title: Novel method to assess cardiac electrophysiology in the rat: characterization of standard ion channel blockers.
abstract: The rat continues to be an important tool to assess cardiac electrophysiologic (EP) effects of test agents and to study the distribution/role of ion channels in cardiovascular diseases. However, no data have been described that accurately measure discrete cardiac EP parameters in rats in vivo. Therefore, we developed a method to assess cardiac EP in rats and then profiled several ion channel agents. Briefly, rats were instrumented with endocardially placed electrodes to assess cardiac refractoriness and conduction. Administration of class I agents resulted in a dose-dependent slowing of ventricular conduction. The potassium channel blocker 4-aminopyridine caused significant increases in atrial and ventricular refractoriness. An IKr blocker had little or no effect on atrial and ventricular refractoriness but significantly increased AV nodal refractoriness. Additionally, an IKs blocker had little effect on rat cardiac EP. The L-type blocker diltiazem caused a dose-dependent delay in AV node conduction and an increase in AV node refractoriness. Overall, this study provides normative data that describe the roles of Na, Ca, and K channels in rat cardiac electrophysiology, in vivo. Furthermore, the model provides a method to assess changes in cardiac electrophysiology in the setting of disease by using well-established rat models of induced or genetic cardiovascular disease.
authors.affiliation: Department of Cardiovascular Disease, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. christopher_regan@merck.com
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Regan
authors.forename: Hillary K
authors.initials: HK
authors.lastname: Cresswell
authors.forename: Rena
authors.initials: R
authors.lastname: Zhang
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Lynch
mesh_terms: D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology; D022062:Electrophysiologic Techniques, Cardiac / Q000379:methods*; D007262:Infusions, Intravenous; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D023421:Models, Animal; D026902:Potassium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D026941:Sodium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D007473:Ion Channels; D026902:Potassium Channel Blockers; D026941:Sodium Channel Blockers