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Endothelin Signaling Pathways in Rat Adrenal Medulla

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1. We further characterized the effect of endothelins (ETs) on receptor-mediated phosphoinositide (PI) turnover, nitric oxide synthase (NOS) activation, and cGMP formation in whole rat adrenal medulla.

2. The PI hydrolysis was assessed as accumulation of inositol monophosphates (InsP1) in the presence of 10 mM LiCl in whole tissue and the analysis of inositol-1-phosphate by Dowex anion exchange chromatography. NOS activity was assayed by monitoring the conversion of radiolabeled L-arginine to L-citrulline. Cyclic GMP formation was assessed as accumulation of cGMP in whole tissue in the presence of phosphodiesterase inhibition, and the amount of cGMP formed was determined by radioimmuno-antibody procedure.

3. ET-1 and ET-3 increased PI turnover by 30% in whole adrenal medulla prelabeled with [3H] myoinositol. Both ETs isoforms, at equimolar doses, increased NOS activity and cGMP levels in similar degree. The selective ETB receptor agonist, IRL-1620, also increased cGMP formation, mimicking the effects of ETs, while IRL-1620 did not alter the PI metabolism. ETs-induced InsP1 accumulation and cGMP was dependent on extracellular calcium. The effect of ETs on PI turnover was inhibited by neomycin. The L-arginine analogue, N-nitro-L-arginine (L-NAME), and two inhibitors of soluble guanylyl cyclase, methylene blue and ODQ, significantly inhibited the increase in cGMP production induced by ETs or IRL-1620. The selective ETA receptor antagonist, BQ 123, inhibited the ETs-induced increase in PI turnover, while the selective ETB receptor antagonist, BQ 788, was ineffective. Likewise, BQ 788, significantly inhibited ET-1- or ET-3-induced NOS activation and cGMP generation but not ETs-induced InsP1 accumulation.

4. Our data indicate that stimulation of PI turnover and NO-induced cGMP generation constitutes ETs signaling pathways in rat adrenal medulla. The former action is mediated through activation of ETA receptor, while the latter through the activation of ETB receptor. These results support the role of endothelins in the regulation of adrenal medulla function.

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ACKNOWLEDGMENTS

This work was supported by grants from FONACIT and CDCH, Universidad Central de Venezuela.

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  1. Laboratory of Neuropeptides, School of Pharmacy, UCV, Caracas, Venezuela

    Israel Anita & Garrido María del Rosario

  2. School of Medicine, J. M. Vargas Universidad Central de Venezuela, Caracas, Venezuela

    Mathison Yaira

  3. Laboratory of Neuropeptides, School of Pharmacy, UCV, Apartado Postal 50176, Sabana Grande 1050 A, Caracas, Venezuela

    Israel Anita

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Anita, I., Yaira, M. & María del Rosario, G. Endothelin Signaling Pathways in Rat Adrenal Medulla. Cell Mol Neurobiol 26, 701–716 (2006). https://doi.org/10.1007/s10571-006-9111-3

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