Disruption In PKC‐mediated K Channel Regulation Contributes To Enhanced Serotonin Mediated Carotid Vessel Constriction from the Fawn Hooded Hypertensive Rat

Abstract

Previous studies indicate Fawn Hooded Hypertensive (FHH) rats exhibit cerebral damage due to diminished cerebrovascular myogenic function associated with elevated BK channel function. Introgression of the 2.4 Mbp region of BN chromosome 1 into the FHH rat restored myogenic response and BK channel function in a FHH.1BN congenic rat. However, results obtained from resistance vessels cannot be extrapolated to conduit vessels due to structural and functional differences. Thus, the present study addresses the hypothesis that carotid vessels of FHH rats exhibit altered serotonin (5‐HT)‐mediated contraction compared to FHH.1BN rats. Using tension myography to measure conduit vascular function, we found that carotid vessels of FHH rats exhibited greater 5‐HT‐mediated contraction than FHH.1BN rats. Activation of BK channels (NS1619: 5 to 30μM) relaxed carotid vessels to a lesser extent (1.17 times less) in FHH rats. On the other hand, inhibition of BK channels (Paxilline or Iberiotoxin: 100nM) had no effect in either strain. Inhibition of voltage gated calcium channels (VGCC, Diltiazem: 10μM) or store operated calcium (SOC) channels (2‐APB: 75μM) relaxed carotid vessels similarly in both strains. Furthermore, PKC activation (PMA: 100nM) or inhibition (GF109203X: 3μM) increased and decreased 5‐HT‐mediated constriction respectively in FHH.1BN rats but had minimal effect in FHH rats. These results suggest that a mutation in the genes located in 2.4Mbp region in FHH rats contribute to a disruption in PKC and its regulation of K channels, causing enhanced 5‐HT‐mediated contraction.Support or Funding InformationThis research has received funding support from the American Heart Association, Scientist Development Grant (13SDG14000006) and the IOSP Undergraduate Summer Research Fellowship supported by the American Physiological Society and a grant from the National Science Foundation Integrative Organismal Systems Award No. IOS‐ 1238831.