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Overexpression of β 1 ‐adrenoceptors in adult rat ventricular myocytes enhances CGP 12177A cardiostimulation: implications for ‘putative’ β 4 ‐adrenoceptor pharmacology
Author(s) -
Lewis Clive J,
Gong Haibin,
Brown Morris J,
Harding Sian E
Publication year - 2004
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705668
Subject(s) - isoprenaline , propranolol , agonist , endocrinology , ibmx , potency , medicine , lusitropy , chemistry , inotrope , myocyte , antagonist , intrinsic activity , pharmacology , biology , receptor , stimulation , in vitro , biochemistry , forskolin , blood pressure , diastole
CGP 12177A mediates cardiostimulation by activation of the ‘putative’ β 4 ‐adrenoceptor; however, it has recently been reported that disruption of the β 1 ‐adrenoceptor gene abolishes this effect. We have adenovirally overexpressed β 1 ‐adrenoceptors in isolated, cultured adult rat ventricular cardiomyocytes and observed the inotropic potency of isoprenaline and CGP 12177A (in the presence of 1 μ M propranolol). Isoprenaline was a full inotropic agonist at rat ventricular myocytes (p D 2 7.69±0.12). CGP 12177A was a nonconventional partial agonist (p D 2 6.34±0.09), increasing inotropy and lusitropy, with an intrinsic activity of 0.34 and antagonised by bupranolol.β 1 ‐adrenoceptor overexpression enhanced the inotropic potency of isoprenaline by 11.7‐fold (p D 2 8.76±0.14) and CGP 12177A by 5.9‐fold (7.11±0.10), respectively. Green fluorescent protein (GFP) overexpression did not alter the potency of isoprenaline or CGP 12177A (p D 2 7.41±0.24 and p D 2 6.60±0.50, respectively). The cardiostimulant effects of CGP 12177A were enhanced by IBMX (phosphodiesterase inhibitor) and decreased by Rp‐cAMPS (cAMP antagonist). CGP 12177A also increased cAMP levels. CGP 12177A but not isoprenaline initiated arrhythmias at lower concentrations following β 1 ‐adrenoceptor overexpression.125 I‐Cyanopindolol saturation binding in Adv. β 1 myocytes demonstrated ∼18‐fold increase in β 1 ‐adrenoceptors. 3 H‐CGP 12177A saturation binding, in the presence of propranolol, increased ∼5‐fold following overexpression of β 1 ‐adrenoceptors. This study demonstrates enhanced cardiostimulation by CGP 12177A (in the presence of propranolol) in rat ventricular myocytes overexpressing β 1 ‐adrenoceptors, mediated by a Gs/cAMP signalling pathway. ‘Putative’ β 4 ‐adrenoceptor pharmacology appears to be mediated by activation of a novel affinity state of the β 1 ‐adrenoceptor.British Journal of Pharmacology (2004) 141 , 813–824. doi: 10.1038/sj.bjp.0705668