Drug-induced changes in the release and uptake of biogenic amines. A study on mast cells.

Abstract

Summary The mechanism of action and the structure-activity relationships (SAR) for d-tubocurarine's and chlorpromazine's Hi releasing effects and influences on the uptake of biogenic amines (5-HT, DA, NA, Hi) were studied in vitro on rat mast cells and in situ on perfused cat paws. The following results were obtained: 1 d-Tubocurarine (>10-4 M) releases Hi by an energy-dependent Ca++ stimulated process during which granules leave the cell. SAR studies indicate that the presence of hydroxyl groups and the structure between the nitrogen groups in the molecule are of importance for the Hi releasing activity. No connection between the Hi releasing activity of these drugs and their neuromuscular blocking effects could be demonstrated. 2 Chlorpromazine (>10-5 M) releases Hi by a process which induces changes in the permeability of the mast cell membrane which result in an increase in the cellular Na+ content and a reduction in the K+ content. Tetrodotoxin reduces both the Hi release and the increase in Na+ content. The release of Hi takes place probably in exchange for Na+ at the binding sites with the granules still in situ. Ca++ (2–4 mM) counteract the release induced by low concentrations of chlorpromazine. SAR studies suggest that the presence of halogen groups in the tricyclic ring system and piperidine or piperazine rings in the side chain increase the activity. Compounds with dimethylated side chains are more active than their monomethylated homologues. There is a significant correlation between the Hi releasing potency and the lipophilic nature of the drugs. 3 No qualitative differences in the release response could be demonstrated in the species studied. 4 5-HT, DA and NA are taken up into mast cells by energy- dependent carrier-mediated transport mechanisms and Hi is taken up by diffusion. The apparent affinity for uptake is highest for 5-HT, namely 3 . 10--6 M: for DA the affinity is only a twentieth, and for NA a sixtieth of that for 5-HT. 5 d-Tubocurarine (2 . 10--5--5 . 10--4 M) does not affect amine uptake. 6 Chlorpromazine (10--7--10--5 M) inhibits both active and passive transport. Ca++ (2–4 mM) counteract chlorpromazine's uptake inhibiting effect as regards 5-HT, DA, NA and Hi and also the uptake of 35S-chlorpromazine. These results suggest that Ca++ are important for chlorpromazine's mechanism of action. 7 Tricyclic neuroleptics and antidepressants inhibit active and passive transport. The uptake of 5-HT and NA is inhibited primarily by antipressants. Tertiary amines are more active than secondary amines with regard to 5-HT uptake, whilst the reverse is true for the uptake of NA. Neuroleptics have relatively little effect on 5-HT uptake and rather powerful effects on NA uptake. In each case the inhibition is competitive. DA uptake is inhibited to a greater extent by the neuroleptics, especially the thioxanthene derivatives, than by the antidepressants. The results demonstrate that these drugs also block amine uptake selectively even in tissues other than nerve tissues. 8 The investigations show that the effects of tricyclic neuroleptics and antidepressants on mast cells are the consequences of changes in permeability. These can reflect the general pharmacodynamic action of the drugs. This relationship does not appear to be applicable to the neuro-muscular blocking drugs.