NICOTINIC AND NONNICOTINIC RECEPTOR-MEDIATED ACTIONS OF VINBLASTINE

Vinblastine has been demonstrated to inhibit nicotinic acetylcholine r eceptor (nAChR) activity in adrenal chromaffin cells and superior cerv ical ganglia and to alter agonist binding affinity to nAChR of the ele ctric organ of Torpedo californica. In cultured chromaffin cells, vinb lastine (IC50, 8.9 muM) is significantly more potent than hexamethoniu m (IC50, 16 muM) and decamethonium (IC50, 18 muM) and significantly le ss potent then d-tubocurarine (IC50, 2 muM), pentolinium (IC50, 0.6 mu M), and mecamylamine (IC50, 0.1 muM) in inhibiting nAChR-stimulated ca techolamine release. These results demonstrate that vinblastine has mo derately potent anti-nAChR activity on adrenal nAChR. On the other han d, vinblastine does not interfere with phrenic nerve stimulation of ra t diaphragm musculature in concentrations up to 200 muM. However, in r elatively high doses, vinblastine (10-200 muM) produces an increase in baseline tension of diaphragm muscle. This effect is concentration re lated (EC50, approximately 88 muM), reversible, and independent of phr enic nerve stimulation. The elevation in baseline tension is unaffecte d by nAChR blockade via d-tubocurarine, but is dependent upon the pres ence of extracellular calcium. The results suggest that vinblastine's antinicatinic actions are selective for neuronal-type AChR and do not extend to nAChR of mammalian skeletal muscle. High concentrations of v inblastine appear to elicit contractures of skeletal muscle that are u nrelated to nAChR.