Adenosine A1 receptor-mediated inhibition of vasopressin action in inner medullary collecting duct.
We examined the effects of adenosine and adenosine analogues on arginine vasopressin (AVP)-induced increases in osmotic water permeability (Pf; micron/s) and adenosine 3',5'-cyclic monophosphate (cAMP) accumulation in rat inner medullary collecting ducts (IMCDs). When added to the bath, the A1 receptor agonist N6-cyclohexyladenosine (CHA) produced a rapid and reversible inhibition of AVP-stimulated (10 pM) Pf (1,781 +/- 195 to 314 +/- 85 microns/s at 0.3 microM CHA; n = 9). The inhibitory effect of CHA was concentration dependent, with a 50% inhibitory concentration of 10 nM. The effect of CHA was inhibited by prior exposure of IMCDs to the A1 receptor antagonist 1,3-dipropylxanthine-8-cyclopentylxanthine (DP-CPX; 1 microM) or by preincubation with pertussis toxin. CHA had no effect on cAMP-induced increases in Pf. In addition to CHA, adenosine and the nonselective agonist 5'-(N-ethylcarboxamido)-adenosine (NECA) inhibited AVP-dependent Pf by > or = 70%, whereas the A2 receptor agonist CGS-21680 had no effect. Luminal adenosine (0.1 mM) had no effect on basal or AVP-stimulated Pf. CHA, NECA, and adenosine but not CGS-21680 inhibited AVP-stimulated cAMP accumulation in a concentration-dependent manner (50% inhibitory concentrations 0.1-300 nM). The inhibitory effect of CHA on AVP-stimulated cAMP accumulation was attenuated by DPCPX. We conclude that adenosine, acting at the basolateral membrane, inhibits AVP action in the IMCD via interaction with A1 receptors. The inhibition occurs proximal to cAMP generation and likely involves an inhibitory G protein.
Edwards
R M
RM
Department of Renal Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406-0939.
Spielman
W S
WS
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D019830:Adenosine-5'-(N-ethylcarboxamide); D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000378:metabolism*; D066298:In Vitro Techniques; D007679:Kidney Medulla / Q000187:drug effects / Q000502:physiology*; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008297:Male; D037342:Pertussis Toxin; D010627:Phenethylamines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018047:Receptors, Purinergic P1 / Q000187:drug effects / Q000502:physiology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D010627:Phenethylamines; D018047:Receptors, Purinergic P1; D010566:Virulence Factors, Bordetella; D014970:Xanthines; D001127:Arginine Vasopressin; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; D019830:Adenosine-5'-(N-ethylcarboxamide); C027513:N(6)-cyclohexyladenosine; C051360:1,3-dipropyl-8-cyclopentylxanthine; D000242:Cyclic AMP; D037342:Pertussis Toxin; D000241:Adenosine