Stable adenine nucleotides inhibit [3H]-noradrenaline release in rabbit brain cortex slices by direct action at presynaptic adenosine A1-receptors.
Effects of adenosine and nucleotides on the release of previously stored [3H]-noradrenaline were studied in rabbit brain cortex slices. The slices were stimulated twice, in most experiments by 6 electrical field pulses delivered at 100 Hz. Adenosine and the nucleotides AMP, ADP, ATP, AMPS, ADP beta S, ATP gamma S, beta,gamma-imido-ATP and beta,gamma-methylene-ATP all reduced the evoked overflow of tritiated compounds. For purines for which concentration-response curves were determined, the order of potency was adenosine greater than ATP approximately ATP gamma S approximately beta,gamma-imido-ATP approximately ADP greater than beta,gamma-methylene-ATP. AMP 30 mumol/l and AMPS 30 mumol/l were approximately equieffective with 30 mumol/l of adenosine and ATP gamma S, and ADP beta S 30 mumol/l was approximately equieffective with 30 mumol/l of ADP. alpha,beta-Methylene-ADP, 2-methylthio-ATP, UTP and GTP gamma S did not change the evoked overflow of tritium. alpha,beta-Methylene-ATP caused an increase; however, the increase was small and became significant only after 59 min of exposure to alpha,beta-methylene-ATP or when the slices were stimulated by 30 pulses, 10 Hz. Neither adenosine deaminase (100 U/l) nor the blocker of 5'-nucleotidase, alpha,beta-methylene-ADP (10 mumol/l), attenuated the inhibition caused by ATP, ATP gamma S and beta,gamma-methylene-ATP, despite the fact that adenosine deaminase abolished the effect of adenosine. 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX, 10 nmol/l) shifted the concentration-response curves of adenosine, ATP gamma S, beta,gamma-imido-ATP and beta,gamma-methylene-ATP to the right by very similar degrees. 8-(p-Sulphophenyl)-theophylline (30 and 300 mumol/l) also markedly antagonized the inhibition produced by ATP gamma S. alpha,beta-Methylene-ATP (10 and 30 mumol/l) and suramin (100 mumol/l) did not modify the effects of adenosine, ATP gamma S and beta,gamma-methylene-ATP. It is concluded that nucleotides themselves can inhibit the release of noradrenaline in the rabbit brain cortex. The nucleotides and adenosine seem to act at the same site, i.e., the A1 subtype of the P1-purinoceptor. The results support the notion that metabolically stable, phosphate chain-modified nucleotides such as ATP gamma S, beta,gamma-imido-ATP and beta,gamma-methylene-ATP can be potent P1 agonists. No evidence was found for presynaptic P2x-, P2y- or P3-purinoceptors.
von Kügelgen
I
I
Pharmakologisches Institut, Freiburg, Federal Republic of Germany.
Späth
L
L
Starke
K
K
D000227:Adenine Nucleotides / Q000494:pharmacology*; D000241:Adenosine / Q000493:pharmacokinetics / Q000494:pharmacology; D058892:Adenosine Deaminase Inhibitors; D000244:Adenosine Diphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D004347:Drug Interactions; D004355:Drug Stability; D004558:Electric Stimulation; D005260:Female; D008297:Male; D009411:Nerve Endings / Q000648:ultrastructure; D009638:Norepinephrine / Q000378:metabolism*; D058914:Purinergic Antagonists; D011817:Rabbits; D011983:Receptors, Purinergic / Q000187:drug effects* / Q000502:physiology; D013498:Suramin / Q000494:pharmacology; D013569:Synapses / Q000187:drug effects* / Q000648:ultrastructure; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology; D014316:Tritium; D014970:Xanthines / Q000494:pharmacology
D000227:Adenine Nucleotides; D058892:Adenosine Deaminase Inhibitors; D058914:Purinergic Antagonists; D011983:Receptors, Purinergic; D014970:Xanthines; C523965:alpha,beta-methyleneadenosine 5'-diphosphate; D014316:Tritium; D013498:Suramin; D000244:Adenosine Diphosphate; C031433:8-(4-sulfophenyl)theophylline; D000255:Adenosine Triphosphate; C051360:1,3-dipropyl-8-cyclopentylxanthine; D013806:Theophylline; D000241:Adenosine; C002630:alpha,beta-methyleneadenosine 5'-triphosphate; D009638:Norepinephrine