Abstract 485: Enhanced Large Conductance Ca+2 -sensitive K+ Channels (bk) Activity Impairs the Myogenic Response in the Cerebral Vasculature of Fawn Hooded Hypertensive (fhh) Rat

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Our recent studies have revealed that the myogenic response in cerebral arteries and autoregulation of cerebral blood flow is impaired in FHH and that transfer of a 2.4 Mb region of chromosome 1 from BN into FHH.1BN congenic strain restores these responses. The present study examined the role of large conductance calcium activated potassium (BK) channel in altering the myogenic response in FHH rats. Whole-cell patch-clamp of cerebral vascular smooth muscle cells (VSMC) revealed a 4.6 fold increase in outward potassium (K) channel current densities (pA/pF) in FHH rats compared to FHH.1BN congenic strain. Iberiotoxin (IBTX -a selective BK channel inhibitor) sensitive current densities are significantly greater in FHH rats compared with the FHH.1BN congenic strain (FHH rats: +40mV; pre IBTX 43.1 ± 7.2, after IBTX 11.8 ± 2.2 pA/pF versus pre IBTX 5.6 ± 1 pA/pF and after IBTX 4.1 ± 0.6 pA/pF in the FHH.1BN congenic strain). In excised patches, the BK channel exhibited similar single-channel slope conductance for FHH and the FHH.1BN rats (208.9 pS versus 208.7 pS). However, the open channel probability (NPo) was ~10 fold higher in FHH rats than in FHH.1BN rats (1μM free (Ca+2)i: +40mV: FHH; 0.8 ± 0.04 versus 0.08 ± 0.004 in FHH.1BN rats). Voltage and Ca2+ sensitivity of the BK channel is similar in cerebral VSMC isolated from FHH and FHH.1BN rats. Middle cerebral arterioles (MCA) isolated from FHH rats increased in diameter from 142 ± 16 to 157 ± 19 μm when pressure was increased from 40 to 140 mmHg. In contrast, the diameter of the MCA decreased by 49% in the FHH.1BN congenic strain from 127 ± 16 to 65 ± 13 μm. Pharmacological block of BK channel by IBTX (100nM) restored myogenic response in FHH rats but had no effect in FHH.1BN rats. These results indicate that the impaired myogenic response of the cerebral vessels in FHH rats is mediated via a gene and mechanism that enhances BKchannel activity.

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