Article date: March 2004
By: Clive J Lewis, Haibin Gong, Morris J Brown, Sian E Harding in Volume 141, Issue 5, pages 813-824
CGP 12177A mediates cardiostimulation by activation of the ‘putative’ β4‐adrenoceptor; however, it has recently been reported that disruption of the β1‐adrenoceptor gene abolishes this effect. We have adenovirally overexpressed β1‐adrenoceptors in isolated, cultured adult rat ventricular cardiomyocytes and observed the inotropic potency of isoprenaline and CGP 12177A (in the presence of 1 μM propranolol).
Isoprenaline was a full inotropic agonist at rat ventricular myocytes (pD2 7.69±0.12). CGP 12177A was a nonconventional partial agonist (pD2 6.34±0.09), increasing inotropy and lusitropy, with an intrinsic activity of 0.34 and antagonised by bupranolol.
β1‐adrenoceptor overexpression enhanced the inotropic potency of isoprenaline by 11.7‐fold (pD2 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 (pD2 7.41±0.24 and pD2 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 β1‐adrenoceptor overexpression.
125I‐Cyanopindolol saturation binding in Adv.β1 myocytes demonstrated ∼18‐fold increase in β1‐adrenoceptors. 3H‐CGP 12177A saturation binding, in the presence of propranolol, increased ∼5‐fold following overexpression of β1‐adrenoceptors.
This study demonstrates enhanced cardiostimulation by CGP 12177A (in the presence of propranolol) in rat ventricular myocytes overexpressing β1‐adrenoceptors, mediated by a Gs/cAMP signalling pathway. ‘Putative’ β4‐adrenoceptor pharmacology appears to be mediated by activation of a novel affinity state of the β1‐adrenoceptor.
CGP 12177A mediates cardiostimulation by activation of the ‘putative’ β4‐adrenoceptor; however, it has recently been reported that disruption of the β1‐adrenoceptor gene abolishes this effect. We have adenovirally overexpressed β1‐adrenoceptors in isolated, cultured adult rat ventricular cardiomyocytes and observed the inotropic potency of isoprenaline and CGP 12177A (in the presence of 1 μM propranolol).
Isoprenaline was a full inotropic agonist at rat ventricular myocytes (pD2 7.69±0.12). CGP 12177A was a nonconventional partial agonist (pD2 6.34±0.09), increasing inotropy and lusitropy, with an intrinsic activity of 0.34 and antagonised by bupranolol.
β1‐adrenoceptor overexpression enhanced the inotropic potency of isoprenaline by 11.7‐fold (pD2 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 (pD2 7.41±0.24 and pD2 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 β1‐adrenoceptor overexpression.
125I‐Cyanopindolol saturation binding in Adv.β1 myocytes demonstrated ∼18‐fold increase in β1‐adrenoceptors. 3H‐CGP 12177A saturation binding, in the presence of propranolol, increased ∼5‐fold following overexpression of β1‐adrenoceptors.
This study demonstrates enhanced cardiostimulation by CGP 12177A (in the presence of propranolol) in rat ventricular myocytes overexpressing β1‐adrenoceptors, mediated by a Gs/cAMP signalling pathway. ‘Putative’ β4‐adrenoceptor pharmacology appears to be mediated by activation of a novel affinity state of the β1‐adrenoceptor.
British Journal of Pharmacology (2004) 141, 813–824. doi:10.1038/sj.bjp.0705668
DOI: 10.1038/sj.bjp.0705668
View this article