ALTERED ATP SENSITIVITY OF ATP-DEPENDENT K+ CHANNELS IN DIABETIC RAT HEARTS

The effects of streptozotocin-induced diabetes (5-7 days or 7 wk) on c ardiac ATP-sensitive potassium channels (K-ATP channels) were investig ated with the use of single-channel and action potential recordings fr om dissociated ventricular myocytes isolated from control and diabetic rat hearts. In inside-out patches from diabetic myocytes (5-7 days), the IC50 for ATP inhibition was 82 +/- 1.2 mu M (mean +/- SE, n = 8), twice that in controls (43 +/- 3.6 mu M, n = 12). For 7-wk diabetic ra ts, the IC50 was 75 +/- 2.3 mu M (n = 6). Increasing internal ADP conc entration attenuated ATP-induced inhibition in both controls and diabe tics. On reducing the internal pH from 7.4 to 6.8, both control and di abetic myocytes showed a 1.7-fold increase in the IC50 for ATP inhibit ion. No differences were observed in either intraburst kinetics or uni tary conductance of single channels from control and diabetic myocytes . In diabetic myocytes, action potential duration at 90% repolarizatio n (APD(90)) was longer and more variable than in controls and was sign ificantly shortened by application of the K-ATP channel opener cromaka lim (50 mu M). Cromakalim scarcely affected APD(90) in controls. Compu ter simulation of the longer diabetic APD(90) required a lower backgro und conductance during the plateau phase in addition to small, measure d changes in the delayed rectifier current, transient outward current, and ATP-sensitive K+ current (K-ATP current, I-KATP) The simulations reproduced the enhanced sensitivity of the diabetic APD(90) to changes in I-KATP These results have important implications for cardiac funct ion in diabetics and their treatment by sulfonylureas.