The effect of nitric oxide on blockade of the norepinephrine transporter, uptake‐1, by methylphenidate (1145.6)

Abstract

We previously showed that fresh synthesis of nitric oxide (NO) mediates transport of substrates across uptake ‐1, norepinephrine (NE), tyramine (T), mephentermine, ephedrine, imipramine and atomoxetine, and blockade by cocaine. Synthesis of NO was blocked by Nw‐nitro‐L‐arginine (L‐NNA) and the rise in arterial pressure it induces was restored to starting level by an infusion of nitroglycerin (NG), a NO donor. In this study we explored the role of NO synthesis on the blockade of uptake‐1 by methylphenidate (MP), a drug used in the treatment of attention deficit disorder, in Sprague Dawley rats in which mean arterial pressure was measured. NE (0.05, 0.1, 0.2 ug) with direct action on adrenergic receptors but is transported across uptake‐1 and sequestered in sympathetic nerve terminals, showed potentiation of its pressor effect after MP (1.52+/‐0.4 mg/kg) by 34%‐56% and not changed further after MP/L‐NNA/NG. The pressor effect of T (0,025, 0.05, 0.1 mg) which acts indirectly by entering across uptake‐1 to release NE, was reduced after MP by 78%‐85% and restored by 424% ‐650% after MP/L‐NNA/NG. The pressor effect of methoxamine, not a substrate of uptake‐1, was not affected by pretreatment with MP or MP/L‐NNA/NG. It is concluded that the blocking effect of MP on uptake‐1 is confirmed and this blockade is significantly dependent on synthesis of NO. Supported by the American University of Beirut.