Role of endogenous endothelins in catecholamine secretion in the rat adrenal gland

We investigated the role of endogenous endothelins in catecholamine secreti on in response to transmural electrical stimulation in the retrogradely per fused rat adrenal gland. (R)2-[(R)-2-[(S)-2-[[1-(hexahydro-1H-azepinyl)]car bonyl]amino-4-methyl-pentanoyl (1-methyl-1H-indoyl)]propionyl]amino-3-(2-py ridyl) propionic acid (FR139317; 0.03-3 mu M), an endothelin ETA receptor a ntagonist, inhibited the electrical stimulation-induced epinephrine and nor epinephrine output. Neither N-cis-2,6-dimethylpiperidinocarbonyl-L-gamma- m ethylleucyl-D-1-methoxycarbonyltryptophanyl-D-norleucine (BQ-788; 0.03 -3 m u M), an endothelin ETB receptor antagonist, nor phosphoramidon (1-100 mM), an endothelin-converting enzyme inhibitor, affected the catecholamine outp ut responses. However, the inhibition by FR139317 of the catecholamine outp ut responses was abolished by pretreatment with phosphoramidon (100 mM) or BQ788 (3 mu M). These results indicate that activation of endothelin ETB re ceptors by endogenous endothelins inhibits the catecholamine output respons es under the condition in which endothelin ETA receptors are blocked. Exoge nous endothelin-l (1-100 nM) did not affect the catecholamine output respon ses, but it inhibited the responses under treatment with phosphoramidon and FR139317. Activation of endothelin ETA receptors may interfere with the en dothelin ETB receptor-mediated inhibitory action on the neuronally evoked s ecretion of adrenal catecholamines. (C) 2000 Elsevier Science B.V. All righ ts reserved.