Figure 3. Downregulation of I_f in the sinus node can explain the training-induced resting bradycardia.

(a) Density of I_f is reduced in trained mice. Top, representative I_f traces, normalized to cell capacitance, during steps to -55 to -135 mV (20 mV increments; holding potential −35 mV) from single sinus node cells isolated from sedentary (left) and trained (right) mice. Bottom, mean (±s.e.m.) I_f IV curves recorded at steady state from sedentary (filled circles; n=17/5 cells per mice) and trained (open circles; n=18/5) mice. Student’s t-test used to test differences between sedentary and trained mice; *P<0.05. (b) Whole-cell conductance of I_f is reduced in trained mice. Top, sample current traces recorded with the protocol used to measure the fully activated IV relationship of I_f from single sinus node cells isolated from sedentary (left) and trained (right) mice. Conditioning activating/deactivating voltages were −125 and −35 mV, and pairs of steps to the same test voltage were applied in sequence from these two levels; records shown for test voltages of −100, −40 and 0 mV. Bottom, mean (±s.e.m.) fully activated I/V relationship, normalized to cell capacitance, from sedentary (filled circles; n=9/5 cells per mice) and trained (open circles; n=11/5) mice. Linear fit of data (straight lines) yielded conductances of 653 and 356 pS/pF and reversal potentials of -26.3 and -27.3 mV for sedentary and trained mice. The two curves are statistically different (F-test; P<0.05). (c,d), Spontaneous rate of isolated rat (c; n=7) and mouse (d; n=6/7) sinus node preparations from sedentary and trained animals before and after I_f block with Cs⁺. (e,f) Heart rate of sedentary and trained mice when conscious (e; n=9/13) and when anaesthetized and after autonomic block (f) before and after I_f block with ivabradine (n=7/14). (g–j) Decrease in heart rate (beats min⁻¹) on blocking I_f in corresponding experiment above (c–f). In c-j, means+s.e.m. shown. Student’s t-test used to test differences between sedentary and trained animals. Normal distribution of data tested using Shapiro–Wilk W-test and equal variance tested using F-test. When null hypothesis of normality and/or equal variance was rejected, non-parametric Mann–Whitney U-test used. *P<0.05.