The effect of nitric oxide on blockade of the norepinephrine transporter, uptake‐1, by atomoxetine

Abstract

We previously showed that fresh synthesis of nitric oxide (NO) mediates transport of substrates across uptake‐1, norepinephrine (NE), tyramine (T), mephentermine, ephedrine and imipramine, 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 in the blockade of uptake‐1 by atomoxetine, a selective NE uptake blocker 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) that acts directly but is taken up by uptake‐1 to be sequestered in sympathetic nerve terminals, was potentiated after A (0.31 mg/kg) by 45%–89% and not changed further after A‐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 by 89%–92% after A and restored by 575%–976% after A‐L‐NNA/NG. The pressor effect of methoxamine, not a substrate of uptake‐1, was not affected by pretreatment with A or A‐L‐NNA/NG. It is concluded that fresh synthesis of NO is significantly involved in the blocking activity of A on uptake‐1. Supported by the American University of Beirut.