Dual impact of a nitric oxide donor, GEA 3175, in human pulmonary smooth muscle.
Nitric oxide (NO) donors could constitute an alternative to inhaled NO as treatment in some patients with pulmonary hypertension. Therefore, the present study investigated the relaxation mechanisms of a novel NO donor, 3-(3-chloro-2-methylphenyl)-5-[[4-methylphenyl)sulphonyl]amino]-)hydroxide (GEA 3175) in segments of human pulmonary arteries and bronchioles, which were mounted in microvascular myographs. GEA 3175 induced concentration-dependent relaxations and was more potent in pulmonary arteries than in bronchioles. A blocker of soluble guanylyl cyclase, 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ), and iberiotoxin, a blocker of large-conductance calcium-activated K channels, both reduced relaxations induced by GEA 3175 in pulmonary arteries and bronchioles. Combining of ODQ and iberiotoxin did not produce additional inhibition. GEA 3175 relaxation is mediated through guanylyl cyclase-dependent mechanisms followed by activation of large-conductance calcium-activated K(+) channels. The dilatation of both pulmonary small arteries and airways by GEA 3175 seems advantageous, if it is considered administered as inhalation therapy for pulmonary hypertension.
Elmedal
Britt
B
Department of Pharmacology, University of Aarhus, 8000 Aarhus C, Denmark.
Mulvany
Michael J
MJ
Simonsen
Ulf
U
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000420:Albuterol / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects / Q000502:physiology; D001993:Bronchodilator Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000494:pharmacology; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects* / Q000502:physiology; D011810:Quinoxalines / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D001993:Bronchodilator Agents; C093084:GEA 3175; D020030:Nitric Oxide Donors; D010069:Oxadiazoles; D010455:Peptides; D011810:Quinoxalines; D014230:Triazoles; D014662:Vasoconstrictor Agents; D009569:Nitric Oxide; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C064719:iberiotoxin; D000420:Albuterol