Ionic mechanisms underlying the positive chronotropy induced by β1-adrenergic stimulation in guinea pig sinoatrial node cells:: a simulation study

Positive chronotropy induced by beta 1-adrenergic stimulation is achieved by multiple interactions of ion channels and transporters in sinoatrial node pacemaker cells (SANs). To investigate the ionic mechanisms, we updated our SAN model developed in 2003 and incorporated the beta 1-adrenergic signaling cascade developed by Kuzumoto et al. (2007). Since the slow component of the delayed rectifier K+ current (I-Ks) is one of the major targets of the beta 1-adrenergic cascade, we developed a guinea pig model with a large I-Ks. The new model provided a good representation of the experimental characteristics of SANs. A comparison of individual current during diastole recorded before and after beta 1-adrenergic stimulation clearly showed the negative shift of the L-type Ca2+ current (I-CaL) takeoff potential, enlargement of the sustained inward current (I-st), and the hyperpolarization-activated nonselective cation current (I-ha) played major roles in increasing the firing frequency. Deactivation of I-Ks during diastole scarcely contributed to the time-dependent decrease in membrane K+ conductance, which was the major mechanism for slow diastolic depolarization, as indicated by calculating the instantaneous equilibrium potential (lead potential). This was because the activation of I-Ks during the preceding action potential was negligibly small. However, I-Ks was important in counterbalancing the increase in I-CaL and the Na+/Ca2+ exchange current (I-NaCa), which otherwise compromised the positive chronotropic effect by elongating the action potential duration. Enhanced Ca2+ release from the sarcoplasmic reticulum failed to induce an obvious chronotropic effect in our model.