Chlorpropamide Upregulates Antidiuretic Hormone Receptors and Unmasks Constitutive Receptor Signaling
| Title: | Chlorpropamide Upregulates Antidiuretic Hormone Receptors and Unmasks Constitutive Receptor Signaling |
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| Authors: | Durr, Jacques A.; Hensen, Johannes; Ehnis, Tobias; Blankenship, Mary S. |
| Publisher: | American Journal of Physiology: Renal Physiology |
| Date Published: | May 01, 2000 |
| Reference Number: | 536 |
The mechanism by which chlorpropamide (CP) treatment promotes antidiuresis is unknown. CP competitively inhibited antidiuretic hormone (ADH) binding and adenylyl cyclase (AC) stimulation (inhibition constants K(i) and K'(i) of 2.8 mM and 250 microM, respectively) in the LLC-PK(1) cell line. CP (333 microM) increased the apparent K(a) of ADH for AC activation (0.31 vs. 0.08 nM) without affecting a maximal response, suggesting competitive antagonism. Because CP lowers "basal" AC activity and the AC activation-ADH receptor occupancy relationship (A-O plots), it is an ADH inverse agonist. Twenty-four-hour CP exposure (100 microM) upregulated the ADH receptors without affecting affinity. This lowered K(a) and increased basal AC activity and maximal response (1. 86 vs. 1.35 and 14.9 vs. 10.6 fmol cAMP. min(-1). 10(3) cells(-1), n = 6, P<0.05). NaCl, which potentiates ADH stimulation, also increased basal AC activity. This, together with the CP-ADH inverse agonism and increased basal AC activity at higher receptor density, unmasks constitutive receptor signaling. The CP-ADH inverse agonism explains receptor upregulation and predicts the need for residual ADH with functional isoreceptors for CP-mediated antidiuresis. This could be why CP ameliorates partial central diabetes insipidus but not nephrogenic diabetes insipidus.
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