Affinity of central adenosine A1 receptors is decreased in spontaneously hypertensive rats

Functional defects in purinergic neurotransmission have been related to the development of arterial hypertension in spontaneously hypertensive rats. In order to elucidate the molecular basis of this perturbation, we have directly characterized adenosine A1 receptors using radioligand binding to rat brain membranes of Wistar Kyoto (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP). Saturation studies with [3H]1,3-dipropylcyclopentylxanthine ([3H]DPCPX) showed a lower affinity in both 5- and 48-week-old SHRSP in comparison with age-matched WKY. Similarly, competition experiments with [3H]DPCPX showed lower affinity of R-N6-phenylisopropyladenosine for the low-affinity binding site in 5- and 48-week-old SHRSP in comparison with WKY. In both studies, the difference in KD values was abolished by guanosine-5'-triphosphate in 5-week-old rats and mitigated in 48-week-old animals. No differences in Bmax values were observed in 5-week-old rats, whereas in 48-week-old SHRSP the number of receptors was significantly higher in comparison with age-matched WKY. Saturation experiments with the A1-selective agonist [3H]2-chloro-N6-cyclopentyladenosine ([3H]CCPA) demonstrated a higher affinity in 5-week-old SHRSP, whereas in 48-week-old hypertensive animals it was lower than in control WKY rats. No difference in receptor number was detected in comparison with age-matched WKY. In conclusion, our data demonstrated a diminished affinity of central adenosine A1 receptors for antagonists and for the low affinity state of the agonist binding site in genetically hypertensive rats. This might be due to structural changes of the receptor protein, to an altered G protein or defective receptor-G protein coupling in arterial hypertension.