Ablation of the gene for phospholamban (PLB), a transmembrane peptide regulator for the cardiac sarcoplasmic reticulum Ca2+ pump, in mice brings about a complete loss of the myocardial responses to β-adrenergic agonists. We have evaluated the functional significance of PLB-independent mechanisms in the myocardial responses to β-adrenergic stimulation in isolated intact ventricular myocardium. We compared the effects of (-)-isoproterenol (ISO) on isometric twitch contraction of paced right ventricular muscle strips of wild type (WT) and PLB-deficient (PLBKO) mice. At 37°C, frequent spontaneous contractions in both types of muscles required the inclusion of lidocaine, an antiarrhythmic, in the bathing medium. Thus the experiments were also performed at two lower temperatures, 30°C and 25°C, at which lidocaine was not needed. Under three conditions, in the absence of ISO, PLBKO ventricular muscles exhibited substantially shortened time to peak tension (TPT) and half relaxation time (TR(1/2)), compared with the WT muscles. In both WT and PLBKO muscles ISO increased the peak developed tension and decreased TPT and TR(1/2) in a dose-dependent manner although the effects were generally smaller in PLBKO than in WT muscles. One micromolar ISO caused TPT and TR(1/2) to decrease by 7.3 ± 1.2% (mean ± SEM) and 7.5 ± 1.2% in PLBKO vs. 22.8 ± 0.7% and 29.1 ± 1.7% in WT at 37°C; by 13.5 ± 0.4% and 14.1 ± 1.2% in PLBKO vs. 31.3 ± 0.8% and 44.8 ± 1.3% in WT at 30°C; by 15.0 ± 2.3% and 21.1 ± 4.9% in PLBKO vs. 25.8 ± 1.9% and 54.0 ± 1.9% in WT at 25°C. These findings strongly suggest that PLB-independent mechanisms play a significant role in mediating the positive inotropic and lusitropic effects of β-adrenergic agonists on ventricular myocardium.
- Excitation-contraction coupling
- Sarcoplasmic reticulum
ASJC Scopus subject areas
- Molecular Biology
- Cardiology and Cardiovascular Medicine