Abstract 1414: Neuropeptide Y2 Receptor Blockade Ameliorates Hypertension-Induced Left Ventricular Hypertrophy in the Rat
Cardiomyocytes express neuropeptide Y Y2 receptor subtype (Y2R) whose signaling involves coupling negatively to cAMP and positively to Ca2+ and K+ channels. In this study we examined whether the Y2R is involved in hypertension-induced left ventricle hypertrophy (LVH).
METHODS: Male Sprague Dawley rats (n=5–7) were rendered hypertensive using 1-kidney 1-clip (1K1C) model and received as a continuous infusion (osmotic pumps) either a Y2R antagonist, BIIE0246 (0.47 μmole/60μl/day/rat, s.c., Gr 3) or vehicle (water, Gr 2) for 28 days. Sham animals (1K, no clip, plus vehicle, Gr 1) were also included. Systolic blood pressure (SBP) was continuously measured by telemetry. Myocardial hypertrophy was assessed by serial measurements of LV posterior wall thickness (LV PWT) using 2D echo (Vivid 7 Echo, GE), histological morphometry of LV cross-section area (LV at the level of the papillary muscle), and by heart weight to body weight (HW/BW) and to femur length (HW/FL) ratios. LV fibrosis was assessed by staining the heart sections with Mason’s trichrome and measured by Metamorph.
RESULTS: Following significant (p<0.05) increases in SBP in Gr 2 and Gr 3 (by 68 and 32 mmHg, respectively, comparing to Gr 1), the LV PWT, the LV cross-section area, HW/BW, HW/FL, and LV fibrotic area were significantly (p<0.05) increased in Gr 2. The treatment with Y2R antagonist almost completely abolished the 1K1C-induced myocardial hypertrophy. For example, at the end of experiment LV PWT in Gr 2 was 2.3 ±0.1 mm and it was reduced by the antagonist to the sham level (1.9 ±0.1 vs 1.8 ±0.1 mm, in Gr 3 vs Gr 1). These differences were confirmed by the three other indices of myocardial hypertrophy used. The Y2R antagonist also completely prevented the 1K1C-induced LV fibrosis (0.75±0.15 vs 0.29±0.05 and 0.41±0.04 mm2 in Gr 2 vs Gr 3 and Gr 1, respectively). LV end-diastolic and systolic chamber diameters were not changed.
CONCLUSION: These results demonstrate that the cardiac Y2 receptor is involved in compensatory LVH. This evidence is further supported by the demonstrated association between the Y2R gene polymorphisms and LV mass phenotypes in humans (abstract submitted to this meeting). Thus, Y2R emerges as a novel drug target for hypertensive LVH.