Nitric oxide suppresses vascular voltage-gated T-type Ca channels through cGMP/PKG signaling

Harraz OF, Brett SE, Welsh DG. Nitric oxide suppresses vascular voltage-gated T-type Ca channels through cGMP/PKG signaling. Am J Physiol Heart Circ Physiol 306: H279–H285, 2014. First published November 15, 2013; doi:10.1152/ajpheart.00743.2013.— Recent reports have noted that T-type Ca channels (CaV3.x) are expressed in vascular smooth muscle and are potential targets of regulation. In this study, we examined whether and by what mechanism nitric oxide (NO), a key vasodilator, influences this conductance. Using patch-clamp electrophysiology and rat cerebral arterial smooth muscle cells, we monitored an inward Ba current that was divisible into a nifedipine-sensitive and -insensitive component. The latter was abolished by T-type channel blocker and displayed classic T-type properties including faster activation and steady-state inactivation at hyperpolarized potentials. NO donors (sodium nitroprusside, S-nitroso-N-acetyl-dl-penicillamine), along with activators of protein kinase G (PKG) signaling, suppressed T-type currents. Inhibitors of guanylyl cyclase/PKG {1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and KT5823, respectively}, had no effect on basal currents; KT5823 did, however, mask T-type Ca channel current inhibition by NO/PKG. Functional experiments confirmed an inhibitory effect for NO on the T-type contribution to cerebral arterial myogenic tone. Cumulatively, our findings support the view that T-type Ca channels are a regulatory target of vasodilatory signaling pathways. This targeting will influence Ca dynamics and consequent tone development in the cerebral circulation.