Purinoceptor-mediated modulation by endogenous and exogenous agonists of stimulation-evoked [3H]noradrenaline release on rat iris.

Abstract

To investigate whether endogenous purinoceptor agonists affect the sympathetic neurotransmission in the rat isolated iris, and to classify the purinoceptors modulating exocytotic [3H]-noradrenaline release, we have determined the effect of adenosine receptor antagonists on, and the relative potency of selected agonists in modulating, the field stimulation-evoked (3 Hz, 2 min) [3H]-noradrenaline overflow. In addition, the apparent affinity constants of 8-phenyltheophylline (8-PT) and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) in antagonizing the prejunctional effects of purinoceptor agonists were estimated. The relatively A1-selective DPCPX 10 and 100 nmol/l increased the evoked [3H]-noradrenaline overflow by about 25%-35% indicating a minor inhibition of evoked release by endogenous purinoceptor agonists probably via an A1 adenosine receptor. Whereas the A1/A2-antagonist 8-PT failed to increase the evoked [3H]-noradrenaline overflow in the absence of exogenous agonists (without or with dipyridamole 1 mumol/l present), the relatively A2-selective antagonist CP-66,713 (4-amino-8-chloro-1-phenyl(1,2,4)triazolo(4,3-a)quinoxaline) 100 nmol/l decreased it by 20%-30% in the absence and continuous presence of DPCPX. This may be compatible with a minor A2-mediated facilitation by an endogenous purinoceptor agonist. All exogenous agonists tested (except UTP 100 mumol/1) inhibited the evoked [3H]-noradrenaline overflow. The relative order of agonist potency (IC40, concentration in mumol/l for inhibition of evoked release by 40%) was CPA (N6-(cyclopentyl)adenosine, 0.004) greater than R-PIA (R(-)N6-(2-phenylisopropyl)adenosine, 0.066) = CHA (N6-(cyclohexyl)adenosine, 0.082) greater than NECA (N5-(ethyl-carboxamido)adenosine 0.44) greater than ADO (adenosine, 4.1). ATP was nearly equipotent with ADO. Maximum inhibition was 70%-80% and similar for all agonists.(ABSTRACT TRUNCATED AT 250 WORDS)