, we aimed to determine (1) the time course of regional myocardial angiotensin II type 1 receptor (AT1R) upregulation and (2) the blocking efficacy of AT1R blockers/ACE inhibitors.

Methods MI was obtained by 20min ligation of the left coronary artery in male Wistar rats (n=33, 220-250g). C-11 KR31173 (KR), an analog of the AT1R blocker SK1080, was injected IV at different time points following surgery (day1, day3, week1, week3, month3, month6). Next, 4 groups of MI rats (n=16) were studied with no treatment, valsartan (daily, 50mg/kg, oral administration, started just after MI), enalapril (daily, 10mg/kg, oral administration, started just after MI), and after complete AT1R blockage (SK-1080, 2mg/kg IV, just before imaging).

Results Autoradiographically, regionally increased C-11 KR uptake peaked in the infarct area at 1-3 weeks after MI (infarct/remote uptake ratio = 0.9±1.0, 1.6±0.3, 2.5±0.4*, 3.0±0.7**, 3.2±0.6**, 1.8±0.7***, 1.3±0.3 at control, day1, day3, week1, week3, month3, month6, respectively, vs. control *p<.01, **p<.001, ***p<.05). The elevated signal was detectable by in vivo PET. While enalapril treatment did not reduce focal tracer uptake, valsartan resulted in partial blocking when compared to SK-1080 (uptake ratio = 2.9±0.5, 2.9±0.6, 2.1±0.3* and 1.3±0.1**, untreated, enalapril, valsartan, SK-1080, vs. control *p<.05, **p<.001).

Conclusions Following myocardial infarction, regional AT1R upregulation can be detected by C-11 KR31173. Upregulation peaks at 1-3 weeks, and inhibitory effects of the clinical agent valsartan can be detected. These results provide a rationale for the use of in vivo imaging to monitor the efficacy of blockade of the molecular target structure in drug therapy directed against neurohumoral activation and ventricular remodeling