Abstract-We have investigated genetic transmission of increased sensitivity to focal cerebral ischemia and the influence of gender in the stroke-prone spontaneously hypertensive rat (SHRSP). Halothane-anesthetized, 3-to 5-month-old male and female Wistar-Kyoto rats (WKY), SHRSP, and the first filial generation rats (F 1 crosses 1 and 2) underwent distal (2 mm) permanent middle cerebral artery occlusion (MCAO) by electrocoagulation. Key Words: rats, stroke-prone spontaneously hypertensive Ⅲ cerebral ischemia, focal Ⅲ gender Ⅲ estrus Ⅲ estrogen Ⅲ middle cerebral artery occlusion T he stroke-prone spontaneously hypertensive rat (SHRSP) was established from Wistar-Kyoto rats (WKY) and is an inbred animal model of cerebrovascular disease. 1 Spontaneous strokes occur in the SHRSP, and the role of a genetic factor in stroke is highlighted by the resistance of the related SHR to spontaneous strokes despite hypertension and similar diets.SHRSP exhibit an increased sensitivity to ischemia and an increased volume of infarction after experimentally induced focal cerebral ischemia compared with their reference strain, the WKY. This has been shown by ligation 2 or electrocoagulation 3,4 of the middle cerebral artery (MCA). One reason for the increased sensitivity of the SHRSP to stroke may be reduced blood flow through collateral vessels between the MCA and anterior and posterior cerebral arteries. The collaterals have been postulated to have an impaired ability to dilate and a smaller internal diameter compared with those in normotensive Wistar rats. 5 In addition, more marked ischemic glutamate increases in SHRSP than WKY may be related to stroke sensitivity. 6 Recently, we revealed a genetic component to the increased sensitivity after experimental ischemia in the SHRSP. We linked increased volume of infarction 24 hours after MCA occlusion (MCAO) to a locus on rat chromosome 5 with a logarithm of odds (LOD) of 16.6. 4 Having previously demonstrated a dominant mode of inheritance for this phenotype in F 1 cross 2 hybrid rats (WKY father), 7 we now use a different set of reciprocal crosses especially bred for these experiments to examine genetic transmission and any influence of the origin of the Y chromosome (SHRSP male progenitor versus WKY male progenitor) on infarct volume. We also investigate the effects of sex differences and control for estrous status during ischemia induction-the first F 1 analysis to do so.
MethodsAll experiments were carried out under license from the Home Office and were subject to the Animals (Scientific Procedures) Act, 1986. Breeding and housing of SHRSP and WKY have been previously described. 4 Two parental crosses were performed espe-