Activation of Ca2+-dependent K+ current by nordihydroguaiaretic acid in porcine coronary arterial smooth muscle cells

The effects of nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor a nd an antioxidant, on membrane currents were examined in single smooth musc le cells isolated from porcine coronary artery. Spontaneous transient outwa rd currents (STOCs) recorded at -30 mV were markedly enhanced by NDGA (grea ter than or equal to 10 mu M). Pretreatment with caffeine and ryanodine abo lished STOCs and reduced NDGA-induced increase in outward current at -30 mV by similar to 60%. NDGA showed dual action on an outward current elicited by step depolarization from -60 to 0 mV: inhibition and enhancement at conc entrations of 3 and greater than or equal to 10 mu M, respectively. In the presence of Cd2+, the inhibition of outward current by NDGA disappeared and the enhancement remained. NDGA inhibited both the voltage-dependent Ca2+ c hannel current (IC50 = 2.5 mu M) and the delayed rectifier K+ current (IC50 = 9.8 mu M). The NDGA-induced enhancement of STOCs and outward currents on depolarization was abolished by 100 nM iberiotoxin but was not affected by glibenclamide or apamin. Under current clamp mode, 30 mu M NDGA significan tly hyperpolarized myocytes. The application of lipoxygenase inhibitors (ca ffeic acid and esculetin), a cyclooxygenase inhibitor (indomethacin), antio xidants (ascorbic acid and erythorbic acid), and structural-related compoun ds of NDGA (catechol and dopamine) did not enhance K+ currents. These resul ts indicate that the opening of the large conductance Ca2+-dependent K+ cha nnel by NDGA, which is independent of its lipoxygenase inhibition or antiox idant effect, results in membrane hyperpolarization.