Effects of Nicorandil on Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats

Abstract

We investigated whether nicorandil might prevent and reverse monocrotaline (MCT)-induced pulmonary arterial hypertension. Rats were injected with 50 mg/kg of MCT subcutaneously and randomized to either 7.5 mg/kg/d of nicorandil in drinking water or placebo for 3 weeks. Animals that were treated with MCT and survived for 3 weeks were assigned to either nicorandil or placebo. Nicorandil markedly attenuated pulmonary arterial hypertension with severe structural remodeling of the pulmonary vessels. The survival rate at 3 weeks after treatment was significantly increased in the nicorandil group compared with the placebo group (73% versus 39%, P<0.05). In the placebo group, endothelial nitric oxide synthase (eNOS) protein was significantly decreased, the numbers of the CD45-positive cells and those of the proliferating cell nuclear antigen-positive cells were increased in the lung tissue, and P-selectin was intensely expressed on the endothelium of the pulmonary arteries. These features were prevented by nicorandil. Late treatment with nicorandil did not palliate established pulmonary arterial hypertension nor improved survival. Thus, nicorandil inhibited development of MCT-induced pulmonary arterial hypertension but failed to reverse it. These effects were associated with marked up-regulation of diminished lung eNOS protein along with improvement of pulmonary vascular endothelial activation and anti-inflammatory and anti-proliferative effects in the lung tissue.

Nicorandil Attenuates FeCl3-Induced Thrombus Formation Through the Inhibition of Reactive Oxygen Species Production

“…This enzyme plays important roles in inhibiting platelet aggregation and relaxing vascular smooth muscle. Previous studies have reported that nicorandil prevented the downregulation of eNOS in the lung tissue of a rat model of monocrotaline-induced pulmonary arterial hypertension 33 and in the hearts of Dahl salt-sensitive hypertensive rats. 9 However, nicorandil did not increase eNOS mRNA levels, eNOS phosphorylation or nitrite production in the present study (Figure 6).…”

Pulmonary arterial hypertension: a disease of tethers, SNAREs and SNAPs?

“…There is a growing consensus that there are reduced NO levels in the pulmonary arterial walls in human and experimental PAH, even though the levels of eNOS protein have been variably reported as unchanged, decreased, or even increased (24,34,40,41,53,67,76,83,101). It is also now clear that the extracellular NO derives from cell-surface caveolar eNOS and that intracellularly active eNOS produces NO in subcellular compartments from where the NO does not reach the extracellular space (27,37).…”

Protective effect of nicorandil on hypoxia-induced apoptosis in HPAECs through inhibition of p38 MAPK phosphorylation

“…Findings of studies on cardiovascular disease have shown that nicorandil protects endothelial function (14) and enhances eNOS expression (16). In a monocrotaline-induced pulmonary arterial hypertension model, similar effects of nicorandil were identified (15). Therefore, in the present study, expression of eNOS was determined and regulatory mechanisms were explored.…”

“…A number of studies (14)(15)(16) have demonstrated the critical role of eNOS in PH, particularly in the maintenance of endothelial function. Findings of studies on cardiovascular disease have shown that nicorandil protects endothelial function (14) and enhances eNOS expression (16).…”

“…Previous studies indicated that KATP channels may also affect the endothelin system. Nicorandil inhibits endothelial apoptosis, enhances eNOS expression and preserves endothelial function via activation of the mitoKATP channels in the endothelial cell (12)(13)(14)(15)(16). In addition, KATP channels have been reported to interact with various MAPK signals (3,(17)(18)(19).…”