Abstract 529: Nicorandil, an Adenosine Triphosphate-sensitive Potassium Channel Opener, Attenuates Monocrotaline-induced Pulmonary Arterial Hypertension in Rats
Background: Nicorandil is a hybrid drug with nitrate-like and adenosine triphosphate-sensitive potassium (KATP) channel activating properties. The aim of this study was to evaluate the efficacy of nicorandil for monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) in rats.
Methods and Results: Sprague-Dawley rats injected intraperitoneally with 60 mg/kg MCT were randomized to receive continuous administration of either vehicle, nicorandil (2.5 mg/kg/day; Nico2.5), nicorandil (5.0 mg/kg/day; Nico5.0), or both of nicorandil (5.0 mg/kg/day) and a KATP channel blocker, glibenclamide (5.0 mg/kg/day), using subcutaneous osmotic pumps. After 28 days, right ventricular systolic pressure (RVSP) was significantly increased in vehicle-group (51.6±4.4 mmHg) than in normal control (21.2±3.5 mmHg; p<0.0001) with marked right ventricular hypertrophy (RVH). The increase of RVSP was significantly attenuated by nicorandil in a dose-dependent manner (42.2±5.8 mmHg in Nico2.5-group and 36.4±5.2 mmHg in Nico5.0-group; p<0.05 vs. vehicle-group), along with attenuated RVH. The beneficial effect of nicorandil against the toxicity of MCT was markedly inhibited by glibenclamide. MCT induced endothelial damage and/or apoptosis in pulmonary arterioles, and down-regulated mRNA and protein expressions of endothelial nitric oxide synthase (eNOS) in lung tissue. These toxic effects of MCT were inhibited by nicorandil, at least partially. Next, human umbilical vein endothelial cells (HUVECs) were cultured on a 24-well plate, and incubated in serum-free medium in the absence or presence of nicorandil (10 to 200 μM) or a KATP channel opener, diazoxide (1 to 10 μM) for 48 hours. HUVECs cultured in serum-free medium displayed apoptosis identified by phase-contrast microscopic images and TUNEL staining. Both nicorandil and diazoxide inhibited the induction of apoptosis of HUVECs in a dose-dependent manner, which was reversed by coadministration of glibenclamide (10 μM) or a NOS inhibitor, L-NAME (2 mM).
Conclusions: These results suggest that nicorandil attenuates the development of MCT-induced PAH in rats, at least partially, by a mechanism possibly involving the protection of pulmonary microvasculature via the enhanced expression of eNOS.