REGULATION OF CELL CYCLIC-AMP IN MEDULLARY THICK ASCENDING LIMB OF HENLE IN A RAT MODEL OF CHRONIC-RENAL-FAILURE

Chronic renal failure (CRF) is accompanied by adaptive changes in elec trolyte reabsorption in the thick ascending limb of Henle of surviving nephrons. To study the cellular mechanism of this adaptation, we meas ured intracellular cAMP in micro-dissected medullary thick ascending l imb (mTAL) segments in rats with CRF. mTAL exhibited in CRF an increas e of basal cAMP from 25.6 +/- 10.0 in controls to 65.8 +/- 11.3 fmol m m(-1) tubule in CRF (P < 0.05). Vasopressin and calcitonin stimulated mTAL adenylate-cyclase in a dose-dependent manner in controls but fail ed to stimulate in CRF. Likewise, maximal stimulation with 10(-3) M 3- isobutyl-1-methylxanthine (IBMX) plus 10(-5) M forskolin increased cAM P in controls to 63.0 +/- 16.0 but not in CRF, where maximal stimulate d values remained at 63.1 +/- 18.8 fmol mm(-1) tubuie (P NS). Alpha(2) -adrenoreceptor activation with clonidine at concentrations ranging fr om 10(-8) to 10(-6) M diminished cAMP production by 37% in CRF(P < 0.0 5), whereas no differences were found in controls. Thus, the basal int racellular cAMP is increased in rat mTAL in CRF. The finding that neit her forskolin nor vasopressin were able to further augment intracellul ar cAMP would suggest that stimulatory pathways of the adenylate-cycla se system are activated in the basal state. However, mTAL cells in CRF seem to retain the response of normal epithelium to inhibitory pathwa ys such as the one mediated by alpha(2)-adrenoreceptors.