Congenic removal of a QTL for blood pressure attenuates infarct size produced by middle cerebral artery occlusion in hypertensive rats

Abstract

A genome-wide screen found a blood pressure quantitative trait locus (QTL) on rat chromosome 1 in stroke-prone spontaneously hypertensive rats of a Japanese colony (SHRSP/Izm). In the present study, we investigated the effects of congenic removal of this QTL from SHRSP/Izm on infarct size produced by middle cerebral artery (MCA) occlusion. To establish the congenic strain (SHRSPwch1.0), the blood pressure QTL was introgressed from Wistar-Kyoto (WKY)/Izm to SHRSP/Izm by repeated backcrossing. Male SHRSP/Izm [10-12 wk old (young adult) n = 8, 5 mo old (adult) n = 17] and SHRSPwch1.0 (young adult n = 7, adult n = 15) were randomly assigned to distal MCA occlusion. Resting mean arterial blood pressure (MABP) was 212 +/- 23 mmHg in adult SHRSPwch1.0, which was significantly lower than 241 +/- 22 mmHg in SHRSP/Izm. Infarct volume in the congenic rats was significantly decreased compared with that in SHRSP/Izm (66.4 +/- 21.5 mm(3) vs. 103.4 +/- 24.8 mm(3)). Cerebral blood flow (CBF), determined at collaterally-perfused cortex with laser-Doppler flowmetry after MCA occlusion, was significantly greater in adult SHRSPwch1.0 compared with CBF in adult SHRSP/Izm. In young adult rats, there were no significant differences in MABP or in infarct volume between SHRSPwch1.0 and SHRSP/Izm. The congenic removal of a blood pressure QTL lowered blood pressure and caused a substantial reduction in infarct volume (-36%) with increased collateral CBF after MCA occlusion in the congenic rat. We demonstrated for the first time that the congenic strategy is useful to investigate the effects of genetic hypertension on focal ischemia or stroke.