Chronotropic and vasodilatory responses to adenosine and B-adrenoceptor activation in mouse hear: effects of adenosine A1 receptor overexpression

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Title Chronotropic and vasodilatory responses to adenosine and B-adrenoceptor activation in mouse hear: effects of adenosine A1 receptor overexpression
Author Headrick, John Patrick; Gauthier, NS; Morrison, RR; Matherne, GP
Journal Name Clinical and Experimental Pharmacology & Physiology
Year Published 2000
Place of publication Australia
Publisher Blackwell Publishing
Abstract 1. Chronotropic and vasodilatory effects of adenosine receptor activation with 2-chloroadenosine (2-ClAdo) and ²-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. ²-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 10 nmol/L 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) produced a comparable increase in the magnitude of the chronotropic response (maximal rate 695±26 b.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 ²-adrenoceptor stimulation by 35% (to 381±28 b.p.m.) without altering potency (pEC50 8.4±0.2). At 10 nmol/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 (pEC50 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 ²-adrenoceptor-mediated chronotropic response in mouse heart. The A1 receptor-mediated depression of ²-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 ²-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.
Peer Reviewed Yes
Published Yes
Publisher URI http://www.blackwell-synergy.com/doi/full/10.1046/j.1440-1681.2000.03218.x
Alternative URI http://www.blackwell-synergy.com/links/doi/10.1046%2Fj.1440-1681.2000.03218.x
Copyright Statement Copyright 2000 Blackwell Publishing. The definitive version is available at [www.blackwell-synergy.com.]
Volume 27
Page from 185
Page to 190
ISSN 0305-1870
Date Accessioned 2001-01-01
Date Available 2007-03-13T21:46:08Z
Language en_AU
Research Centre Griffith Health Institute; Heart Foundation Research Centre
Subject Medical & Health Sciences
URI http://hdl.handle.net/10072/3472
Publication Type Article in Scholarly Refereed Journal
Publication Type Code c1

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