Hemodynamics and metabolism in stroke-prone spontaneously hypertensive rats before manifestation of brain infarcts

Genomic screening of hybrids from stroke-prone (SHR-SP) and stroke-resistan t spontaneously hypertensive rats (SHR) identified a STR1 locus on the rat chromosome 1, which correlates with the susceptibility to cerebral stroke b ut not with hypertension. The authors examined whether this genetic abnorma lity is associated with hemodynamic or metabolic alterations in the brain t hat can be detected before the manifestation of brain infarction. Starting at 6 weeks of age, SHR-SP were fed with a salt-rich diet to accelerate arte rial hypertension. At the age of 12 weeks, animals developed functional sym ptoms and were age-matched with symptom-negative SHR-SP to differentiate be tween presymptomatic and postsymptomatic changes. Brains were investigated by multiparametric imaging comprising quantitative double-tracer autoradiog raphy of CBF and cerebral protein synthesis (CPS); bioluminescence imaging of regional ATP, glucose, and lactate content; and umbellifer-one fluorosco pic imaging of tissue pH. None of the animals exhibited focal hemodynamic o r biochemical abnormalities. Ln symptom-negative SHR-SP, global CBF was 1.1 +/- 0.3 mt g(-1) min-L, cortical CPS was 10.1 +/- 3.1 mol,g(-1) min(-1) an d cortical ATP, glucose, lactate, and pH levels were in the normal range. I n SHR-SP with functional symptoms, ATP, glucose, and lactate levels also we re normal, but tissue pH exhibited periventricular alkalosis, CBF was signi ficantly reduced to 0.7 +/- 0.2 mt g(-1) min(-1) (P < 0.001), and cortical CPS was significantly reduced to 6.7 +/- 2.1 nmol g(-1) min(-1) (P < 0.001) . The decline in brain perfusion of SHR-SP correlated significantly with bo th the severity of functional deficits and the decline of protein synthesis . Our observations demonstrate that SHR-SP had already developed functional symptoms before the manifestation of overt brain infarcts and that the sym ptoms are initiated by a decline in global CBF and cortical CPS. Genetic ab normalities in SHR-SP are associated with a diffuse vascular process that r esults in global decompensation of blood flow well before the onset of foca l brain infarction.