Effects of isoproterenol on twitch contraction of wild type and phospholamban-deficient murine ventricular myocardium

Ablation of the gene for phospholamban (PLB), a transmembrane peptide regul ator for the cardiac sarcoplasmic reticulum Ca2+ pump, in mice brings about a complete loss of the myocardial responses to beta-adrenergic agonists (e .g., Luo el al., Circ. Res, 1994; 75: 401), We have evaluated the functiona l significance of PLB-independent mechanisms in the myocardial responses to beta-adrenergic stimulation in isolated intact ventricular myocardium. We compared the effects of (-)-isoproterenol (ISO) on isometric twitch contrac tion of paced right ventricular muscle strips of wild type (WT) and PLB-def icient (PLBKO) mice. At 37 degrees C. frequent spontaneous contractions in both types of muscles required the inclusion of lidocaine, an antiarrhythmi c, in the bathing medium. Thus the experiments were also performed at two l ower temperatures, 30 degrees C and 25 degrees C, at which lidocaine was no t needed. Under three conditions, in the absence of ISO, PLBKO ventricular muscles exhibited substantially shortened time to peak tension (TPT) and ha lf relaxation time (TR1/2), compared with the WT muscles. In both WT and PL BKO muscles ISO increased the peak developed tension and decreased TPT and TR1/2 in a dose-dependent manner although the effects were generally smalle r in PLBKO than in WT muscles. One micromolar ISO caused TPT and TR1/2 to d ecrease 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 degrees C; by 13.5+/-0.4% and 14.1+/-1.2% in PL BKO vs. 31.3+/-0.8%, and 44.8+/-1.3% in WT at 30 degrees 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 degree s C, These findings strongly suggest that PLB-independent mechanisms play a significant role in mediating the positive inotropic and luistropic effect s of beta-adrenergic agonists on ventricular myocardium (C) 1999 Academic P ress.