Effects of desipramine, trifluoperazine and other inhibitors of calmodulin on the secretion of catecholamines from the adrenal medulla and postganglionic sympathetic nerves of the salivary gland.

Abstract

The effects of various drugs, known to be inhibitors of calmodulin, were tested on the secretion of catecholamines (CA) from the adrenal medulla and sympathetic nerves of the salivary gland of the rat. Secretion of CA from the perfused adrenal gland was evoked by injection of acetylcholine (ACh, 50 micrograms), excess K (700 micrograms), or transmural stimulation of splanchnic nerves (300 pulses at 10 Hz). Release of 3H-noradrenaline in the perfused salivary gland was evoked by transmural stimulation at 3 Hz for 30 s. CA secretion was reduced in a dose-dependent manner by 0.3 microM to 10 microM desipramine or imipramine. The effect of low doses (0.3 microM) was more pronounced on the secretion evoked by ACh and splanchnic nerve stimulation than that by excess K. The inhibition was independent of the frequency of nerve stimulation. Trifluoperazine (10-100 microM) and chlorpromazine (10-100 microM) reduced CA secretion evoked by all of the three procedures. The inhibitory effects of desipramine, trifluoperazine and chlorpromazine were completely reversed within 1 h after their washout. Secretion of CA obtained after reintroduction of Ca to the adrenal gland previously perfused with Ca-free medium was not blocked by desipramine or trifluoperazine. In fact, these agents markedly enhanced the secretory response. None of the drugs enhanced spontaneous secretion of CA from the adrenal gland during the nonstimulation period. Adrenal medullary cells accumulated significant amounts of Ca45 (0.88 pg/mg) after stimulation with ACh.(ABSTRACT TRUNCATED AT 250 WORDS)