Vol. 291, Issue 1, 140-146, October 1999

Activation of Ca²⁺-Dependent K⁺ Current by Nordihydroguaiaretic Acid in Porcine Coronary Arterial Smooth Muscle Cells¹

H. Yamamura, N. Nagano, M. Hirano, K. Muraki, M. Watanabe and Y. Imaizumi

Departments of Pharmacology and Therapeutics (H.Y., Y.I.) and Chemical Pharmacology (N.N., M.H., K.M., M.W.), Faculty of Pharmaceutical Sciences, Nagoya City University, Nagoya, Japan

The effects of nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor and an antioxidant, on membrane currents were examined in single smooth muscle cells isolated from porcine coronary artery. Spontaneous transient outward currents (STOCs) recorded at 30 mV were markedly enhanced by NDGA (10 µM). Pretreatment with caffeine and ryanodine abolished STOCs and reduced NDGA-induced increase in outward current at 30 mV by ~60%. NDGA showed dual action on an outward current elicited by step depolarization from 60 to 0 mV: inhibition and enhancement at concentrations of 3 and 10 µM, 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⁺ channel current (IC₅₀ = 2.5 µM) and the delayed rectifier K⁺ current (IC₅₀ = 9.8 µM). 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 µM NDGA significantly hyperpolarized myocytes. The application of lipoxygenase inhibitors (caffeic acid and esculetin), a cyclooxygenase inhibitor (indomethacin), antioxidants (ascorbic acid and erythorbic acid), and structural-related compounds of NDGA (catechol and dopamine) did not enhance K⁺ currents. These results indicate that the opening of the large conductance Ca²⁺-dependent K⁺ channel by NDGA, which is independent of its lipoxygenase inhibition or antioxidant effect, results in membrane hyperpolarization.