ABSTRACT
There are gender differences in the electrocardiographic parameters and in the prevalence of arrhythmias. Women have faster heart rale, longer QT interval, shorter PR interval and shorter atrioventricular node [AVN] effective refractory period as compared to men. These changes may be due to gender differences in ion channel expression and thereby in currents responsible for the electrophysiological function of the AVN, Gender differences in the electrophysiological function in the AVN have been investigated using extracellular potential recording from isolated spontaneously beating A VN preparations from adult male and female New Zealand White rabbits under control conditions and after the application of ion channel b lockers. Cycle length of isolated A VN preparations was significantly longer in adult female as compared to adult male. 2 mMCs, an Ifblocker, significantly increased the cycle length of adult male [i.e. slowed the spontaneous activity of the AVN; by 120%] and tended to increase the cycle length in adult female by 28%. Hundred nM TTX, a b locker of TTX sensitive neuronal l[na] tended to increase the cycle length of both adult male and female. In conclusion, If and TTX-sensitive currents may be partly responsible for the difference in AVN cycle length and thereby in the AVN rate/ pacemaking between adult male and female
Subject(s)
Male , Female , Animals, Laboratory , Electrophysiology , Sex Differentiation , RabbitsABSTRACT
The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels modulate and regulate cardiac rhythm and rate. It has been suggested that, unlike the HCN1 and HCN2 channels, the slower HCN4 channel may not exhibit voltage-dependent hysteresis. We studied the electrophysiological properties of human HCN4 (hHCN4) channels and its modulation by cAMP to determine whether hHCN4 exhibits hysteresis, by using single-cell patch-clamp in HEK293 cells stably transfected with hHCN4. Quantitative real-time RT-PCR was also used to determine levels of expression of HCNs in human cardiac tissue. Voltage-clamp analysis revealed that hHCN4 current (I(h)) activation shifted in the depolarizing direction with more hyperpolarized holding potentials. Triangular ramp and action potential clamp protocols also revealed hHCN4 hysteresis. cAMP enhanced I(h) and shifted activation in the depolarizing direction, thus modifying the intrinsic hHCN4 hysteresis behavior. Quantitative PCR analysis of human sinoatrial node (SAN) tissue showed that HCN4 accounts for 75% of the HCNs in human SAN while HCN1 (21%), HCN2 (3%), and HCN3 (0.7%) constitute the remainder. Our data suggest that HCN4 is the predominant HCN subtype in the human SAN and that I(h) exhibits voltage-dependent hysteresis behavior that can be modified by cAMP. Therefore, hHCN4 hysteresis potentially plays a crucial role in human SAN pacemaking activity.