Mechanism of imipramine inhibition of platelet 5-hydroxytryptamine transport.
Plasma membrane vesicles isolated from porcine blood platelets take up approximately 8 to 15 pmol of [3H]imipramine per mg of membrane protein. This apparent binding requires Na+ in the external medium and is reversed by 5-hydroxytryptamine and fluoxetine. The apparent KD for imipramine uptake is 23 nM, which agrees well with the KI for competitive inhibition of 5-hydroxytryptamine transport by imipramine. In contrast to 5-hydroxytryptamine transport, imipramine uptake is not dependent on transmembrane Na+ and K+ gradients and is insensitive to ionophores such as nigericin and gramicidin which dissipate these gradients. Although 5-hydroxytryptamine rapidly and competitively displaces imipramine from membrane vesicles, imipramine does not cause 5-hydroxytryptamine efflux and inhibits 5-hydroxytryptamine exchange. These results are consistent with the proposal that imipramine binds to the substrate site of the 5-hydroxytryptamine transporter but cannot be transported.
D000818:Animals; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D007099:Imipramine / Q000378:metabolism / Q000494:pharmacology*; D007700:Kinetics; D011955:Receptors, Drug / Q000378:metabolism; D012701:Serotonin / Q000097:blood*; D012964:Sodium / Q000494:pharmacology; D013552:Swine
D011955:Receptors, Drug; D012701:Serotonin; D012964:Sodium; D007099:Imipramine