Adenosine receptors mediate a pertussis toxin-insensitive prejunctional inhibition of noradrenaline release on a papillary muscle model.
The effects of adenosine receptor agonists and antagonists on field-stimulated release of radioactivity from superfused guinea-pig papillary muscles preincubated with [3H] noradrenaline were studied. N6-cyclopentyladenosine (CPA), N6-(R-phenylisopropyl)-adenosine, and 5'-N-ethylcarboxamidoadenosine caused concentration-dependent inhibition of evoked overflow with a rank order of potency typical for interaction of the compounds with the A1-subtype of adenosine receptors. Maximum inhibition was 80%. The A1-selective antagonist 8-cyclopentyl-1,3-dipropyl-xanthine (DPCPX) induced a rightward shift of the concentration-response curve for CPA with a pA2 of 8.35. However, DPCPX per se had no effect on stimulation-evoked tritium overflow. On the other hand, in the presence of 4-nitrobenzylthioinosine (2 mumol/l) and deoxycoformycin (1 mumol/l), inhibitors of adenosine uptake and deamination, respectively, DPCPX produced a concentration-dependent increase in overflow with a pD2 of 8.1. Pretreatment of the animals with pertussis toxin caused a substantial reduction in the activity of toxin-sensitive G proteins, as indicated by a lack of [32P]ADP ribosylation in a ventricular membrane preparation. Nevertheless, the inhibitory effect of the adenosine receptor agonists on stimulus-evoked overflow remained unaffected. These results are compatible with the existence of inhibitory prejunctional adenosine receptors in guinea-pig papillary muscle, which appear to be coupled to a pertussis toxin-insensitive G protein. The role of endogenous adenosine in occupying these receptors seems minimal under basal conditions.
Schütz
W
W
Institute of Pharmacology, University of Vienna, Wien, Austria.
Ströher
M
M
Freissmuth
M
M
Valenta
B
B
Singer
E A
EA
D000818:Animals; D004558:Electric Stimulation; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology; D006168:Guinea Pigs; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D009705:Nucleosides / Q000378:metabolism; D010210:Papillary Muscles / Q000378:metabolism*; D037342:Pertussis Toxin; D058914:Purinergic Antagonists; D011983:Receptors, Purinergic / Q000187:drug effects / Q000502:physiology*; D013868:Thioinosine / Q000031:analogs & derivatives / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D009705:Nucleosides; D058914:Purinergic Antagonists; D011983:Receptors, Purinergic; D010566:Virulence Factors, Bordetella; D013868:Thioinosine; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; C001789:4-nitrobenzylthioinosine; D009638:Norepinephrine