ZD7288 and mibefradil inhibit the myogenic heartbeat in Daphnia magna indicating its dependency on HCN and T-type calcium ion channels

Comp Biochem Physiol A Mol Integr Physiol. 2018 Aug:222:36-42. doi: 10.1016/j.cbpa.2018.04.009. Epub 2018 Apr 21.

Abstract

Daphnia magna heartbeat is myogenic-originating within the animal's heart. However, the mechanism for this myogenic automaticity is unknown. The mechanism underlying the automaticity of vertebrate myogenic hearts involves cells (pacemaker cells), which have a distinct set of ion channels that include hyperpolarization activated cyclic nucleotide-gated (HCN) and T-type calcium ion channels. We hypothesized that these ion channels also underlie the automatic myogenic heartbeat of Daphnia magna. The drugs, ZD7288 and mibefradil dihydrochloride, block HCN and T-type calcium ion channels respectively. Application of these drugs, in separate experiments, show that they inhibit the heartbeat of Daphnia magna in a dose-dependent manner. Calculation of the percent difference between the heart rate of pretreatment (before drug application) and heart rate following drug application (post-treatment) allowed us to graph a dose-response curve for both ZD7288 and mibefradil, revealing that ZD7288 produces a greater effect on decreasing heart rate. This indicates the HCN ion channels play a foremost role in generating Daphnia magna heartbeat. Our results show conclusively that HCN and T-type calcium ion channels underlie the automatic myogenic heartbeat in Daphnia magna-and suggest a conserved mechanism for generating myogenic heartbeat within the animal kingdom. Thus, Daphnia magna represents a credible model system for further exploration of cardiac physiology.

Keywords: Daphnia magna; HCN channel; Heart; Mibefradil; Myogenic; T-type Ca(2+) channel; ZD7288.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Channel Blockers / administration & dosage
  • Calcium Channel Blockers / pharmacology*
  • Calcium Channels, T-Type / drug effects*
  • Cardiotonic Agents / administration & dosage
  • Cardiotonic Agents / pharmacology*
  • Cyclic Nucleotide-Gated Cation Channels / drug effects*
  • Daphnia / physiology*
  • Dose-Response Relationship, Drug
  • Heart Rate / drug effects*
  • Mibefradil / administration & dosage
  • Mibefradil / pharmacology*
  • Pyrimidines / administration & dosage
  • Pyrimidines / pharmacology*

Substances

  • Calcium Channel Blockers
  • Calcium Channels, T-Type
  • Cardiotonic Agents
  • Cyclic Nucleotide-Gated Cation Channels
  • Pyrimidines
  • ICI D2788
  • Mibefradil