Abstract
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.
Footnotes
-
Send reprint requests to: Dr. Yuji Imaizumi, Department of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Nagoya City University, 3-1 Tanabedori, Mizuhoku, Nagoya 467-8603, Japan. E-mail: yimaizum{at}phar.nagoya-cu.ac.jp
-
↵1 This work was supported by a grant-in-aid for Scientific Research from the Ministry of Education, Science, Sports and Culture (to Y.I.).
- Abbreviations:
- BK channel
- large conductance Ca2+-dependent K+ channel
- NDGA
- nordihydroguaiaretic acid
- IK-Ca
- Ca2+-dependent K+ current
- IKD
- delayed rectifier K+ current
- SR
- sarcoplasmic reticulum
- STOCs
- spontaneous transient outward currents
- IbTx
- iberiotoxin
- TEA
- tetraethylammonium
- DMSO
- dimethyl sulfoxide
- Received October 15, 1998.
- Accepted June 3, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|