PURPOSE: To identify the effect of the benzimidazalone derivative, NS1619, on modulating pulmonary vascular tone in lungs from rats exposed to normoxia (21% FiO2) or chronic hypoxia (10% FiO2) for three weeks. METHODS: Isolated perfused lungs were preconstricted (U46619), and dose-dependent vasodilation to NS1619 was assessed. To elucidate the mechanisms responsible, NS1619 vasodilatory responses were assessed following inhibition of large-conductance Ca(2+)-activated (BKCa; iberiotoxin and paxilline), L-type Ca2+ (nifedipine), K+ (tetraethylammonium), Cl- (niflumic acid), and cation/TRP (lanthanum) channels, as well as nitric oxide synthase (L-NAME). RESULTS: Compared to normoxia, NS1619-induced vasodilation was significantly greater following hypoxia; however, NO-dependent vasodilation and BKCa-mediated vasodilation, in response to NS1619, were similar in the normoxic and hypoxic lungs. In contrast, direct activation of L-type Ca2+ and non-BKCa K+ channel was involved in the NS1619-induced vasodilation only in hypoxic lungs. CONCLUSIONS: NS1619 causes pulmonary vasodilation by affecting multiple complementary pathways, including stimulation of NO production, activation of BKCa channels, other TEA-sensitive K+ channels, and L-type Ca2+ channels, and could be considered as a therapeutic agent in hypoxic PH.
PURPOSE: To identify the effect of the benzimidazalone derivative, NS1619, on modulating pulmonary vascular tone in lungs from rats exposed to normoxia (21% FiO2) or chronic hypoxia (10% FiO2) for three weeks. METHODS: Isolated perfused lungs were preconstricted (U46619), and dose-dependent vasodilation to NS1619 was assessed. To elucidate the mechanisms responsible, NS1619 vasodilatory responses were assessed following inhibition of large-conductance Ca(2+)-activated (BKCa; iberiotoxin and paxilline), L-typeCa2+ (nifedipine), K+ (tetraethylammonium), Cl- (niflumic acid), and cation/TRP (lanthanum) channels, as well as nitric oxide synthase (L-NAME). RESULTS: Compared to normoxia, NS1619-induced vasodilation was significantly greater following hypoxia; however, NO-dependent vasodilation and BKCa-mediated vasodilation, in response to NS1619, were similar in the normoxic and hypoxic lungs. In contrast, direct activation of L-typeCa2+ and non-BKCa K+ channel was involved in the NS1619-induced vasodilation only in hypoxic lungs. CONCLUSIONS:NS1619 causes pulmonary vasodilation by affecting multiple complementary pathways, including stimulation of NO production, activation of BKCa channels, other TEA-sensitive K+ channels, and L-typeCa2+ channels, and could be considered as a therapeutic agent in hypoxic PH.
Authors: Hossein A Ghofrani; Robert Voswinckel; Frank Reichenberger; Norbert Weissmann; Ralph T Schermuly; Werner Seeger; Friedrich Grimminger Journal: Cardiovasc Res Date: 2006-08-01 Impact factor: 10.787
Authors: Gaurav Choudhary; Frederick Troncales; Douglas Martin; Elizabeth O Harrington; James R Klinger Journal: J Heart Lung Transplant Date: 2011-05-08 Impact factor: 10.247
Authors: Alexander Vang; Denielli da Silva Gonçalves Bos; Ana Fernandez-Nicolas; Peng Zhang; Alan R Morrison; Thomas J Mancini; Richard T Clements; Iuliia Polina; Michael W Cypress; Bong Sook Jhun; Edward Hawrot; Ulrike Mende; Jin O-Uchi; Gaurav Choudhary Journal: JCI Insight Date: 2021-06-22