Jacob Bell
New Member
Direct cerebrovascular effects of CB1 receptor activation by the synthetic endocannabinoid HU-210 in vivo
Marion A Simpson1, J Leanne Leith2, Linda Ferrington2 and Paul A T Kelly2
1Division of Clinical Neuroscience, University of Edinburgh, Edinburgh, UK
2Division of Neuroscience, University of Edinburgh, Edinburgh, UK
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Background and Purpose
In addition to their presence on central neuronal processes, cannabinoid (CB1) receptors, mediating vasodilatation, have also been identified on cerebral blood vessels 1. To investigate the possible role of CB1 receptors in cerebrovascular regulation in vivo, we examined the effects of the synthetic endocannabinoid HU-210 on local cerebral blood flow (LCBF) and glucose use (LCMRglu) in parallel groups of rats.
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Methods
Adult male Dark Agouti rats were injected with either 100 mg/kg i. v. HU-210 (n=12) or saline with 5% propylene glycol and 2% Tween 80 (n=12). Measurement of LCBF (with [14C]-iodoantipyrine) or LCMRglu (with [14C]-2-deoxyglucose) was initiated at 30 and 20 minutes post-treatment respectively 2 in equal numbers from either treatment group. Tissue samples were dissected post mortem from hippocampus, striatum, and three neocortical brain areas for assessment of tracer concentrations 2. Mean arterial blood pressure (MABP) and heart rate (HR) were monitored constantly, and blood gases at intervals with the final measurement immediately before the start of blood flow measurements. Data (meanplusminusSEM) were analysed by t-test, and LCBF/ LCMRglu ratios by Mann-Whitney U-test (P<0.05).
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Results
HU-210 significantly decreased MABP (from 142plusminus1 to 105plusminus6 mmHg) and HR (from 484plusminus6 to 232plusminus18 beats. min-1), and significantly increased PaCO2 (from 32.0plusminus0.7 to 45.7plusminus1.6 mmHg). These effects were established by 5 minutes and persisted relatively unchanged throughout the rest of the experimental period. HU-210 induced significant decreases in LCMRglu in all five brain regions examined, ranging from -19% in frontal cortex (from 69plusminus1 to 55plusminus3 ìmol.100 g-1.min-1) to -31% in occipital cortex (from 60plusminus1 to 41plusminus2mumol.100g-1.min-1). In contrast, there was a tendency for LCBF to be increased in all regions following HU-210, although significant increases were found only in striatum (+19%; from 122plusminus4 to 145plusminus6 ml.100g-1.min-1) and hippocampus (+16%; from 94plusminus2 to 110plusminus3 ml.100g-1.min-1). However, the hypercapnia associated with HU-210 treatment could in itself result in cerebrovascular dilatation and increased cerebral blood flow. With a conservative correction factor introduced to allow for hypercapnia (3 ml.mmHg-1 rise in PaCO2 from control mean), corrected LCBF values were found to be similar to control with no significant increases or decreases, despite the decreases in metabolism. Thus, even with a correction factor introduced for hypercapnia, HU-210 administration was associated with a change in the fundamental relationship that normally links cerebral perfusion to metabolic demand, and the ratios of flow to metabolism across the brain areas as a whole were significantly increased. The effect was most marked in parietal and occipital cortices where ratios increased from 2.25 and 2.03, to 2.83 and 2.61 respectively.
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Conclusions
The consistent increase in LCBF/LCMRglu ratios throughout the brain suggests that, as well as its depressant effects on neuronal activity, HU-210 may also interact with cerebrovascular CB1 receptors to produce dilatatory effects which are independent of metabolic drive. This hyperaemia, relative to metabolic demand, could provide a contributory mechanism to the neuroprotective properties that have been reported for cannabinoids.
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References
Gebremedhin D et al. (1999) Am J Physiol 276:H2085—2093 | PubMed | ISI | ChemPort |
Kelly PAT et al. (1994) Brain Res 665:315—318 | Article | PubMed | ChemPort |
Source: Journal of Cerebral Blood Flow & Metabolism - Direct cerebrovascular effects of CB1 receptor activation by the synthetic endocannabinoid HU-210 in vivo
Marion A Simpson1, J Leanne Leith2, Linda Ferrington2 and Paul A T Kelly2
1Division of Clinical Neuroscience, University of Edinburgh, Edinburgh, UK
2Division of Neuroscience, University of Edinburgh, Edinburgh, UK
Top of page
Background and Purpose
In addition to their presence on central neuronal processes, cannabinoid (CB1) receptors, mediating vasodilatation, have also been identified on cerebral blood vessels 1. To investigate the possible role of CB1 receptors in cerebrovascular regulation in vivo, we examined the effects of the synthetic endocannabinoid HU-210 on local cerebral blood flow (LCBF) and glucose use (LCMRglu) in parallel groups of rats.
Top of page
Methods
Adult male Dark Agouti rats were injected with either 100 mg/kg i. v. HU-210 (n=12) or saline with 5% propylene glycol and 2% Tween 80 (n=12). Measurement of LCBF (with [14C]-iodoantipyrine) or LCMRglu (with [14C]-2-deoxyglucose) was initiated at 30 and 20 minutes post-treatment respectively 2 in equal numbers from either treatment group. Tissue samples were dissected post mortem from hippocampus, striatum, and three neocortical brain areas for assessment of tracer concentrations 2. Mean arterial blood pressure (MABP) and heart rate (HR) were monitored constantly, and blood gases at intervals with the final measurement immediately before the start of blood flow measurements. Data (meanplusminusSEM) were analysed by t-test, and LCBF/ LCMRglu ratios by Mann-Whitney U-test (P<0.05).
Top of page
Results
HU-210 significantly decreased MABP (from 142plusminus1 to 105plusminus6 mmHg) and HR (from 484plusminus6 to 232plusminus18 beats. min-1), and significantly increased PaCO2 (from 32.0plusminus0.7 to 45.7plusminus1.6 mmHg). These effects were established by 5 minutes and persisted relatively unchanged throughout the rest of the experimental period. HU-210 induced significant decreases in LCMRglu in all five brain regions examined, ranging from -19% in frontal cortex (from 69plusminus1 to 55plusminus3 ìmol.100 g-1.min-1) to -31% in occipital cortex (from 60plusminus1 to 41plusminus2mumol.100g-1.min-1). In contrast, there was a tendency for LCBF to be increased in all regions following HU-210, although significant increases were found only in striatum (+19%; from 122plusminus4 to 145plusminus6 ml.100g-1.min-1) and hippocampus (+16%; from 94plusminus2 to 110plusminus3 ml.100g-1.min-1). However, the hypercapnia associated with HU-210 treatment could in itself result in cerebrovascular dilatation and increased cerebral blood flow. With a conservative correction factor introduced to allow for hypercapnia (3 ml.mmHg-1 rise in PaCO2 from control mean), corrected LCBF values were found to be similar to control with no significant increases or decreases, despite the decreases in metabolism. Thus, even with a correction factor introduced for hypercapnia, HU-210 administration was associated with a change in the fundamental relationship that normally links cerebral perfusion to metabolic demand, and the ratios of flow to metabolism across the brain areas as a whole were significantly increased. The effect was most marked in parietal and occipital cortices where ratios increased from 2.25 and 2.03, to 2.83 and 2.61 respectively.
Top of page
Conclusions
The consistent increase in LCBF/LCMRglu ratios throughout the brain suggests that, as well as its depressant effects on neuronal activity, HU-210 may also interact with cerebrovascular CB1 receptors to produce dilatatory effects which are independent of metabolic drive. This hyperaemia, relative to metabolic demand, could provide a contributory mechanism to the neuroprotective properties that have been reported for cannabinoids.
Top of page
References
Gebremedhin D et al. (1999) Am J Physiol 276:H2085—2093 | PubMed | ISI | ChemPort |
Kelly PAT et al. (1994) Brain Res 665:315—318 | Article | PubMed | ChemPort |
Source: Journal of Cerebral Blood Flow & Metabolism - Direct cerebrovascular effects of CB1 receptor activation by the synthetic endocannabinoid HU-210 in vivo
