16 April 2007
The mechanism of endothelium-dependent vasodilator signaling involves three components such as nitric oxide, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF). Although EDHF is distinct from nitric oxide and prostacyclin, it requires activation of Ca<sup>2+</sup>-sensitive K<sup>+</sup> channels (K<sub>Ca</sub>) and cytochrome P<sub>450</sub> metabolites. However, the physiological role of EDHF in the pulmonary circulation is unclear. Thus, we tested if EDHF would regulate vascular tone in rat lungs of control and monocrotaline (MCT)-induced pulmonary hypertension. Inhibition of EDHF with a combination of K<sub>Ca</sub> blockers, charybdotoxin (50 n M) plus apamin (50 n M), increased baseline vascular tone in MCT-induced hypertensive lungs. Thapsigargin (TG; 100 n M), an inhibitor of Ca-ATPase, caused greater EDHF-mediated vasodilation in MCT-induced hypertensive lungs. TG-induced vasodilation was abolished with the charybdotoxin-apamin combination. Sulfaphenazole (10 µ M), a cytochrome P<sub>450</sub> inhibitor, reduced the TG-induced vasodilation in MCT-induced hypertensive lungs. RT-PCR analysis exhibited an increase in K<sub>Ca</sub> mRNA in MCT-treated lungs. These results indicate the augmentation of tonic EDHF activity, at least in part, through the alteration in cytochrome P<sub>450</sub> metabolites and the upregulation of K<sub>Ca</sub> expression in MCT-induced pulmonary hypertension.