Effects of ATP-sensitive K+ channel openers on pacemaker activity in isolated single rabbit sino-atrial node cells

Electrophysiologic effects of ATP-sensitive K+ channel openers (cromakalim, pinacidil, and nicorandil) in single rabbit sino-atrial (SA) node cells were examined by a whole-cell voltage- and current-clamp technique. Cromakalim (> 30 microM), pinacidil (> 1 microM), and nicorandil (> 500 microM) caused a negative chronotropic effect. At low concentrations, the maximum diastolic potential was hyperpolarized and the maximum rate of depolarization was enhanced, but at high concentrations, both were reversed and action potential amplitude (APA) was decreased significantly. Pinacidil (> 30 microM) and nicorandil (> 3 microM) prolonged AP duration (APD), but cromakalim did not affect it. In whole-cell voltage-clamp experiments, cromakalim (100 microM), pinacidil (> 30 microM), and nicorandil (> 300 microM) inhibited the Ca2+ current significantly but had little or no effect on the delayed rectifying K+ current and the hyperpolarization-activated inward current. Glibenclamide (1 microM) did not antagonize the effects of K+ channel openers on Ca2+ current and APs. These results indicate that the K+ channel openers have direct inhibitory actions on spontaneous APs and Ca2+ current in rabbit SA node cells (but K+ current was unaffected), resulting in decreased pacemaker activity.