title: 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.1BNcongenic 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 FHH compared with FHH.1BNrats. 5-HT (0.1 μM)-mediated vasoconstriction was about twofold lower, and inhibition of the BK channel increased the vasoconstrictor response by about threefold in FHH compared with FHH.1BNrats. 5-HT (3 μM) decreased BK channel and spontaneous transient outward currents in VSMCs isolated from FHH.1BNbut had no effect in FHH rats. 5-HT significantly depolarized the membrane potential in MCAs of FHH.1BNthan 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.1BNrats. 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.
authors: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi mpabbidi@umc.edu.
authors: Mallikarjuna R
authors: MR
authors: Pabbidi
authors: Department of Pharmacology and Toxicology, University of Mississippi Medical Center, Jackson, Mississippi.
authors: Richard J
authors: RJ
authors: Roman
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D002478:Cells, Cultured; D002536:Cerebral Arteries / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015640:Ion Channel Gating / Q000187:drug effects; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D011918:Rats, Inbred SHR; D011985:Receptors, Serotonin / Q000737:chemistry; D012701:Serotonin / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D051036:Large-Conductance Calcium-Activated Potassium Channels; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D012701:Serotonin
keywords: K+ channels; calcium; myogenic response; serotonin (5-HT)