Comparison of the signaling mechanisms involved in the ETB receptor-mediated secretagogue action of endothelin-1 on dispersed zona glomerulosa cells and capsule-zona glomerulosa preparations of the rat adrenal gland

Endothelin-1 (ET-1) is a hypertensive peptide, which is expressed in the ra t adrenal gland, where it stimulates aldosterone secretion from zona glomer ulosa (ZG) by activating the ETB receptor subtype. A higher effectiveness o f ET-1 has been frequently observed when the integrity of adrenal tissue is preserved. Hence, we compared the aldosterone secretagogue action of ET-1 on dispersed rat ZG cells and capsule-ZG strips. ET-1 concentration-depende ntly raised aldosterone output by both preparations with similar potency. H owever, the efficacy of the maximal effective concentration of ET-1 (10(-8) M) was about 2.7-fold higher in capsule-ZG strips. The ETB-receptor antago nist BQ-788 (10(-7) M) abolished aldosterone response to 10(-8) M ET-1 in b oth ZG preparations, while the ETA receptor antagonist BQ-123 was ineffecti ve. The aldosterone secretagogue action of 10(-8) M ET-1 on dispersed ZG ce lls was concentration-dependently suppressed by the protein kinase (PK) inh ibitor calphostin-C. Conversely, both calphostin-C and the nitric oxide (NO ) synthase (NOS) inhibitor N-G-nitro-L-arginine methyl ester (L-NAME) evoke d a concentration-dependent partial reversal of the aldosterone response to 10(-8) M ET-1 of capsule-ZG strips. The NO donor L-arginine enhanced basal aldosterone yield of capsular strips, but not dispersed ZG cells. The PKA, cyclooxygenase and lipoxygenase inhibitors H-89, indomethacin and phenidon e, as well as the beta-adrenoceptor antagonist l-alprenolol, were ineffecti ve. Collectively, these findings allow us to conclude that in the rat i) th e ETB receptor-mediated PKC activation is the main signaling mechanism invo lved in the direct stimulatory effect of ET-1 on ZG cells; and ii) the high er responsiveness of capsular strips to ET-1 may be accounted for by the ET B receptor-mediated release by stromal elements of NO, which in turn increa ses aldosterone secretion from ZG cells in a paracrine manner.