title: Chronotropic and vasodilatory responses to adenosine and isoproterenol in mouse heart: effects of adenosine A1 receptor overexpression.
abstract: 1. Chronotropic and vasodilatory effects of adenosine receptor activation with 2-chloroadenosine (2-ClAdo) and beta-adrenoceptor activation with isoproterenol were studied in wild-type murine hearts and transgenic hearts overexpressing the A1 adenosine receptor. 2. Treatment of wild-type hearts with 2-ClAdo induced bradycardia (pEC50 6.4+/-0.2) and vasodilatation (pEC50 7.9+/-0.1; minimal resistance 2.2+/-0.2 mmHg/mL per min per g). The A1 receptor-mediated bradycardia was 20-fold more sensitive in transgenic hearts (pEC50 7.7+/-0.2), whereas coronary vasoactivity of 2-ClAdo was unaltered (pEC50 7.6+/-0.1). 3. beta-Adrenoceptor stimulation with isoproterenol increased heart rate (pEC50 8.5+/-0.2; maximal rate 594+/-23 b.p.m.) and produced vasodilation (pEC50 8.7+/-0.1; minimal resistance 1.7 +/-0.2 mmHg/ml, per min per g) in wild-type hearts. Treatment with 10 IU/mL adenosine deaminase increased the magnitude of the tachycardia (maximal rate 653+/-27 b.p.m.) without altering potency (pEC50 8.5+/-0.1). Antagonism of A1 receptors with 10nmol/L 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) produced a comparable increase in the magnitude of the chronotropic response (maximal rate 695+/-26b.p.m.) without altering potency (pEC50 8.3+/-0.1). 4. Isoproterenol-mediated vasodilatation was unaltered by transgenic A1 receptor overexpression. Overexpression of A1 receptors significantly reduced the maximal heart rate during beta-adrenoceptor stimulation by 35% (to 381 +/-28 b.p.m.) without altering potency (pEC50 8.4+/-0.2). At 10nmol/L, DPCPX increased the magnitude of the chronotropic response to isoproterenol in transgenic hearts (maximal heart rate 484+/-36 b.p.m.) without altering potency (pECs50 8.3+/-0.2). 5. The data show that transgenic A1 receptor overexpression selectively sensitizes the cardiovascular A1 receptor response and that A1 receptor activation by endogenous adenosine depresses the magnitude, but not potency, of the beta-adrenoceptor-mediated chronotropic response in mouse heart. The A1 receptor-mediated depression of beta-adrenoceptor responsiveness is non-competitive (reduced response magnitude with no change in sensitivity). This indicates that A1 receptor activation non-competitively inhibits effector mechanisms activated by beta-adrenoceptors (e.g. adenylate cyclase) and/or A1 receptors activate unrelated but opposing mechanisms. This inhibitory response may have physiological importance during periods of sympathetic stimulation of cardiac work.
authors.affiliation: Rotary Centre for Cardiovascular Research, Griffith University, Southport, Queensland, Australia. j.headrick@gu.edu.au
authors.forename: J P
authors.initials: JP
authors.lastname: Headrick
authors.forename: N S
authors.initials: NS
authors.lastname: Gauthier
authors.forename: R R
authors.initials: RR
authors.lastname: Morrison
authors.forename: G P
authors.initials: GP
authors.lastname: Matherne
mesh_terms: D015762:2-Chloroadenosine / Q000494:pharmacology; D000241:Adenosine / Q000494:pharmacology*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000465:Algorithms; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects; D018047:Receptors, Purinergic P1 / Q000096:biosynthesis* / Q000235:genetics; D014655:Vascular Resistance / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D000318:Adrenergic beta-Agonists; D018047:Receptors, Purinergic P1; D014665:Vasodilator Agents; D015762:2-Chloroadenosine; D000241:Adenosine; D007545:Isoproterenol