Effect of an adenosine A(1) receptor agonist and a novel pyrimidoindole onmembrane properties and neurotransmitter release in rat cortical and hippocampal neurons

Activation of adenosine A(1) receptors by endogenous adenosine plays a neur oprotective role under various pathophysiological conditions including hypo xia. Intracellular recordings were made in rat pyramidal cells of the somat osensory cortex. Hypoxia (5 min) induced a membrane depolarization and a de crease of input resistance. The A(1) receptor agonist N-6-cyclopentyladenos ine (CPA, 100 muM) reversibly inhibited the hypoxic depolarization. The inh ibition was also present after blockade of the A(2A) A(2B) and A(3) recepto r subtypes by selective antagonists. CPA had no effect on the hypoxic decre ase of input resistance. 1,3-Dipropyl-8-cyclopentylxanthine (DPCPX), a sele ctive A(1) receptor antagonist, which did not alter hypoxic depolarization when given alone abolished the inhibitory effect of CPA. Neither CPA nor DP CPX influenced membrane potential or apparent input resistance under normox ic conditions. The novel pyrimidoindole (R)-9-(1-methylbenzyl)-2-(4'-pyridy l)-9H-pyrimido[4,5-b]indole-4-amine (APPPI, 1 and 10 muM) reversibly dimini shed hypoxic depolarization but had no significant effect on input resistan ce. The effect of APPPI at a concentration of 1 muM, but not at 10 muM, was blocked by DPCPX (0.1 muM). CPA (100 muM) inhibited [H-3]-noradrenaline ([ H-3]-NA) release from rat hippocampal brain slices significantly only in th e presence of rauwolscine (0.1 muM), an alpha (2)-adrenoceptor antagonist. APPPI (1 and 10 muM) exhibited an inhibitory effect similar to that observe d with CPA. The effects of both CPA and APPPI were antagonized by DPCPX (0. 1 muM). The present data suggest that mainly presynaptic mechanisms prevent neurons from hypoxic changes by an inhibition of transmitter release. Howe ver, in contrast to CPA, APPPI exhibited additional effects, which require further investigation. (C) 2001 Elsevier Science Ltd. All rights reserved.