Older versus newer antidepressants: substance P or calcium antagonism?

Substance P (SP) is possibly involved in the pathophysiology of depression and anxiety. We investigated interactions between antidepressants on SP-induced effects and their potential calcium-blocking activity in the isolated guinea pig ileum. All the antidepressants tested, except pargyline, moclobemide, mianserin, and reboxetine, were able to inhibit in a concentration-dependent manner the contraction induced by 100 nmol/L SP. Clomipramine, fluoxetine, maprotiline, and amitriptyline (all at 3 mumol/L) flattened the concentration-response curves to SP, resulting in a reduction of up to 59%, 63%, 32%, and 23%, respectively, of the maximum contractile effect. All the antidepressants tested (3 mumol/L), except pargyline, moclobemide, and mianserin, produced a rightward parallel shift of the concentration-response curve to CaCl2. The L-type selective calcium blocker nifedipine and the T-type selective mibefradil showed similar behaviour against both agonists used, SP and CaCl2. The relative order of potency was nifedipine (pA2, 7.6 +/- 0.1) > clomipramine (pA2, 7.0 +/- 0.1) > fluoxetine (pKB, 6.5 +/- 0.1) = mibefradil (pKB, 6.6 +/- 0.1) > amitriptyline (pKB, 6.3 +/- 0.1) = maprotiline (pKB, 6.2 +/- 0.1) > fluvoxamine (pKB, 5.9 +/- 0.1). The data reported in the present study suggest that the antidepressants tested did not behave as competitive antagonists versus NK1-receptor subtypes, but their inhibitory action seems to be related to their calcium-blocking properties.