Nitric oxide‐dependent modulation of the delayed rectifier K+ current and the L‐type Ca2+ current by ginsenoside Re, an ingredient of Panax ginseng, in guinea‐pig cardiomyocytes

• Published in: British journal of pharmacology Vol. 142; no. 3; pp. 567 - 575
• Main Authors: Bai, Chang‐Xi, Takahashi, Kentaro, Masumiya, Haruko, Sawanobori, Tohru, Furukawa, Tetsushi
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.06.2004; Nature Publishing
• Subjects: Action Potentials - drug effects; amphotericin B; Animals; Biological and medical sciences; Calcium Channels, L-Type - metabolism; cardiac; Cells, Cultured; Delayed Rectifier Potassium Channels; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; General pharmacology; ginsenoside Re; Ginsenosides - isolation & purification; Ginsenosides - pharmacology; Guinea Pigs; herb medicine; ion channel; Medical sciences; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Myocytes, Cardiac - physiology; nitric oxide; Nitric Oxide - physiology; Nitric Oxide Donors - pharmacology; nitric oxide synthase; Nitric Oxide Synthase - antagonists & inhibitors; Panax - chemistry; Panax ginseng; Patch-Clamp Techniques; patch‐clamp; Pharmacognosy. Homeopathy. Health food; Pharmacology. Drug treatments; Potassium Channels, Voltage-Gated - metabolism; potassium current; Protein Kinase Inhibitors - pharmacology; Protein Kinases - metabolism; Heart; Calcium; patch-clamp; Electrophysiology; Ionic channel; Ionic current; Inorganic element; Panax ginseng; Medicinal plant; potassium current; Guinea pig; ion channel; Dicotyledones; Angiospermae; nitric oxide synthase; Mechanism of action; Araliaceae; nitric oxide; Enzyme; Pharmacognosy; Rodentia; Cardioprotective agent; herb medicine; ginsenoside Re; amphotericin B; Nitric-oxide synthase; Vertebrata; Mammalia; Polyenic compound; Animal; Spermatophyta; Circulatory system; Oxidoreductases; Potassium; cardiac
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0705814

Ginsenoside Re, a major ingredient of Panax ginseng, protects the heart against ischemia–reperfusion injury by shortening action potential duration (APD) and thereby prohibiting influx of excessive Ca2+. Ginsenoside Re enhances the slowly activating component of the delayed rectifier K+ current (IKs) and suppresses the L‐type Ca2+ current (ICa,L), which may account for APD shortening. We used perforated configuration of patch‐clamp technique to define the mechanism of enhancement of IKs and suppression of ICa,L by ginsenoside Re in guinea‐pig ventricular myocytes. S‐Methylisothiourea (SMT, 1 μM), an inhibitor of nitric oxide (NO) synthase (NOS), and N‐acetyl‐L‐cystein (LNAC, 1 mM), an NO scavenger, inhibited IKs enhancement. Application of an NO donor, sodium nitroprusside (SNP, 1 mM), enhanced IKs with a magnitude similar to that by a maximum dose (20 μM) of ginseonside Re, and subsequent application of ginsenoside Re failed to enhance IKs. Conversely, after IKs had been enhanced by ginsenoside Re (20 μM), subsequently applied SNP failed to further enhance IKs. An inhibitor of guanylate cyclase, 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ, 10 μM), barely suppressed IKs enhancement, while a thiol‐alkylating reagent, N‐ethylmaleimide (NEM, 0.5 mM), clearly suppressed it. A reducing reagent, di‐thiothreitol (DTT, 5 mM), reversed both ginsenoside Re‐ and SNP‐induced IKs enhancement. ICa,L suppression by ginsenoside Re (3 μM) was abolished by SMT (1 μM) or LNAC (1 mM). NEM (0.5 mM) did not suppress ICa,L inhibition and DTT (5 mM) did not reverse ICa,L inhibition, whereas in the presence of ODQ (10 μM), ginsenoside Re (3 μM) failed to suppress ICa,L. These results indicate that ginsenoside Re‐induced IKs enhancement and ICa,L suppression involve NO actions. Direct S‐nitrosylation of channel protein appears to be the main mechanism for IKs enhancement, while a cGMP‐dependent pathway is responsible for ICa,L inhibition. British Journal of Pharmacology (2004) 142, 567–575. doi:10.1038/sj.bjp.0705814