Abstract 661: The KATP-channel Opener, Nicorandil, Attenuates Monocrotaline-induced Endothelial Damage in Pulmonary Vasculature through the Enhanced Expressions of eNOS and Anti-apoptotic Factors via PI3K/Akt and MAPK pathways
Background: Recent evidence suggests that nicorandil, a KATP channel opener, reveals a number of beneficial cardiovascular actions; however, its effects on pulmonary vasculature in the context of pulmonary hypertension (PH) have not yet been elucidated.
Methods and Results: Sprague-Dawley rats injected with 60 mg/kg monocrotaline (MCT)-IP were randomized to receive either vehicle, nicorandil (2.5–7.5 mg/kg/day), nicorandil +glibenclamide (a KATP channel blocker), nicorandil +L-NAME (a NOS inhibitor), or ZVAD-fmk (a caspase inhibitor; 3.3 mg/kg-IV). After 28 days, the increased right ventricular systolic pressure in vehicle-group (51.6 ± 4.4 mmHg) was significantly attenuated by nicorandil in a dose-dependent manner (33.6 ± 4.5 mmHg in Nico7.5-group; p<0.05) or ZVAD-fmk (32.2 ± 3.1 mmHg; p<0.05). Nicorandil and ZVAD-fmk protected pulmonary endothelium from MCT-induced damage and apoptosis via the enhanced expression of eNOS in lungs, followed by inhibition of both thromboembolic formation in pulmonary microcirculation and medial wall thickening in pulmonary arterioles. These beneficial effects by nicorandil were markedly prevented by coadministration of glibenclamide or L-NAME. Next, HUVECs were incubated in the absence or presence of nicorandil (100 μM) or another KATP channel opener, diazoxide. TUNEL staining and the MTS assay revealed that HUVECs in serum-free medium displayed apoptosis, which was attenuated by both nicorandil and diazoxide. To study the signaling pathways implicated in the nicorandil-stimulated protective responses, we determined the phosphorylation status of Akt and ERK1/2. Incubation of HUVECs with nicorandil increased both Akt and ERK1/2 phosphorylation in a time-dependent manner. In addition, nicorandil upregulated the protein levels of eNOS and an apoptosis inhibitor, Bcl-2 in HUVECs. These effects by nicorandil on HUVECs were blocked by coadministration of glibenclamide, L-NAME, LY294002 (a PI3K inhibitor), or PD98059 (a MEK inhibitor), respectively.
Conclusions: Nicorandil attenuates MCT-induced endothelial damage in pulmonary vasculature through the enhanced expressions of eNOS and anti-apoptotic factors via PI3K/Akt and MAPK pathways. Nicorandil may have a therapeutic potential for PH.