The Role of DPO-1 and XE991-Sensitive Potassium Channels in Perivascular Adipose Tissue-Mediated Regulation of Vascular Tone

摘要

The anti-contractile effect of perivascular adipose tissue (PVAT) is an important mechanism in the modulation of vascular tone in peripheral arteries. Recent evidence has implicated the XE991-sensitive voltage-gated K_(V)(KCNQ) channels in the regulation of arterial tone by PVAT. However, until now the in vivo pharmacology of the involved vascular K_(V)channels with regard to XE991 remains undetermined, since XE991 effects may involve Ca~(2+)activated BK_(Ca)channels and/or voltage-dependent K_(V)1.5 channels sensitive to diphenyl phosphine oxide-1 (DPO-1). In this study, we tested whether K_(V)1.5 channels are involved in the control of mesenteric arterial tone and its regulation by PVAT. Our study was also aimed at extending our current knowledge on the in situ vascular pharmacology of DPO-1 and XE991 regarding K_(V)1.5 and BK_(Ca)channels, in helping to identify the nature of K~(+)channels that could contribute to PVAT-mediated relaxation. XE991 at 30 μM reduced the anti-contractile response of PVAT, but had no effects on vasocontraction induced by phenylephrine (PE) in the absence of PVAT. Similar effects were observed for XE991 at 0.3 μM, which is known to almost completely inhibit mesenteric artery VSMC K_(V)currents. 30 μM XE991 did not affect BK_(Ca)currents in VSMCs. Kcna5 ~(?/?)arteries and wild-type arteries incubated with 1 μM DPO-1 showed normal vasocontractions in response to PE in the presence and absence of PVAT. K_(V)current density and inhibition by 30 μM XE991 were normal in mesenteric artery VSMCs isolated from Kcna5 ~(?/?)mice. We conclude that K_(V)channels are involved in the control of arterial vascular tone by PVAT. These channels are present in VSMCs and very potently inhibited by the KCNQ channel blocker XE991. BK_(Ca)channels and/or DPO-1 sensitive K_(V)1.5 channels in VSMCs are not the downstream mediators of the XE991 effects on PVAT-dependent arterial vasorelaxation. Further studies will need to be undertaken to examine the role of other K_(V)channels in the phenomenon.