Abstract 18903: Stimulation of Angiotensin Type 2 Receptor as a Potential Therapy for Pulmonary Hypertension
Pulmonary hypertension (PH) is characterized by an increased pressure in the lung vasculature, often leading to right heart failure, and for which current therapies are lacking. Activation of the ACE2/Ang-(1-7)/Mas axis of the renin angiotensin system attenuates much of the associated pathophysiology related to PH. Along with the ACE2/Ang-(1-7)/Mas axis, the AT2 receptor (AT2R) is considered vasoprotective, and activation of these components often mimic each other. In fact, both ACE2 and AT2R have a protective role in acute lung injury; however, the role of AT2R has yet to be investigated in PH. We hypothesize that activation of the AT2R, via selective agonist Compound 21 (C21), could be an effective treatment against PH. Sprague Dawely rats were injected sc with 50mg/kg of monocrotaline (MCT) at 8 weeks of age to induce PH. Control (Con) animals were given saline. After 2 weeks, when right ventricular systolic pressures (RVSP) were significantly elevated (PH 48.33±8.8; Con 32.0 ±2.4 mmHg), treatment began with animals receiving either 0.03mg/kg/day C21 ip (MCT+C21), 0.3mg/kg/day PD-123,319 (MCT+PD), C21 and PD (MCT+C21+PD), or vehicle (MCT, Con) for an additional 2 weeks, after which RV hemodynamic parameters were measured and tissues collected. Treatment with C21 significantly attenuated PH and associated cardiac pathophysiologies. The increase in RVSP and RV hypertrophy induced by MCT was significantly blunted by C21 treatment, and PD prevented this reduction. Furthermore, right heart dysfunction as measured by dP/dtmax, was significantly attenuated by C21 treatment, but was exacerbated in rats treated with PD. PD treatment also worsened the lung weight to tibia length ratio in comparison to MCT. To our knowledge these are the first results to indicate that activation of the AT2R halts the progression of PH and C21 should be considered for an additional drug arsenal in PH therapy.
- © 2012 by American Heart Association, Inc.