Sole activation of three luminal adenosine receptor subtypes in different parts of coronary vasculature.
In isolated guinea pig hearts saline perfused at constant flow, adenosine A(1), A(2A), and A(3) (A(x)) agonists covalently bound to a large polymer (Pol; 2,000 kDa) were intracoronarily administered, and three effects were studied: dromotropic, vascular and inotropic. The rank order of potencies were the following: dromotropic (Pol-A(2A)Pol-A(1)>Pol-A(3)) and vascular and inotropic (Pol-A(2A)> or =Pol-A(1)Pol-A(3)), where the rank order of potency for Pol-A(x) depends on the part of the coronary vascular network involved; i.e., there is a vascular heterogeneity. The large size of Pol-A(x) prevents extravascular diffusion and causes it to act solely in the endothelial luminal surface. This implies their cardiac effects are due to endothelial mediators. Inhibition of nitric oxide (NO) and prostaglandin (PG) synthesis with N(G)-nitro-l-arginine methyl ester and indomethacin, respectively, show that the three cardiac effects of Pol-A(1) were mediated by NO and PG, whereas for Pol-A(2A) and Pol-A(3) the mediator was mainly NO but not PG. These results suggest that if Pol-A(x) activated the corresponding endothelial A(x)-receptor subtype, a different mediator would be produced.
Rubio
Rafael
R
Departamento de Fisiologia, Faculdad de Medicina de la Universidad Autonoma de San Luis Potosi, Mexico. rrubio@deimos.tc.uaslp.mx
Ceballos
Guillermo
G
D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010477:Perfusion; D010627:Phenethylamines / Q000008:administration & dosage / Q000494:pharmacology; D011108:Polymers; D020033:Protein Isoforms / Q000378:metabolism; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D014661:Vasoconstriction; D014664:Vasodilation
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; C086112:N(6)-2-(4-aminophenyl)ethyladenosine; D010627:Phenethylamines; D011108:Polymers; D020033:Protein Isoforms; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C106045:adenosine amine congener; D000241:Adenosine; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin