Submitted on July 23, 2007
Accepted on January 14, 2008
Vasopressin regulation of inner medullary collecting ducts and compensatory changes in mice lacking adenosine A1 receptors
Timo Rieg1, Kanishka Pothula, Jana Schroth, Joseph Satriano2, Hartmut Osswald3, Jurgen B Schnermann4, Paul A. Insel5, Richard A Bundey6, and Volker Vallon7*
1 San Diego, California, United States
2 Div Nephrology, Dept Medicine, UC San Diego / VA Medical Center, San Diego, California, United States
3 Department of Pharmacology and Toxicology, University of Tuebingen, Tuebingen, Germany
4 United States
5 Pharmacology, UCSD, San Diego, California, United States
6 Pharmacology, University of California, San Diego, La Jolla, California, United States
7 Medicine and Pharmacology, University of California San Diego & VAMS, La Jolla, California, United States
* To whom correspondence should be addressed. E-mail: vvallon{at}ucsd.edu.
Activation of adenosine A1 receptors (A1R) can inhibit arginine-vasopressin (AVP)-induced cAMP formation in isolated cortical and medullary collecting ducts. To assess the in vivo consequences of the absence of A1R, we performed experiments in mice lacking A1R (A1R-/-). We assessed the effects of the vasopressin V2 receptor (V2R) agonist, 1-desamino-8-D-arginine vasopressin (dDAVP), on cAMP formation in isolated inner medullary collecting ducts (IMCD) and on water excretion in conscious water-loaded mice. dDAVP-induced cAMP formation in isolated IMCD was significantly greater (~2-fold) in A1R-/- compared to wild-type mice (WT) and, in contrast to WT, not inhibited by the A1R agonist N6-cyclohexyladenosine. A1R-/- and WT had similar basal urinary excretion of vasopressin, expression of aquaporin-2 protein in renal cortex and medulla, and acute increases in urinary flow rate and electrolyte-free water clearance in response to the V2R antagonist SR121463 or acute water loading; the latter increased inner medullary A1R expression in WT. Dose-dependence of dDAVP-induced antidiuresis after acute water loading was not different between the genotypes. However, A1R-/- had greater inner medullary expression of cyclooxygenase-1 under basal conditions and of the P2Y2 and EP3 receptor in response to water loading compared to WT mice. Thus, vasopressin-induced cAMP formation is enhanced in isolated IMCD of mice lacking A1R, but the adenosine-A1R/V2R interaction demonstrated in vitro is likely compensated in vivo by multiple mechanisms, a number of which can be "uncovered" by water loading.
