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1 Department of Cardiology, King's College London, SE5 9PJ, UK2 University of Illinois at Chicago, IL, USA
PKA-dependent phosphorylation of cardiac troponin I (cTnI) contributes significantly to ß-adrenergic agonist-induced acceleration of myocardial relaxation (lusitropy). However, the role of PKA-dependent cTnI phosphorylation in the positive inotropic response to ß-adrenergic stimulation is unclear. We studied the contractile response to isoprenaline (10 nM) in isolated hearts and isolated cardiomyocytes from transgenic mice with cardiac-specific expression of slow skeletal TnI (ssTnI, which lacks the N-terminal protein extension containing PKA-sensitive phosphorylation sites in cTnI) and matched wild-type littermate controls. As expected, the lusitropic effect of isoprenaline was significantly blunted in ssTnI hearts. However, the positive inotropic response to isoprenaline was also blunted in ssTnI hearts. This effect was especially prominent for ejection-phase indices in isolated auxotonically loaded ssTnI hearts whereas the positive inotropic response of isovolumic hearts or unloaded isolated myocytes was much less affected. Isoprenaline decreased left ventricular end-systolic volume in wild-type hearts (10.6 ± 1.6 to 6.2 ± 0.4 µl at a preload of 20 cmH2O; P < 0.05) but not transgenic hearts (11.4 ± 1.3 to 10.9 ± 1.3 µl; P= n.s.). Likewise, isoprenaline increased stroke work in control hearts (14.5 ± 1.0 to 22.5 ± 1.8 mmHg µl mg–1; P < 0.05) but not transgenic hearts (15.4 ± 1.3 to 18.3 ± 1.2 mmHg µl mg–1; P= n.s.). The end-systolic pressure–volume relation was increased by isoprenaline to a greater extent in control than transgenic hearts. However, isoprenaline induced a similar rise in intracellular Ca2+ transients in transgenic and non-transgenic cardiomyocytes. These results indicate that cTnI has a pivotal role in the positive inotropic response of the murine heart to ß-adrenergic stimulation, an effect that is highly dependent on loading conditions and is most evident in the auxotonically loaded ejecting heart.
(Received 14 January 2004;
accepted after revision 10 February 2004;
first published online 13 February 2004)
Corresponding author A. M. Shah: Department of Cardiology, GKT School of Medicine, Bessemer Road, London SE5 9PJ, UK. Email: ajay.shah{at}kcl.ac.uk
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