THE SIGMA-COMPOUNDS 1,3-DI-O-TOLYLGUANIDINE AND N-ALLYLNORMETAZOCINE INHIBIT AGONIST-STIMULATED INOSITOL PHOSPHOLIPID-METABOLISM IN BOVINE ADRENAL-MEDULLARY CELLS

Muscarine stimulated a concentration-dependent accumulation of [H-3]inositol phosphates in bovine adrenal medullary cells preloaded with [H-3]inositol. This muscarinic activation of inositol phospholipid metabolism was fully inhibited by the sigma-ligand 1,3-di-o-tolylguanidine (DTG) with an IC50 of approximately 45 mu M. Higher concentrations (100 mu M) of (+) N-allylnormetazocine (SKF-10047) also partially inhibited this response. A concentration of DTG sufficient to fully inhibit the muscarinic response also produced a significant partial inhibition of [H-3]inositol phosphate accumulation in response to histamine but not to angiotensin II. These data demonstrate that sigma-compounds inhibit agonist-stimulated inositol phospholipid metabolism in bovine adrenal medullary cells, with a degree of selectivity towards the muscarinic response.