Impact of modulators of mitochondrial ATP-sensitive potassium channel (mitoK(ATP)) on hypoxic pulmonary vasoconstriction.

ABSTRACT

Previously, we demonstrated that hypoxic pulmonary vasoconstriction (HPV) of intra-acinar arteries (IAA) requires mitochondrial complex II (= succinate dehydrogenase, SDH) activity (citeauthor ch41paddenberg2006, Respir Res, 793, citeyear ch41paddenberg2006). Interestingly, SDH subunits A and B have recently been described as components of a multiprotein mitochondrial ATP-sensitive potassium channel (mitoK(ATP)), together with mitochondrial ATP-binding cassette protein-1, adenine nucleotide translocator (ANT), ATP synthase, and phosphate carrier (citeauthor ch41ardehali2004, Proc Natl Acad Sci USA, 101(32)11880-5, citeyear ch41ardehali2004). Hence, we tested the hypothesis that such an SDH-containing mitoK(ATP) is involved in HPV. For this purpose, the impact of modulators of mitoK(ATP) on HPV of IAA was studied videomorphometrically in precision cut murine lung slices. Inhibitors of mitoK(ATP) (glibenclamide, 5-hydroxydecanoate) completely suppressed HPV, mitoK(ATP) activators (pinacidil, diazoxide) even induced vasodilatation, and ANT inhibitors (bongkrekic acid, atractyloside) attenuated HPV. This pharmacological profile differs clearly from that described for mitoK(ATP). Accordingly, co-immunoprecipitation experiments provided no evidence for association of complex II subunits SDH-A, -B and -C with ANT, ATP synthase or cytochrome c oxidase in murine heart mitochondria. Hence, it is likely that the inhibitory effects on HPV that we observed in our experiments result from modulation of several mitochondrial protein complexes independently involved in the signalling cascade such as ROS-producing complex II and ANT-regulated mitochondrial permeability transition pore.