Tyrphostin-23 enhances steroid-hormone secretion from dispersed human and rat adrenocrotical cells.
Tyrphostin-23 is commonly used as inhibitor of tyrosine kinase (TK). We found that tyrphostin-23 concentration-dependently increased basal steroid-hormone secretion from dispersed human and rat adrenocortical cells, the maximal effective concentration being 10(-5) M. Tyrphostin-23 (10(-5) M) enhanced 10(-9) M angiotensin-II- and endothelin-1-stimulated secretion of human and rat adrenocortical cells, but not the secretory response to 10(-9) M ACTH However, it increased the response to lower concentrations (10(-12) or 10(-11) M) of ACTH. The secretagogue effect of tyrphostin-23 on dispersed rat adrenocortical cells was abolished by either the adenylate cyclase inhibitor SQ-22536 (10(-4) M) or the protein kinase A (PKA) inhibitor H-89 (10(-5) M). Tyrphostin-23 (10(-5) M) raised basal cyclic-AMP release by dispersed rat adrenocortical cells, but in the presence of the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX, 10(-3) M) it was ineffective. Both tyrphostin-23 and IBMX increased cyclic-AMP release by rat adrenocortical cells in response to 10(-10) M ACTH, and their effects were not additive. Taken together, our findings suggest that tyrphostin-23, acting as an inhibitor of phosphodiesterases in adrenocortical cells, increases the intracellular concentration of cyclic-AMP available for PKA activation thereby stimulating steroid-hormone secretion. They also stress that caution must be used in interpreting the results of studies aimed at investigating the possible cross-talk between adenylate cyclase- and TK-dependent signaling cascades.
Andreis
P G
PG
Department of Human Anatomy and Physiology, University of Padua, Italy.
Neri
G
G
Tortorella
C
C
Gottardo
L
L
Nussdorfer
G G
GG
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000067956:Adenylyl Cyclase Inhibitors; D000302:Adrenal Cortex / Q000187:drug effects* / Q000378:metabolism*; D000305:Adrenal Cortex Hormones / Q000096:biosynthesis / Q000378:metabolism*; D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000450:Aldosterone / Q000096:biosynthesis; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D003345:Corticosterone / Q000096:biosynthesis; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D019332:Endothelin-1 / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides; D020032:Tyrphostins / Q000494:pharmacology*
D000067956:Adenylyl Cyclase Inhibitors; D000305:Adrenal Cortex Hormones; D019332:Endothelin-1; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D013449:Sulfonamides; D020032:Tyrphostins; D000804:Angiotensin II; C017759:9-(tetrahydro-2-furyl)-adenine; D000450:Aldosterone; D000324:Adrenocorticotropic Hormone; D000242:Cyclic AMP; D011505:Protein-Tyrosine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D000225:Adenine; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C060641:tyrphostin A23; D015056:1-Methyl-3-isobutylxanthine; D003345:Corticosterone; D006854:Hydrocortisone