To identify the effect of the benzimidazalone derivative, NS1619, on modulating pulmonary vascular tone in lungs from rats exposed to normoxia (21% F iO 2) or chronic hypoxia (10% F iO 2) for 3 weeks.
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 (BK Ca; iberiotoxin and paxilline), L-type Ca 2+ (nifedipine), K + (tetraethylammonium), Cl − (niflumic acid) and cation/TRP (lanthanum) channels, as well as nitric oxide synthase (L-NAME).
Compared to normoxia, NS1619-induced vasodilation was significantly greater following hypoxia, however, NO-dependent vasodilation and BK Ca-mediated vasodilation, in response to NS1619, was similar in the normoxic and hypoxic lungs. In contrast, direct activation of L-type Ca 2+ and non-BK Ca K + channel was involved in the NS1619-induced vasodilation only in hypoxic lungs.