Sex differences in the modulation of K+ currents in diabetic rat cardiac myocytes

A transient (Ipeak) and a sustained (Isus) outward K+ current were measured, using whole-cell voltage-clamp methods, in isolated rat ventricular myocytes obtained by enzymatic dispersion. A comparison was made between male and female rats following induction of (insulin-deficient) diabetes with streptozotocin (STZ). In control (non-diabetic) rats, both currents were smaller in cells obtained from females, as compared to males (P<0.005). However, whereas inducing diabetes in male rats significantly attenuated both Ipeak and Isus (P<0.005), Ipeak was unchanged in female diabetic rats. Isus was significantly (P<0.005) reduced, but the extent of reduction was smaller (P<0.02) than in males. The formation of angiotensin II (ATII) or endothelin-1 (ET-1) was blocked using inhibitors of angiotensin-converting enzyme (ACE) and endothelin-converting enzyme (ECE), respectively. In cells from diabetic males both inhibitors significantly (P<0.005) enhanced K+ currents. In contrast, no effect was observed in cells from female diabetic rats. However, in ovariectomized (Ovx) diabetic females the in vitro inhibition of ATII and ET-1 formation augmented the two K+ currents, but not when oestradiol was administered in vivo prior to cell isolation. In cells from diabetic males, incubation with 100 nM 17beta-oestradiol significantly (P<0.005) enhanced both Ipeak and Isus. This effect was blocked if ATII or ET-1 was added to the medium. These results show that autocrine modulation of K+ currents by renin-angiotensin and endothelin systems is attenuated or absent in female diabetic rats. Oestradiol plays a key role in reducing this modulation. These results may underlie some of the sex differences associated with development of cardiac arrhythmias.