Recent evidence suggests that hypoxic pulmonary vasoconstriction (HPV) is mediated by
hypoxia-induced closure of
voltage-gated potassium channels in pulmonary vascular smooth muscle cells. It is also claimed that various
vasoconstrictor mediators such as
thromboxane A2 (TXA2),
platelet activating factor (PAF), cysteinyl
leukotrienes (cys-LTs) or
endothelin-1 (ET-1) contribute to HPV. Their role, however, has not been unequivocally accepted. On the contrary, it is well known that
endothelium-derived nitric oxide negatively modulates HPV. Since NO counteracts action of
vasoconstrictor mediators, we tested the hypothesis that modulatory role of TXA2 PAF, cys-LTs and ET-1 in HPV would become apparent in absence of endogenous NO. For that purpose we assessed contribution of these mediators to HPV in the isolated blood-perfused rat lung pretreated with a non-selective NOS inhibitor,
L-NAME. HPV, which was greatly augmented by
L-NAME (300 microM) alone, was inhibited neither by a TXA2 synthase inhibitor (
Camonagrel, 300 pM), nor by a PAF receptor antagonist (
WEB 2170, 100 microM), nor by an inhibitor of five-lipooxygenase-activating
protein (
MK 886, 10 microM), nor by a non-selective ET-1 receptor antagonist (
LU 302872, 30 pM). In summary, in isolated blood-perfused rat lung, TXA2, PAF, cys-LTs and ET-1 seem not to be involved in HPV, whereas we confirm the dominant role of endogenous NO in blunting HPV.