Adenosine analogues prevent phorbol ester-induced PKC depletion in porcine coronary artery via A1 receptor.
This study was undertaken to determine the adenosine receptor involved in the modulation of protein kinase C (PKC) in porcine coronary artery. Endothelium-denuded arterial rings were incubated with phorbol 12,13-dibutyrate (PDBu) in the presence or absence of adenosine receptor agonists and antagonists for 24 h. After incubation, contractile responses to endothelin-1 (ET-1) were compared in various treatment groups. Arterial rings incubated with PDBu alone failed to produce significant contractions in response to ET-1. (2s)-N6-[2-endo-norbornyl]adenosine (ENBA), an A1-receptor agonist, attenuated the PDBu-induced blunting of the ET-1 contractions. Incubation with ENBA alone elevated ET-1 contractility by about twofold. Inclusion of A1-receptor antagonists completely blocked both effects of ENBA: protection against PDBu and increase in ET-1 contractility. On the contrary, arterial rings incubated with the A2-receptor agonist 2-p-(2-carboxyethyl)phenethyl-amino-5'-N-ethylcarboxamidoadenosine (CGS-21680) did not show significant alteration of the ET-1 contractility when incubated with CGS-21680 alone or in combination with PDBu. Inclusion of A2-receptor antagonist in combination with CGS-21680 mimicked the effects of ENBA alone, i.e., protected against PDBu and enhanced ET-1 contractions. Measurement of PKC activities in arteries indicated that exposure to ENBA caused a twofold increase in the enzyme activity, whereas exposure to CGS-21680 had no significant effect on PKC activity. Adenosine analogues caused an accumulation of PKC through the activation of A1- but not A2-adenosine receptors. These results indicate that the modulation of PKC by adenosine analogues is mediated through A1-adenosine receptors in the coronary artery.
Marala
R B
RB
Department of Pharmacology, School of Medicine, East Carolina University, Greenville, North Carolina 27858.
Mustafa
S J
SJ
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D016232:Endothelins / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D009636:Norbornanes / Q000494:pharmacology; D010627:Phenethylamines / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1 / Q000502:physiology*; D018048:Receptors, Purinergic P2 / Q000502:physiology; D013552:Swine
D016232:Endothelins; C089285:N(6)-(2-endo-norbornyl)adenosine; D009636:Norbornanes; D010627:Phenethylamines; D058906:Purinergic P1 Receptor Agonists; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D018048:Receptors, Purinergic P2; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C073387:N 0861; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D000225:Adenine; D000241:Adenosine