Evidence for gender differences in electrophysiological properties of canine Purkinje fibres

Abstract

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.

Figure 1

Effect of stimulation rate on APD₉₀. (a) and (b) show representative APs recorded in fibres from male (M) and female (F) animals in either normal or low K⁺ conditions and stimulated at a stimulation rate of 1.0 or 0.2 Hz. (c) The mean % change in APD₉₀ following a change in stimulation rate from 1.0 to 0.2 Hz in both M and F animals (10 dogs were used in each gender to obtain n=13 in F and 14 in M animals). ^*P<0.01 versus values in M animals. ^NSP>0.05 versus values in low K⁺ conditions.

Figure 2

Effect of dofetilide (an I_Kr blocker) on APD₉₀ in canine PFs at a stimulation rate of 1.0 Hz. (a) and (b) show representative APs recorded in fibres from male (M) and female (F) animals in either normal or low K⁺ conditions in the presence and the absence of dofetilide (3 μM). (c) The mean % change in APD₉₀ induced by dofetilide with a stimulation rate of 1.0 Hz in both M and F animals (10 dogs were used in each gender to obtain n=13 in F and 14 in M animals). ^NSP>0.05 versus values in M animals. ^*P>0.05 and ^†P<0.01 versus values in M and F animals in normal K⁺ condition, respectively.

Figure 3

Mean % change in APD₉₀ induced by dofetilide in canine PFs. A stimulation rate of 0.2 Hz was used in both male (M) and female (F) animals (10 dogs were used in each gender to obtain n=13 in F and 14 in M animals). ^*P<0.05 versus values in M animals. ^†P<0.05 and ^$P<0.01 versus values in F and M animals in normal K⁺ conditions, respectively.

Figure 4

EAD activity in canine PFs following I_Kr block at a stimulation rate of 0.2 Hz. (a) and (b) show representative APs recorded in fibres from male (M) and female (F) animals in either normal or low K⁺ conditions in the presence and the absence of dofetilide (3 μM). (c) The mean EAD activity in fibres from both M and F animals after exposure to dofetilide (3 μM) at a stimulation rate of 0.2 Hz (see also Table 2).

Figure 5

STA in canine PFs. (a) Shows a representative STA recorded in a fibre from a female (F) animal in the presence of dofetilide (3 μM) with low K⁺ solution and stimulated at a stimulation rate of 0.2 Hz. (b) Reversal of STA and repolarisation of AP when the same fibre as in (a) was incubated with dofetilide (3 μM) prepared in normal K⁺ solution.