Abstract
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. 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 micrograms.kg-1.min-1 (n = 6). The role of muscarinic receptor activation in the CBF response to OXO (50 micrograms.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 micrograms.kg-1.min-1) either 30 (n = 6) or 60 minutes (n = 5) after administration of 50 mg/kg N omega-nitro-L-arginine (LNA). CBF to forebrain (pre-OXO, 144 +/- 12 mL.min-1.100 g-1) was unchanged with OXO 0.5 or 5 micrograms.kg-1.min-1 but increased at 10 (209 +/- 26 mL.min-1 x 100 g-1) and 30 minutes (243 +/- 35 mL.min-1 x 100 g-1) of OXO infusion at 50 micrograms.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. In halothane-anesthetized cats, OXO (50 micrograms.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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