Role of nitric oxide in cholecystokinin octapeptide alleviation of tumor necrosis factor alpha induced changes in rabbit pulmonary arterial reactivity

To explore the mechanism underlying cholecystokinin-octapeptide (CCK-8) induced attenuation in pulmonary arterial hypertension (PAH) in endotoxic shock (ES), the effect of CCK-8 on the changes in rabbit pulmonary arterial reactivity induced by tumor necrosis factor-alpha (TNF-α) was observed with isolated arterial ring technique and by examination of nitric oxide synthase (NOS). The contractile response to 10 -6 mol/L phenylephrine (PE) and the endothelium-dependent relaxation response to 10 -6 mol/L acetylcholine (ACh) were not affected by TNF-α (4*#000 U/ml) after incubation for 2 h; the relaxation response was decreased significantly when the incubation was prolonged to 7 or 14 h, which, however, could be reversed by a concomitant exposure to CCK-8 (0 5 μg/ml), but the incubation of pulmonary arterial rings with CCK-8 (0 5 μg/ml) alone did not bring out any contractile responses. The endothelium-dependent relaxation response to 10 -6 mol/L ACh was restored by L-arginine in the TNF-α group which had been incubated for 7 h, but was not affected by AG in each group, while the contractile response to 10 -6 mol/L PE increased significantly in the TNF-α group. The relaxant response to 10 -6 mol/L ACh changed into a contractile response after preincubation with L-NNA in each group, while the contraction response to 10 -6 mol/L PE increased significantly. The NOS activity increased in the TNF-α and the TNF-α+CCK-8 groups, while no significant difference was observed between the vehicle and the CCK-8 groups. These results suggest that CCK-8 prevents TNF-α induced impairment in endothelium-dependent relaxation response, and the effects of both CCK-8 and TNF-α are related to NO.