Time-Dependent Inhibition of Oxotremorine-Induced Cerebral Hyperemia by N ω -Nitro- l -Arginine in Cats

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Abstract
Background and Purpose Oxotremorine (OXO) is a cholinergic agonist that increases cerebral blood flow (CBF) when administered intravenously. We tested the hypothesis that OXO causes a dose-related increase in CBF in cats via a muscarinic mechanism that involves stimulation of nitric oxide synthase. Methods Halothane-anesthetized male cats were studied under controlled ventilation. In three groups we measured cerebral blood flow (CBF; microspheres) during 30 minutes of intravenous OXO infusion at doses of 0.5 (n=3), 5 (n=6), or 50 μg · kg −1 · min −1 (n=6). The role of muscarinic receptor activation in the CBF response to OXO (50 μg · kg −1 · min −1 ) was assessed by determining the effect of atropine sulfate (2 mg · kg −1 , n=6) pretreatment in a separate group of cats. The role of nitric oxide synthase was assessed by determining the CBF response to OXO (50 μg · kg −1 · min −1 ) either 30 (n=6) or 60 minutes (n=5) after administration of 50 mg/kg N ω -nitro- l -arginine (LNA). Results CBF to forebrain (pre-OXO, 144±12 mL · min −1 ·100 g −1 ) was unchanged with OXO 0.5 or 5 μg · kg −1 · min −1 but increased at 10 (209±26 mL · min −1 · 100 g −1 ) and 30 minutes (243±35 mL · min −1 · 100 g −1 ) of OXO infusion at 50 μg · kg −1 · min −1 ( P <.05). Atropine sulfate prevented OXO-induced hyperemia at 10 minutes of infusion but not at 30 minutes of infusion (135±12% of pre-OXO). LNA decreased baseline CBF by approximately 50%. Treatment with LNA 30 minutes before OXO did not affect the extent of OXO-induced hyperemia (CBF, 142±15% of pre-OXO at 10 minutes and 153±18% of pre-OXO at 30 minutes of OXO infusion). Treatment with LNA 60 minutes before OXO ablated OXO-induced hyperemia. Conclusions In halothane-anesthetized cats, OXO (50 μg · kg −1 · min −1 ) increases forebrain CBF by a muscarinic mechanism that involves stimulation of nitric oxide synthase. The ability of nitric oxide synthase inhibitors to block agonist-induced nitric oxide–mediated vasodilation (response to OXO) is time dependent and may not be predicted by ability of the inhibitor to significantly decrease basal CBF.

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