Systems biology and polygenic traits elevated K+ channel activity opposes vasoconstrictor response to serotonin in cerebral arteries of the fawn hooded hypertensive rat

Abstract

Previous studies suggest that middle cerebral arteries (MCAs) of Fawn Hooded Hypertensive (FHH) rats exhibit impaired myogenic response and introgression of a small region of Brown Norway chromosome 1 containing 15 genes restored the response in FHH.1BN congenic rat. The impaired myogenic response in FHH rats is associated with an increase in the activity of the large conductance potassium (BK) channel in vascular smooth muscle cells (VSMCs). The present study examined whether the increased BK channel function in FHH rat alters vasoconstrictor response to serotonin (5-HT). Basal myogenic tone and spontaneous myogenic response of the MCA was attenuated by about twofold and about fivefold, respectively in FHHBN compared with FHH.1BN rats. 5-HT (0.1 μ M)-mediated vasoconstriction was about twofold lower, and inhibition of the BK channel increased the vasoconstrictor response by about threefold in FHH compared with FHH.1BN rats. 5-HT (3 μ M) decreased BK channel and spontaneous transient outward currents in VSMCs isolated from FHH.1BN but had no effect in FHH rats. 5-HT significantly depolarized the membrane potential in MCAs of FHH.1BN than FHH rats. Blockade of the BK channel normalized 5-HT-induced depolarization in MCAs of FHH rats. The 5-HT-mediated increase in cytosolic calcium concentration was significantly reduced in plateau phase in the VSMCs of FHH relative to FHH.1BN rats. These findings suggest that sequence variants in the genes located in the small region of FHH rat chromosome 1 impairs 5-HT-mediated vasoconstriction by decreasing its ability to inhibit BK channel activity, depolarize the membrane and blunt the rise in cytosolic calcium concentration.