Cardiac desensitization to adenosine analogues after prolonged R-PIA infusion in vivo.
To determine the effects of chronic in vivo stimulation of adenosine receptors, R-(-)-N6-(2-phenylisopropyl)adenosine (R-PIA), a selective A1 receptor agonist, was administered to rats as a continuous 7-day infusion (200 nmol/h). Inotropic and chronotropic responses of isolated atria to adenosine receptor agonists were markedly desensitized compared with the responses of atria from age-matched control animals. Carbachol's negative chronotropic effect was also attenuated, indicating a heterologous mode of desensitization. Antagonist radioligand binding assays indicated a 52% reduction in A1 adenosine receptor maximum binding, and competition binding assays revealed a significant loss of G protein-coupled high-affinity A1 receptors in atria from R-PIA-treated rats. Inhibitory G proteins (Gi) were significantly reduced, as quantified by immunoblot analysis, with no change in the amount of stimulatory G proteins. Ventricular membranes from R-PIA rats showed loss of Gi and uncoupling of A1 receptors, without a significant change in A1 receptor density. Thus chronic R-PIA infusion desensitized rat atrial muscle to the effects of adenosine receptor agonists via several regulatory adaptations, including downregulation of A1 adenosine receptors, uncoupling of A1 receptors from their associated G proteins, and loss of Gi proteins.
Lee
H T
HT
Department of Physiology, New York Medical College, Valhalla 10595.
Thompson
C I
CI
Hernandez
A
A
Lewy
J L
JL
Belloni
F L
FL
D015762:2-Chloroadenosine / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019830:Adenosine-5'-(N-ethylcarboxamide); D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D015536:Down-Regulation; D019204:GTP-Binding Proteins / Q000378:metabolism; D006321:Heart / Q000187:drug effects*; D006325:Heart Atria; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000378:metabolism; D010660:Phenylisopropyladenosine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D013997:Time Factors
D018047:Receptors, Purinergic P1; D015762:2-Chloroadenosine; D010660:Phenylisopropyladenosine; D019830:Adenosine-5'-(N-ethylcarboxamide); C048599:N(6)-cyclopentyladenosine; D002217:Carbachol; D019204:GTP-Binding Proteins; D000241:Adenosine