Evidence for gender differences in electrophysiological properties of canine Purkinje fibres.
Women are more prone to develop torsades de pointes, a rare life-threatening polymorphic ventricular tachycardia, than are men during administration of medicines that have the potential to block I(Kr) (rapid delayed rectifier cardiac K(+) current) and to prolong the QT interval. Blockade of I(Kr), hypokalaemia and extreme bradycardia were used to evaluate whether there are gender differences in cardiac repolarisation in canine Purkinje fibres (PFs). Microelectrode techniques were employed to measure action potential (AP) parameters in PFs from adult female and male dogs. Under control conditions, fibres from female animals in normal or low K(+) conditions exhibited significantly longer AP durations at 50% (APD(50)) and 90% (APD(90)) of repolarisation as compared with APDs of fibres from male animals. Gender-related difference to rate adaptation was also present in APD(90) of fibres from female animals compared to males. At a stimulation rate of 0.2 Hz, but not at 1.0 Hz, dofetilide elicited a significantly higher increase in APD(90), incidence of early afterdepolarisations, triggered and sustained-triggered activities (TAs) in fibres from female animals compared to males in either normal or low K(+) conditions. The sustained TAs were reversed by raising the concentration of [K(+)](0) in Purkinje preparations from both male (one out of one) and female (12 out of 12) dogs. In conclusion, our data provide experimental evidence pointing to gender differences in canine AP repolarisation. PFs from female dogs can be used in safety pharmacology studies as a sensitive model for evaluating the potential proarrhythmic events in vitro of a new medicinal product.
Abi-Gerges
Najah
N
Safety Pharmacology Department, Safety Assessment U.K., AstraZeneca R&D, Alderley Park, Macclesfield, Cheshire SK10 4TG.
Small
Ben G
BG
Lawrence
Chris L
CL
Hammond
Tim G
TG
Valentin
Jean-Pierre
JP
Pollard
Chris E
CE
D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D004285:Dogs; D004594:Electrophysiology; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D010627:Phenethylamines / Q000494:pharmacology; D011690:Purkinje Fibers / Q000187:drug effects / Q000502:physiology*; D012727:Sex Characteristics; D013449:Sulfonamides / Q000494:pharmacology
D010627:Phenethylamines; D013449:Sulfonamides; C063533:dofetilide