COUPLING OF ADENOSINE RECEPTORS TO ADENYLATE-CYCLASE IN POSTISCHEMIC RAT-BRAIN

The potential usefulness of adenosine receptor stimulation in the ther apy for ischemic brain disease is dependent upon retention of adenosin e receptors and their transduction mechanisms after ischemia. The rece ptors most clearly associated with adenosine-dependent cerebral inhibi tion are the A1-type (A1-AR), which work via a G(i) protein to inhibit adenylate cyclase. In brain membranes from rats recovering at various times after 15 min of complete cardiac arrest-induced ischemia, the l evels of A1-AR decreased temporarily to 60% of the control values. How ever, agonist affinities for A1-AR, as well as guanine nucleotide-sens itive high-affinity binding, remain unchanged. The significant decreas e of agonist affinities to A1-AR produced by calcium depletion in cont rol membranes was markedly attenuated after ischemia. Moreover, the A1 -AR agonist-induced inhibition of cAMP production parallels the decrea se in these receptor numbers. It was blocked in the postischemic membr anes but reverts to control levels upon extending the recovery period to one week after the insult. It is concluded that in addition to the lowering of the number of A1-AR binding sites, the coupling of A1 rece ptor activation to adenylate cyclase response is inhibited after ische mia, but not at the level of receptor-G(i) protein interaction.