Neuronal nitric oxide has a role as a perfusion regulator and a synaptic modulator in cerebellum but not in neocortex during somatosensory stimulation—An animal PET study
Introduction
Cerebral blood flow (CBF) varies in association with local neuronal activity, which is known as neurovascular coupling (Roy and Sherrington, 1890). As neuronal electrical activity requires amount of energy to maintain membrane potential and glucose is almost the only substrate for energy metabolism in the brain, neuronal activity is coupled to glucose metabolism (Jueptner and Weiller, 1995). Thus, CBF and glucose metabolism were expected to be linearly coupled, and it was actually confirmed in autoradiographic and positron emission tomographic (PET) studies during neuronal activation in animal and in human (for review, see Clarke and Sokoloff, 1999). However, the detail mechanism of CBF control to couple neuronal activity remains to be elucidated.
Nitric oxide (NO) has been the most powerful candidate as a mediator of neurovascular coupling. Several studies disclosed that pharmacological inhibition of NO synthesis attenuated activation-induced increases in CBF in animals (Goadsby et al., 1992, Northington et al., 1992, Akgoren et al., 1994, Iadecola et al., 1995, Yang et al., 1999). On the other hand, others found no effect of NO inhibition on the functional CBF response in rats (Wang et al., 1993, Adachi et al., 1994, Greenberg et al., 1999) and in humans (White et al., 1999), neither in the studies using NO synthase (NOS)-mutant mice (Ayata et al., 1996, Ma et al., 1996).
There may be several reasons for these opposite findings. First, they can be due to regional difference in functional mechanism of NO in neurovascular coupling. Although immunohistochemical studies have shown that NOS neurons are the most abundant in basal nucleus and cerebellum, but less in the cerebral cortex (Bredt et al., 1990, Cork et al., 1998), there are few reports, which directly compared regional differences in NO function. Second, few studies performed simultaneous recording of local neuronal activity in accompany with CBF. NO is synthesized at post-synaptic site and acts as a modulator of pre-synaptic activity (Faraci and Breese, 1993, Montague et al., 1994). Thus, to evaluate not only perfusion but also neuronal activity would be necessary to discriminate direct NO function in perfusion control from secondary reflection of synaptic modulation in the brain.
The present study was carried out in order to clarify the regional difference in neurovascular control of neuronal NO by direct comparison of perfusion and glucose metabolism in α-chloralose-anesthetized cats. The unilateral forepaw of animals was subjected to electrical somatosensory stimulation using a selective neuronal NOS inhibitor, 7-nitroindazole (7-NI), to investigate the role of neurogenic NO. CBF was measured using a PET scanner for animal use, as well as cerebral metabolic rate of glucose (CMRglc). Voxel-based (VB) analysis, as well as the regions of interest (ROI) analysis, were applied to the PET data, and global and regional alterations for perfusion and metabolism were evaluated.
Section snippets
Animals
Sixteen adult male cats weighing 3.32±0.3 kg (mean±SD) were used for this experiment (Liberty Research, NY, USA). This protocol was conducted within the guidelines for experimental procedures of animal research on Human Care and Use of Laboratory Animals (Rockville, National Institute of Health/Office for Protection from Research Risks, 1996) and approved by the ethical committee for animal research in Kyoto University Graduate School of Medicine (Medkyo01174).
The animals were fasted overnight
Results
Physiological variables revealed no significant changes during Studies I and II, except for a significant decrease in heart rate after administration of 7-NI compared to the control group (Table 1).
Discussion
The present study was the first to investigate the difference of regional neurovascular coupling by direct comparison of perfusion and metabolic images obtained using PET in the same animal. Somatosensory stimulation in the unilateral forepaw of cats elicited coupled increase in CBF and CMRglc in the contralateral primary somatosensory cortex (7%) and the ipsilateral cerebellum (8%) (Fig. 3, Table 3). Both VB and ROI analysis showed that inhibition of neuronal NOS induced a relatively low CBF
Acknowledgements
The outline of this article was presented at Brain Activation and Cerebral Blood Flow Control, Satellite Symposium of Brain 2001 in Tokyo, Japan. We appreciate Drs S. Matsuzaki and M. Ogawa for their help with the treatment of animals and Dr Y. Magata and H. Kitano for their technical assistance with the PET studies. This work was supported by Research for the Future Program (RFTF) JSPS-RFTF97L00201 from the Japan Society for the Promotion of Science and a General Research Grant for Aging and
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Present address: Department of Investigative Radiology, Research Institute, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan.