Inhibition of the cannabinoid-1 receptor enhances the cerebrocortical hyperemic response to hypoxia/hypercapnia

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Activation of cannabinoid-1 (CB1) receptors may evoke diverse vascular effects under physiological conditions: it has been shown to induce vasodilation but also to increase the vascular tone by inhibition of the endothelium-derived hyperpolarizing factor (EDHF). However, the role of CB1 receptors in certain pathophysiological states is obscure. We hypothesized that activation of the CB1 receptors may influence the cerebral hyperemic response to hypoxia/hypercapnia (H/H). Therefore, we investigated the effect of the CB1-antagonist AM-251 on H/H-induced vasodilation in the cerebral cortex. Adult male Wistar rats were anesthetized with intraperitoneal injection of 1.3 g/kg Urethane. Femoral arteries were cannulated for monitoring arterial blood pressure and for measuring arterial blood gas and acid-base parameters. CBF was measured in the parietal cortex simultaneously on both sides by laser-Doppler (LD) flowmetry. H/H was induced by inhalation of different gas mixtures. In the first step, during mild H/H, animals inhaled a gas mixture of 10%O2-10%CO2-80%N2, which produced arterial pO2 of 75-85 mmHg and pCO2 of 50-60 mmHg. In the second step, during moderate H/H, animals inhaled a gas mixture of 5%O2-20%CO2-75%N2, which produced arterial pO2 of 55-65 mmHg and pCO2 of 80-90 mmHg. In the third step, during severe H/H, animals inhaled a gas mixture of 0%O2-20%CO2-80%N2, which produced arterial pO2 of 45-50 mmHg and pCO2 of 90-100 mmHg. In the first experimental group, animals were subjected to these three steps of H/H, then brought back to physiological conditions. After steady state obtained, 10 mg/kg AM-251 was injectedintravenously, followed by repetition of the stepwise H/H. In the second, control group the same protocol was performed, but between the two series of H/H only the vehicle (ethanol and emulphor, dissolved in saline) was administered intravenously. Inhalation of the different gas mixtures induced similar changes of the blood gas tensions and acid-base parameters before and after administration of AM-251 or its vehicle. Application of AM-251 did not alter baseline LD flow or arterial blood pressure. AM-251 has significantly increased, however the H/H-induced hyperemia in each step: by 30% during mild H/H, by 22% during moderate H/H, and by 14% during severe H/H. In contrast, vehicle of AM-251 had no significant effect. H/H did not change significantly the mean arterial pressure of the untreated or vehicle-treated animals, but it has induced slight hypertension (116 mmHg) following AM-251 treatment. The observed enhancement of the cerebrocortical hyperemic response to H/H after blockade of the CB1 receptors indicates that during hypoxia/hypercapnia the activation of CB1 receptors attenuates the vasodilation in the cerebral cortex. A possible explanation of these results is that endothelial CB1 receptors suppress the production of EDHF or other vasodilator mediators during H/H. If this is the case, increased cannabinoid levels during H/H limit the magnitude of reactive hyperemia in the brain tissue. Alternatively, activation of neuronal CB1 receptors may also affect the cerebrocortical blood flow during H/H by influencing the cerebral metabolic rate or the neural regulatory mechanisms of the cerebrovascular tone.