Purinoceptor-mediated modulation by endogenous and exogenous agonists of stimulation-evoked [3H]noradrenaline release on rat iris.
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)
Fuder
H
H
Pharmakologisches Institut, Universität Mainz, Federal Republic of Germany.
Brink
A
A
Meincke
M
M
Tauber
U
U
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D004558:Electric Stimulation; D066298:In Vitro Techniques; D007498:Iris / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D011983:Receptors, Purinergic / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D009435:Synaptic Transmission / Q000187:drug effects; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D011719:Pyrazines; D011983:Receptors, Purinergic; D014970:Xanthines; C048599:N(6)-cyclopentyladenosine; C072107:CP 66713; C051360:1,3-dipropyl-8-cyclopentylxanthine; D013806:Theophylline; C028322:8-phenyltheophylline; D000241:Adenosine; D009638:Norepinephrine