The substance P receptor subtype modulating catecholamine release from adrenal chromaffin cells.

Substance P (SP) has two distinct actions on catecholamine (CA) release from cultured bovine adrenal chromaffin cells: SP inhibits acetylcholine (ACh)- or nicotine-induced [3H]norepinephrine ([3H]NE) release; and SP protects against desensitization of ACh- or nicotine-induced [3H]NE release. In order to characterize the SP receptor subtypes modulating these two actions, we have tested several SP-related tachykinins and SP analogues for their ability to act as agonists of SP for these actions. The naturally occurring tachykinins, physalaemin, eledoisin and kassinin, were about equipotent and all much less potent than SP in inhibiting nicotine-induced [3H]NE release. Physalaemin and eledoisin were also approximately equipotent and much less potent than SP in protecting against desensitization of nicotine-induced [3H]NE release; kassinin slightly enhanced nicotinic desensitization. These results indicate that neither a kassinin-like nor a physalaemin-like peptide are likely to modulate adrenal CA release. The 'SP-P' receptor-selective analogue, SP-methyl ester, was an agonist, equipotent with SP, for both of SP's actions on [3H]NE release. [D-Pro2,D-Trp7,9]-SP, a potent antagonist of SP's actions in many SP-responsive tissues, was inactive as an antagonist of both of SP's actions on [3H]NE release from adrenal chromaffin cells; however, this analogue was a potent SP agonist in chromaffin cells. The rank order of potency of these and other SP-related peptides for inhibition of [3H]NE release was similar to their order of potency for protection against desensitization. Thus the chromaffin cell SP receptors mediating inhibition of nicotine-induced [3H]NE release appear to be very similar to those mediating protection against desensitization of nicotine-induced [3H]NE release. The results indicate that the SP receptors modulating adrenal CA release are different from either the 'SP-P' or 'SP-E' receptor subtypes; bovine adrenal chromaffin cells appear to possess a third subtype of SP receptor which shares similar characteristics with the SP receptors mediating histamine release from rat mast cells.