Effects of 5HT uptake inhibitors on the pressor response to 5HT in the pithed rat. The significance of the 5HT blocking property

Evaluation of the potential for interactions of paroxetine with diazepam, cimetidine, warfarin, and digoxin

“…Paroxetine is a specific and potent inhibitor of serotonin uptake, and is under development as an antidepressant (1)(2)(3)(4). The pharmacokinetic disposition of paroxetine has been fully reviewed (5,6,7), and includes effective absorption following oral administration, an apparent volume of distribution much greater than the vascular volume, and reversible binding to plasma proteins of about 95% ofthe circulating drug.…”

Is Ro 11-2465 (Cyan-imipramine) an antagonist of postsynaptic serotonin receptors?

“…8). The effect is proportional to the dose used and closely resembles the action of typical 5-HT receptor antagonists such as cyproheptadine and pizotifen as well as that of these 5-HT uptake inhibitors, which are well known to block the postsynaptic 5-HT receptors (Petersen et al, 1977;Kwiatek et al, 1980). Most probably, therefore, it is due to the antagonistic action of Ro 11-2465 on 5-HT receptors located in the vascular bed.…”

“…8, low doses of Ro 11-2465 clearly potentiate the pressor response to 5-HT (0.01 mg/kg i.v.). This potentiation is most probably related to the inhibition of 5-HT uptake by the drug (Petersen et al, 1977). However, higher doses, above 0.3 mg/kg i.v., inhibit the pressor action of 5-HT and even lead to the appearance of a depressor phase (Fig.…”

“…Recent binding studies have shown that the compound binds itself to two subpopulations of specific binding sites in brain tissue, from which it can be partially displaced by 5-HT and LSD (Burkard, 1980). Tricyclic antidepressants, in addition to their inhibitory action on monoamine uptake, also show some affinity for postsynaptic 5-HT receptors, and owing to that, they block these receptors when given in high doses (Corne et al, 1963;Fuxe et al, 1977;Maj et al, 1977;Petersen et al, 1977;Ogren et al, 1979;Kwiatek et al, 1980;Pawtowski et al, 1980). The most potent 5-HT receptor antagonists are doxepine and amitriptyline, whereas clomipramine and imipramine are less effective in this respect.…”

Potentiation of the vasospastic response to angioplasty by pretreatment with fluoxetine. A study in the atherosclerotic rabbit.

“…Other serotonin uptake inhibitors that, like fluoxetine, do not have significant S^ blocking effects have been shown to potentiate the serotonin pressor response in pithed rats, presumably by preventing uptake and clearance of the infused serotonin. 53 - 54 Second, it is possible that fluoxetine exerts a direct effect through modification of both Si and S2 receptors. 55 …”