PET O-15 cerebral blood flow and metabolism after acute stroke in spontaneously hypertensive rats

doi:10.1016/j.brainres.2008.03.033

Brain Research

Volume 1212, 30 May 2008, Pages 18-24

https://doi.org/10.1016/j.brainres.2008.03.033 Get rights and content

Abstract

Hypertension is a major stroke risk factor and is correlated with worse outcome after stroke. Thus, the effects of hypertension on cerebral hemodynamics and metabolism within an hour after stroke must be evaluated in detail. Cerebral blood flow (CBF), oxygen extraction fraction (OEF), cerebral metabolic rate for oxygen (CMRO₂) and cerebral metabolic rate for glucose (CMRglc) were measured 1 h after the occlusion of the right middle cerebral artery (MCA) in male spontaneously hypertensive rats (SHR) and male normotensive Wistar Kyoto rats (WKY). Physiological responses were determined by positron emission tomography (PET) using ¹⁵O-H₂O and radiolabeled ¹⁵O-O₂ blood (methodology previously developed in this laboratory) and by autoradiography (ARG) using ¹⁸F-FDG. The right hemisphere of SHR showed lower CBF values than the left hemisphere after stroke (right: 0.17 ± 0.07 mL/min/g; left: 0.29 ± 0.08 mL/min/g), CMRO₂ (right: 2.55 ± 0.80 mL/min/100 g; left: 4.11 ± 0.84 mL/min/100 g) and CMRglc (right: 52.4 ± 16.2 mg/min/100 g; left: 65.6 ± 10.2 mg/min/100 g). WKY rats exhibited significant decreases only in CBF and CMRO₂. These results suggest greater underlying physiologic disturbances in SHR. Also, the occlusion significantly reduced CBF in both hemispheres of SHR compared with WKY, suggesting a disturbance of the autoregulatory mechanism in SHR. In summary, our results indicate that hypertension intensifies metabolic disturbances after the onset of stroke, at least in the first hour. Therefore, we suggest that hypertension not only increases the incidence of stroke but also exacerbates stroke-mediated damage.

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.

References (34)

HertzL.
Intercellular metabolic compartmentation in the brain: past, present and future
Neurochem. Int.
(2004)
SabbatiniM.
Hypertensive brain damage: comparative evaluation of protective effect of treatment with dihydropyridine derivatives in spontaneously hypertensive rats
Mech. Ageing Dev.
(2001)
TemmaT.
Availability of N-isopropyl-p-[125I]iodoamphetamine (IMP) as a practical cerebral blood flow (CBF) indicator in rats
Nucl. Med. Biol.
(2004)
YasudaT.
Persistent hypertension does not alter the cerebral blood flow and glucose utilization in young-adult Dahl salt-sensitive rats
J. Neurol. Sci.
(2002)
AmentaF.
Arterial hypertension and brain damage — evidence from animal models (review)
Clin. Exp. Hypertens.
(2003)
DoganA.
Intraluminal suture occlusion of the middle cerebral artery in spontaneously hypertensive rats
Neurol. Res.
(1998)
FredrikssonK.
The hemodynamic effect of bilateral carotid artery ligation and the morphometry of the main communicating circuit in normotensive and spontaneously hypertensive rats
Acta Physiol. Scand.
(1984)
FujishimaM.
Cerebral blood flow and brain function in hypertension
Hypertens. Res.
(1995)
FujishimaM.
Autoregulation of cerebral blood flow in young and aged spontaneously hypertensive rats (SHR)
Gerontology
(1984)
FukudaS.
Age-related changes in blood pressure, hematological values, concentrations of serum biochemical constituents and weights of organs in the SHR/Izm, SHRSP/Izm and WKY/Izm
Exp. Anim.
(2004)

GrabowskiM.

Brain capillary density and cerebral blood flow after occlusion of the middle cerebral artery in normotensive Wistar-Kyoto rats and spontaneously hypertensive rats

J. Hypertens.

(1993)

HamacherK.

Efficient stereospecific synthesis of no-carrier-added 2-[18F]-fluoro-2-deoxy-d-glucose using aminopolyether supported nucleophilic substitution

J. Nucl. Med.

(1986)

HeinertG.

Hypercapnic cerebral blood flow in spontaneously hypertensive rats

J. Hypertens.

(1998)

JacewiczM.

The CBF threshold and dynamics for focal cerebral infarction in spontaneously hypertensive rats

J. Cereb. Blood Flow Metab.

(1992)

KatsutaT.

Decreased local cerebral blood flow in young and aged spontaneously hypertensive rats

Fukuoka Igaku Zasshi

(1997)

KitaH.

Cerebral blood flow and glucose metabolism of the ischemic rim in spontaneously hypertensive stroke-prone rats with occlusion of the middle cerebral artery

J. Cereb. Blood Flow Metab.

(1995)

KitanoH.

Performance assessment of O-18 water purifier

Ann. Nucl. Med.

(2001)

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Research ReportPET O-15 cerebral blood flow and metabolism after acute stroke in spontaneously hypertensive rats

Abstract

Introduction

Section snippets

Physiological parameters

Quantitative values

Discussion

Conclusions

Animals

Preparation of labeled compounds

Acknowledgments

Neurochem. Int.

Mech. Ageing Dev.

Nucl. Med. Biol.

J. Neurol. Sci.

Arterial hypertension and brain damage — evidence from animal models (review)

Clin. Exp. Hypertens.

Intraluminal suture occlusion of the middle cerebral artery in spontaneously hypertensive rats

Neurol. Res.

The hemodynamic effect of bilateral carotid artery ligation and the morphometry of the main communicating circuit in normotensive and spontaneously hypertensive rats

Acta Physiol. Scand.

Cerebral blood flow and brain function in hypertension

Hypertens. Res.

Autoregulation of cerebral blood flow in young and aged spontaneously hypertensive rats (SHR)

Gerontology

Age-related changes in blood pressure, hematological values, concentrations of serum biochemical constituents and weights of organs in the SHR/Izm, SHRSP/Izm and WKY/Izm

Exp. Anim.

Brain capillary density and cerebral blood flow after occlusion of the middle cerebral artery in normotensive Wistar-Kyoto rats and spontaneously hypertensive rats

J. Hypertens.

Efficient stereospecific synthesis of no-carrier-added 2-[18F]-fluoro-2-deoxy-d-glucose using aminopolyether supported nucleophilic substitution

J. Nucl. Med.

Hypercapnic cerebral blood flow in spontaneously hypertensive rats

J. Hypertens.

The CBF threshold and dynamics for focal cerebral infarction in spontaneously hypertensive rats

J. Cereb. Blood Flow Metab.

Decreased local cerebral blood flow in young and aged spontaneously hypertensive rats

Fukuoka Igaku Zasshi

Cerebral blood flow and glucose metabolism of the ischemic rim in spontaneously hypertensive stroke-prone rats with occlusion of the middle cerebral artery

J. Cereb. Blood Flow Metab.

Performance assessment of O-18 water purifier

Ann. Nucl. Med.

Research Report
PET O-15 cerebral blood flow and metabolism after acute stroke in spontaneously hypertensive rats