Pharmacological characterization of the heartbeat in an extant vertebrate ancestor, the Pacific hagfish, Eptatretus stoutii

Pharmacological ion-channel blockers were used to investigate the spontaneous heart rates in Pacific hagfish, Eptatretus stoutii. Zatebradine, a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker, vastly reduced atrial and ventricular contraction rates in a similar concentration-dependent manner, indicating a major role for HCN in setting intrinsic heart rate. When voltage-gated Na+ channels were blocked with tetrodotoxin (TTX), atrial contraction rate declined in a dose-dependent manner, but remained faster than ventricular rate even at very high TTX concentrations. This TTX resistance compared with other fish suggests an important role for a TTX-sensitive inactivation-resistant Na+ current in atrioventricular conduction and chamber synchrony, and a lesser role in setting intrinsic heart rate. T and L-type calcium channel blockers, nickel and nifedipine respectively, also reduced atrial and ventricular contraction rates, nickel having a larger effect on the atrium. These novel results for hagfish are consistent with intrinsic atrial and ventricular rates being set mostly by HCN, with lesser contributions from other ion channels. We suggest that future electrophysiological studies will reveal that hagfishes, with their ancestral position in the evolution of the vertebrate-type chambered heart, share some but not all features of vertebrate intrinsic heart rate control.