Activity of endothelium-derived hyperpolarizing factor is augmented in monocrotaline-induced pulmonary hypertension of rat lungs

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 Ca2+ - sensitive K+ channels ( K-Ca) and cytochrome P-450 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-Ca blockers, charybdotoxin ( 50 nM) plus apamin ( 50 nM), increased baseline vascular tone in MCT- induced hypertensive lungs. Thapsigargin ( TG; 100 nM), 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 mu M), a cytochrome P-450 inhibitor, reduced the TG- induced vasodilation in MCT- induced hypertensive lungs. RT- PCR analysis exhibited an increase in K-Ca mRNA in MCT- treated lungs. These results indicate the augmentation of tonic EDHF activity, at least in part, through the alteration in cytochrome P-450 metabolites and the upregulation of K-Ca expression in MCT- induced pulmonary hypertension. Copyright (c) 2007 S. Karger AG, Basel.