A review of the sensitivity of genetically hypertensive rats to cerebral ischemia was presented together with original data describing the systematic comparison of the effects of focal ischemia (permanent and temporary with reperfusion) performed in hypertensive and normotensive rats (i.e., blood pressures verified in conscious instrumented rats). Microsurgical techniques were used to isolate and occlude the middle cerebral artery (MCAO) of spontaneously hypertensive (SHR), Sprague-Dawley (SD) and Wistar Kyoto (WKY) rats at the level of the inferior cerebral vein. Following permanent (24 h) MCAO, persistent and similar decreases in local microvascular perfusion (i.e., to 15.6 +/- 1.7% of pre-MCAO levels) were verified in the primary ischemic zone of the cortex for all strains using Laser-Doppler flowmetry. A contralateral hemiplegia that occurred following MCAO, evidenced by forelimb flexion and muscle weakness, was greater in SHR (neurological grade = 2.0 +/- 0. 1) than SD (1.0 +/- 0.4) or WKY (0.7 +/- 0.4) rats (N = 7-9, p < 0.05). SHR also exhibited sensory motor deficits following MCAO compared to sham-operation, with decreased normal placement response of the hindlimb (% normal = 20 vs. 83, N = 23-30, p decreased rota-rod (41 +/- 7 vs. 126 +/- 19 on rod, N = 10-15, p < 0.05) and balance beam (25 +/- 5 vs. 116 +/- 29 s on beam, N = 5-7, p < 0.05) performance. However, an index of general motor activity was not affected by permanent MCAO. Triphenyltetrazolium-stained forebrain tissue analyzed by planimetry revealed a significantly larger and more consistent cortical infarction in SHR (hemispheric infarction = 27.9 +/- 1.5%) compared to SD (15.4 +/- 4.1%) and WKY (4.0 +/- 2.4%) rats (N = 7-9, p < 0.05), occupying predominantly the frontal and parietal areas. Also, a significant degree of ipsilateral hemispheric swelling (4.6 +/- 0.9%, N = 7-9, p < 0.05) and increased brain water content (78.4 +/- 0.3% to 80.4 +/- 0.2%, N = 8-9, p < 0.05) was identified in SHR that was not observed in SD or WKY rats. A novel model of temporary MCAO also was evaluated in the hypertensive and normotensive rat strains. Initially, the effect of increasing MCAO-time followed by 24 h reperfusion in SHR was studied. During temporary MCAO (20 to 300 min), persistent and stable decreases in local microvascular perfusion (i.e., to 15-20% of pre-MCAO levels) were verified in the primary ischemic zones of the cortex. Upon reperfusion of the artery, local microvascular perfusion returned immediately to pre-MCAO levels and remained at those levels. An occlusion-time-related increase in the degree of cortical infarction, hemispheric swelling and neurological deficits was observed (N = 6-8 per timepoint, p < 0.05). Following temporary MCAO, the largest cortical infarcts and neurological deficits (i.e., the maximum effects under these conditions) were produced by 160 min MCAO with reperfusion. Using these optimum parameters, SD (6.7 +/- 2.07%) and WKY (1.4 +/- 0.8%) rats exhibited significantly smaller cortical infarctions than SHR (13.2 +/- 2.0%, N = 6-7, p < 0.05). The susceptibility to global and focal ischemia of SHR compared to normotensive rats was discussed in detail. Specifically, the increased SHR neuropathology following ischemia and the potential mechanisms for these effects in genetic hypertension was evaluated based on the available literature/data. Although, much information suggests that SHR are a useful model of focal ischemia (i.e., the histopathological and functional consequences due to MCAO are large and highly reproducible), SHR do exhibit significant differences in the morphology of cerebral blood vessels that impact on functional collateral cerebral circulation and its regulation. Factors such as increased arterial vessel wall thickness and reduced internal diameter, increased collateral vessel resistance and impaired vasodilation reserve can limit collateral blood flow and predispose SHR to cerebral ischemia and infarction. Also, an increased number and/or sensitivity of perivascular mononuclear leukocytes and associated cytokine release is observed in the cerebral circulation of SHR. These cytokines (e.g., Tumor Necrosis Factor-alpha) can predispose the vascular endothelium to a procoagulant surface membrane so that ischemia can more readily provoke local vessel obstruction and/or hemorrhage. These appear to be important mechanistic factors contributing to increased SHR ischemic damage compared to normotensive animals. This increased susceptibility/sensitivity of hypertensive rats to the effects of ischemia appears to underlie hypertension as a risk factor in focal stroke.
