Comparative study on blockade of the norepinephrine transporter, uptake-1 by drugs of different chemical classes and the role of nitric oxide in the blockade -

Abstract

Evidence on the role of nitric oxide in modulating the activity of the norepinephrine transporter known as uptake-1 is scarce. The few studies available in the literature provide conflicting evidence on the subject. In preliminary studies in the laboratory showed that fresh synthesis of nitric oxide is needed for the transport activity of uptake-1, in postganglionic sympathetic nerve terminals, of two major substrates: norepinephrine, a direct agonist of the adrenergic receptors, and tyramine which is an indirectly acting sympathomimetic amine that enters across uptake-1 to the sympathetic nerve terminals to release norepinephrine from the adrenergic vesicles. The blocking effect of cocaine, atomoxetine and reboxetine on uptake-1 and its dependence on fresh synthesis of nitric oxide were also studied.In this study, we explored the role of fresh synthesis of nitric oxide in the blockade of uptake-1 by methylphenidate (1.52±0.4 mg-kg) and imipramine (4± 0.7 mg-kg), the therapeutic counterparts of the experimental blocker of uptake-1 cocaine, in Sprague-Dawley rats in which mean arterial pressure was measured. Synthesis of nitric oxide was blocked by nitro-L-arginine (L-NNA) and the rise in mean arterial pressure it induces was restored to starting level by an infusion of nitroglycerin, a nitric oxide donor. Norepinephrine (0.05, 0.1, 0.2 µg) showed potentiation of its pressor effect after methylphenidate by 56± 11percent, 40± 6percent and 34 ± 6percent respectively. Treatment with L-NNA and an infusion of nitroglycerin did not further change the pressor effect of norepinephrine. The pressor effect of tyramine (0.025, 0.05, 0.1 mg) was reduced by 85 ± 2percent, 83 ± 2percent and 78 ± 2percent after methylphenidate and restored by 650 ± 106percent, 472 ± 86percentand 424 ± 129percent after treatment with L-NNA and an infusion of nitroglycerin. The pressor effect of methoxamine, not a substrate of uptake-1, was not affected by either pretreatment with methylphenidate, or L-NNA and nitroglycerin. Nor