Figure 3. β-adrenergic stimulation induces a long QT phenotype in Calm1N98S/+ mice.
A, Left panels: superimpositions of representative action potentials electrically recorded from single myocytes isolated from the left ventricular free wall of a Calm1+/+ (blue) and a Calm1N98S/+ (red) heart. Cells were paced at 1 and 7 Hz. Right panels: single action potentials at 1 and 7 Hz pacing at expanded time scales. B, Dot plots of APD30, APD50 and APD90 in single ventricular myocytes paced at 1 and 7 Hz. Black lines denote mean ± SEM; 11 cells each from 3 Calm1+/+ mice and from 4 Calm1N98S/+ mice. * P = 0.004 vs. Calm1N98S/+ 1 Hz by paired t-test. C, Superimpositions of representative action potentials recorded from a Calm1+/+ and a Calm1N98S/+ ventricular myocyte at baseline, during isoproterenol (50 nM; Iso) treatment, and during washout. Action potentials were evoked by 2-ms square current injections delivered at 1 Hz. D, Summary of the effect of isoproterenol (Iso) on APD90 in Calm1+/+ and Calm1N98S/+ ventricular myocytes; 14 cells from 5 Calm1+/+ mice and 10 cells from 4 Calm1N98S/+ mice. * P < 0.01 by Repeated Measures ANOVA followed by Tukey test for pairwise multiple comparisons. Numbers denote mean ± SEM in ms. Base: baseline. E, Original recordings of a delayed afterdepolarization (*) and delayed afterdepolarization-triggered action potentials (arrows) in a Calm1+/+ and a Calm1N98S/+ ventricular cardiomyocyte, respectively. Traces show the terminal 6 paced action potentials from a 10-s train at 7 Hz in the presence of 50 nM isoproterenol. F, Summary of the effects of propranolol (1 mg/kg) or isoproterenol (0.17 mg/kg) on heart rate. Horizontal black lines denote mean ± SEM. Propranolol (Prop): N = 8, Calm1+/+ mice; N = 14, Calm1N98S/+ mice. Isoproterenol (Iso): N = 7, Calm1+/+; N = 7, Calm1N98S/+. P values by unpaired and paired t-test. Base: baseline. G, Representative QT interval changes in conscious male Calm1+/+ and Calm1N98S/+ mice following intraperitoneal injection of propranolol (1 mg/kg) or isoproterenol (0.17 mg/kg). Shown are signal-averaged ECGs obtained by overlaying all consecutive cycles recorded within a 5- to 10-s interval, ca. 20 min after injection. Arrows mark QT intervals. H, Summary of the effects of propranolol and isoproterenol on QTc interval. Horizontal black lines denote mean ± SEM. Propanolol (Prop): N = 8, Calm1+/+ mice; N = 14, Calm1N98S/+ mice. Isoproterenol (Iso): N = 7, Calm1+/+; N = 7, Calm1N98S/+. P values by unpaired and paired t-test. Base: baseline.