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Regulation of intracerebral arteriolar tone by Kv channels: Effects of glucose and PKC.
Straub SV, Girouard H, Doetsch PE, Hannah RM, Wilkerson MK, Nelson MT
American Journal of Physiology: Cell Physiology. 2009;.
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Abstract
Voltage gated potassium (Kv) channels in vascular smooth muscle cells (VSMC) are critical regulators of membrane potential and vascular tone. These channels exert a hyperpolarizing influence to counteract the depolarizing effects of intraluminal pressure and vasoconstrictors. However, the contribution of Kv channel activity to the functional regulation of cerebral penetrating arterioles is unknown. Thus, Kv channel properties in penetrating arteriolar SMCs were characterized. Isolated, pressurized penetrating arterioles and arterioles in cortical brain slices exhibited robust constriction in the presence of the Kv channel inhibitor 4-AP. 4-AP also decreased the amplitude of Kv currents recorded from SMCs. The steady-state activation and inactivation kinetics of Kv currents suggested that these channels are comprised of Kv1.2 and 1.5 subunits, which was confirmed by RT-PCR. Kv channels can be regulated by extracellular glucose, which may be involved in the functional hyperemic response in the brain. Thus the effects of glucose on Kv channel activity and arteriolar function were investigated. Elevation of glucose from 4 to 14 mM significantly decreased the peak Kv current amplitude and constricted arterioles in brain slices. Arteriolar constriction was prevented by inhibition of protein kinase C (PKC), consistent with previous studies showing enhanced PKC activity in the presence of elevated glucose. In cortical brain slices, the dilation generated by neuronal activity induced by electrical field stimulation was decreased by 54% in 14 mM glucose compared to the dilation in 4 mM glucose. In anesthetized mice the whisker stimulation-induced increase in local cerebral blood flow was also significantly decreased in 14 mM glucose, and this effect was also prevented by PKC inhibition. These findings point to a critical role for Kv channels in the regulation of intracerebral arteriolar function, and suggest that changes in perivascular glucose levels could directly alter vascular diameter resulting in a modulation of local cerebral blood flow. Key words: smooth muscle, arteriole, cerebral, potassium channel, glucose.