title: Contractile effects of adenosine, coronary flow and perfusion pressure in murine myocardium.
abstract: 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.
authors.affiliation: Heart Foundation Research Centre, School of Medical Science, Griffith University, Southport, Queensland, 4217, Australia.
authors.forename: Laura
authors.initials: L
authors.lastname: Willems
authors.forename: John P
authors.initials: JP
authors.lastname: Headrick
mesh_terms: 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
chemical_list: 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