Abstract 127: Identification of a Region of Rat Chromosome 1 That Impairs the Myogenic Response and Cerebral Blood Flow Autoregulation in Fawn Hooded Hypertensive Rats.

Abstract

This study examined the effect of transfer of a 2.4 Mbp region of Brown Norway (BN) rat Chr 1 into the Fawn Hooded Hypertensive (FHH) genetic background on autoregulation (AR) of cerebral blood flow (CBF) and the myogenic response of isolated middle cerebral arteries (MCA). Autoregulation of CBF measured by laser Doppler flowmetry was poor in FHH rats (AR index (AI), 0.8±0.1) and in FHH.1BN congenic strains which excluded the critical region (AR-: AI, 0.9± 0.1). In contrast, autoregulation of CBF was completely restored by transfer of the region of BN Chr 1 between 258.8 to 261.2 Mbp in AR+ FHH.1BN congenic strains (AI, 0.3 ± 0.1). The diameter of MCA of FHH rats and AR- congenic strains increased by ∼10% (140 ± 1 to 157± 2 μm), when transmural pressure was increased from 40 to 140 mmHg. In contrast, the diameter of the MCA in AR+ congenic strain fell from 127 ± 2 to 65 ± 1 μm. Whole-cell patch-clamp of cerebral VSM cells revealed a 4.3-fold increase in BK channel current densities at depolarized potentials in FHH versus AR+ rats (105 ± 2 versus 24 ± 4 pA/pF at +80mV). Using single channel analysis we found that the increase in BK channel current was largely due to a marked increase in the NPo of BK channel in FHH as compared to AR+ rats (0.9 ± 0.1 and 0.2 ± 0.1 at +80mV). To explore the significance of the impaired myogenic response, we compared changes in CBF and infarct size following transient occlusion and reperfusion of the MCA in FHH rats and the AR- and AR+ congenic strains. Occlusion of MCA reduced CBF similarly in all the strains. However, the hyperemic response following reperfusion in FHH and AR- strains was significantly greater and more prolonged than that seen in AR+ rats (AR-: 173 ± 1%, 45 min versus AR+: 124 ± 5%, 15 min). Moreover, infarct size and edema formation was significantly greater in the AR- congenic strain (39 ± 3 % and 12 ± 2 %) in comparison to that seen in the AR+ strain (28 ± 2 %; 7 ± 1%). These results indicate that there is a gene that plays a critical role in the regulation of the myogenic response of the cerebral vasculature by altering BK channel activity in the critical 2.4 Mb region of Chr 1 containing just 15 genes and that transfer of this region from BN to FHH rats restores autoregulation of CBF, vascular reactivity and reduces infarct size following ischemia/reperfusion injury.