Research ReportPET O-15 cerebral blood flow and metabolism after acute stroke in spontaneously hypertensive rats
Introduction
Hypertension increases the incidence of stroke and degrades functional outcome following the onset of stroke. Several reports detail the comparatively poorer outcome of hypertensive patients following stroke (Leonardi-Bee et al., 2002, Sprigg et al., 2006). Hypertension is known to cause long-lasting damage to blood vessels and tissues (Amenta et al., 2003, Fredriksson et al., 1984, Grabowski et al., 1993), altering cerebral blood flow (CBF), oxygen extraction fraction (OEF), cerebral metabolic rate for oxygen (CMRO2) and cerebral metabolic rate for glucose (CMRglc) (Fujishima et al., 1995, Fujishima et al., 1984). Accordingly, it is of great importance to clarify the relationship of hypertension to cerebral hemodynamics and metabolism, and functional outcome.
It is impractical to measure such parameters in patients during the first hours following a stroke because of the demands of the therapeutic time window. Consequently, several researchers have studied the progress of cerebral hemodynamics and metabolism after the onset of stroke using spontaneously hypertensive rats (SHR), a widely employed hypertensive model (Fujishima et al., 1984, Fukuda et al., 2004, Grabowski et al., 1993, Katsuta, 1997, Okamoto and Aoki, 1963, Sadoshima et al., 1985). However, due to methodologic limitations in evaluating cerebral oxygen metabolism, only CBF and infarction have been examined (Dogan et al., 1998, Jacewicz et al., 1992). To the best of our knowledge, no report has focused on the relationship between hypertension and changes of cerebral oxygen metabolism after the onset of stroke. We recently developed a radiopharmaceutical, injectable 15O-O2 for use in positron emission tomography (PET) and established a method for estimating cerebral oxygen metabolism in small animals (Magata et al., 2003, Temma et al., 2006).
In this study, we evaluated the effects of hypertension on cerebral hemodynamics and metabolism in the first hour following the onset of stroke. Specifically, we measured CBF, OEF, CMRO2 and CMRglc using injectable 15O-O2 and 2-[18F]fluoro-2-deoxy-d-glucose (18F-FDG) in SHR. This allowed us to measure differences in metabolic responses between SHR and normotensive rats 1 h after arterial occlusion.
Section snippets
Physiological parameters
Table 1 summarizes arterial blood gas measurements before the occlusion of the MCA (pre) and after the PET experiments (post). The blood gas levels were within physiological ranges, although slight differences in several parameters were found between pre and post and between SHR and WKY.
Quantitative values
Fig. 1 shows the values and statistical analyses for CBF, OEF, CMRO2 and CMRglc. SHR showed significant differences between the left and right hemispheres in CBF, CMRO2 and CMRglc, while WKY showed differences
Discussion
It has been suggested that hypertension affects the brain's physiologic responses after the onset of stroke. In this study, we measured parameters of cerebral hemodynamics and metabolism such as CBF, OEF, CMRO2 and CMRglc 1 h after the occlusion of the MCA in SHR.
The area damaged by the occlusion was larger in SHR than in WKY rats. Thus, our experimental system is consistent with previous reports (Dogan et al., 1998, Grabowski et al., 1993). Our experiments provided the following results.
Conclusions
In this paper, we estimated CBF, OEF, CMRO2 and CMRglc 1 h after the onset of MCAO in SHR. SHR exhibited greater disturbances of metabolic parameters compared with WKY rats, indicating that hypertension probably contributes to degraded metabolic functions and poorer prognosis after the onset of stroke.
Animals
Male SHR (13–17 week old, 276–330 g) and male Wistar Kyoto rats (WKY, 14–17 week old, 314–388 g) were supplied by Japan SLC Co. (Hamamatsu, Japan) and were housed under a 12 h light/12 h dark cycle and given free access to food and water. The animal experiments in this study were conducted in accordance with institutional guidelines and approved by the Kyoto University Animal Care Committee.
Preparation of labeled compounds
The production of 15O-H2O and injection of 15O-oxygenated blood (injectable 15O-O2) were conducted as
Acknowledgments
This study was supported by Grants-in-Aid for Scientific Research and by the 21st Century Center of Excellence Programs at Kyoto University “Knowledge Information Infrastructure for Genome Science” and at Hamamatsu University School of Medicine “Medical Photonics” from the Ministry of Education, Culture, Sports, Science and Technology, Japan. Part of this study was supported by the Mitsubishi Pharma Research Foundation.
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