Contractile effects of adenosine, coronary flow and perfusion pressure in murine myocardium.
There is mixed evidence adenosine receptors (ARs) may enhance myocardial contractility, although this remains contentious. We assessed inotropic actions of adenosine (50 muM) and selective AR activation with 100 nM N (6)-cyclohexyladenosine (CHA; A(1)AR agonist), 25 nM 2-[p-(2-carboxyethyl) phenethylamino]-5'-N-ethylcarboxamidoadenosine (CGS-21680; A(2A)AR agonist) and 100 nM 2-chloro-N (6)-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA; A(3)AR agonist) in mouse hearts perfused at constant pressure, constant flow, or conditions of stable flow and pressure (following maximal nitroprusside-mediated dilatation at constant flow). Adenosine and CGS-21680 significantly (although modestly) increased force in constant-pressure perfused hearts (</=10 mmHg elevations in systolic pressure), effects paralleled by coronary vasodilatation (</=10 ml min(-1) g(-1) elevations in flow). Neither CHA nor Cl-IB-MECA altered force or flow. With constant-flow perfusion, adenosine and CGS-21680 reduced systolic pressure in parallel with perfusion pressure. When changes in coronary flow and pressure were prevented, CGS-21680 failed to alter contractility. However, adenosine still enhanced systolic pressure up to 10 mmHg. Relations between flow, perfusion pressure and ventricular force evidence substantial Gregg effects in murine myocardium: systolic force increases transiently by approximately 1 mmHg ml(-1) min(-1) g(-1) rise in flow during the first minutes of hyperaemia and in a sustained manner (by approximately 1 mmHg mmHg(-1)) during altered perfusion pressure. These effects contribute to inotropism with AR agonism when flow/pressure is uncontrolled. In summary, we find no evidence of direct A(1) or A(3)AR-mediated inotropic responses in intact myocardium. Inotropic actions of A(2A)AR agonism appear entirely Gregg-related. Nonetheless, the endogenous agonist adenosine exerts a modest inotropic action independently of flow and perfusion pressure. The basis of this response remains to be identified.
Willems
Laura
L
Heart Foundation Research Centre, School of Medical Science, Griffith University, Southport, Queensland, 4217, Australia.
Headrick
John P
JP
D000241:Adenosine / Q000031:analogs & derivatives / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects*; D003331:Coronary Vessels / Q000187:drug effects / Q000502:physiology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009200:Myocardial Contraction / Q000187:drug effects*; D010477:Perfusion; D010627:Phenethylamines / Q000494:pharmacology; D011312:Pressure; D058906:Purinergic P1 Receptor Agonists; D013997:Time Factors
D010627:Phenethylamines; D058906:Purinergic P1 Receptor Agonists; C061282:2-(4-(2-carboxyethyl)phenethylamino)-5'-N-ethylcarboxamidoadenosine; C027513:N(6)-cyclohexyladenosine; D000241:Adenosine; C090034:2-chloro-N(6)-(3-iodobenzyl)adenosine-5'-N-methyluronamide