title: Activity of endothelium-derived hyperpolarizing factor is augmented in monocrotaline-induced pulmonary hypertension of rat lungs.
abstract: 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(2+)-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 muM), 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.
authors: Department of Respiratory Medicine, Juntendo University School of Medicine, Tokyo, Japan. ymorio@med.juntendo.ac.jp
authors: Yoshiteru
authors: Y
authors: Morio
authors: Noriyuki
authors: N
authors: Homma
authors: Hideki
authors: H
authors: Takahashi
authors: Akihito
authors: A
authors: Yamamoto
authors: Tetsutaro
authors: T
authors: Nagaoka
authors: Koichi
authors: K
authors: Sato
authors: Masashi
authors: M
authors: Muramatsu
authors: Yoshinosuke
authors: Y
authors: Fukuchi
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology; D001030:Apamin / Q000494:pharmacology; D001685:Biological Factors / Q000378:metabolism*; D018999:Charybdotoxin / Q000494:pharmacology; D006152:Cyclic GMP / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D008297:Male; D016686:Monocrotaline / Q000633:toxicity; D009498:Neurotoxins / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D024681:Potassium Channels, Calcium-Activated / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013426:Sulfaphenazole / Q000494:pharmacology; D019284:Thapsigargin / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D000890:Anti-Infective Agents; D001685:Biological Factors; D004791:Enzyme Inhibitors; D009498:Neurotoxins; D024681:Potassium Channels, Calcium-Activated; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1; C067410:endothelium-dependent hyperpolarization factor; D013426:Sulfaphenazole; D018999:Charybdotoxin; D001030:Apamin; D009569:Nitric Oxide; D019284:Thapsigargin; D016686:Monocrotaline; D011464:Epoprostenol; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP