Abstract
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.1 BN 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.1 BN congenic strain. Iberiotoxin (IBTX -a selective BK channel inhibitor) sensitive current densities are significantly greater in FHH rats compared with the FHH.1 BN 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.1 BN congenic strain). In excised patches, the BK channel exhibited similar single-channel slope conductance for FHH and the FHH.1 BN rats (208.9 pS versus 208.7 pS). However, the open channel probability (NP o ) was ~10 fold higher in FHH rats than in FHH.1 BN rats (1μM free (Ca +2 ) i : +40mV: FHH; 0.8 ± 0.04 versus 0.08 ± 0.004 in FHH.1 BN rats). Voltage and Ca 2+ sensitivity of the BK channel is similar in cerebral VSMC isolated from FHH and FHH.1 BN 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.1 BN 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.1 BN 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 BK channel activity.
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