NS1619-induced vasodilation is enhanced and differentially mediated in chronically hypoxic lungs

Abstract

Purpose:

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.

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 (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).

Results:

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.

Conclusions:

NS1619 causes pulmonary vasodilation by affecting multiple complementary pathways including stimulation of NO production, activation of BK _Ca channels, other TEA-sensitive K ⁺ channels and L-type Ca ²⁺ channels, and could be considered as a therapeutic agent in hypoxic PH.