Rhythm Generating Mechanisms in Rat Sinoatrial Node

Background: The major membrane currents responsible for sinoatrial (SA) rhythm generation are generally studied in isolated cardiac cells using electrophysiological tools. Such studies are resource and labor-intensive. Materials and Methods: Here, we have studied four major currents in isolated rat heart preparations, perfused in Langendorff mode, and demonstrate that this is a good preparation for such studies. Heart rates of isolated perfused rat hearts were recorded using surface electrocardiogram before and after perfusion with drugs and solutions that affect the four major currents responsible for SA rhythm generation. Results: The rates of whole isolated hearts beating with SA rhythm decreased with cesium and decreased by about half with ivabradine, both blockers of the funny current (If). Importantly, the rhythm was not abolished even with a high dose of ivabradine at which total blockade of If is expected. The rate was not affected by nickel, a blocker of T-type calcium current. The SA rhythm was abolished by the reduction or removal of sodium from the perfusate (interventions that inhibit the calcium-extrusive mode of the sodium-calcium exchanger) or by nifedipine, the L-type calcium channel blocker. Discussion: The inferences made based on these observations are (a) If contributes significantly to pacemaking, (b) ICaT does not play a role and (c) INCX and ICaL are obligatory rhythm-generating currents in the SA node. Cyclical calcium release from SR during diastole (the calcium clock), responsible for driving INCX in its forward mode is probably a phenomenon independent of membrane events, as total If blockade did not abolish rhythm generation. These results corroborate with published literature where most studies were done on single cells.