Dimethyl lithospermate B, an extract of Danshen, suppresses arrhythmogenesis associated with the Brugada syndrome.
BACKGROUND
Dimethyl lithospermate B (dmLSB) is an extract of Danshen, a traditional Chinese herbal remedy, which slows inactivation of INa, leading to increased inward current during the early phases of the action potential (AP). We hypothesized that this action would be antiarrhythmic in the setting of Brugada syndrome.


RESULTS
The Brugada syndrome phenotype was created in canine arterially perfused right ventricular wedge preparations with the use of either terfenadine or verapamil to inhibit INa and ICa or pinacidil to activate IK-ATP. AP recordings were simultaneously recorded from epicardial and endocardial sites together with an ECG. Terfenadine, verapamil, and pinacidil each induced all-or-none repolarization at some epicardial sites but not others, leading to ST-segment elevation as well as an increase in both epicardial and transmural dispersions of repolarization (EDR and TDR, respectively) from 12.9+/-9.6 to 107.0+/-54.8 ms and from 22.4+/-8.1 to 82.2+/-37.4 ms, respectively (P<0.05; n=9). Under these conditions, phase 2 reentry developed as the epicardial AP dome propagated from sites where it was maintained to sites at which it was lost, generating closely coupled extrasystoles and ventricular tachycardia and fibrillation. Addition of dmLSB (10 micromol/L) to the coronary perfusate restored the epicardial AP dome, reduced EDR and TDR to 12.4+/-18.1 and 24.4+/-26.7 ms, respectively (P<0.05; n=9), and abolished phase 2 reentry-induced extrasystoles and ventricular tachycardia and fibrillation in 9 of 9 preparations.


CONCLUSIONS
Our data suggest that dmLSB is effective in eliminating the arrhythmogenic substrate responsible for the Brugada syndrome and that it deserves further study as a pharmacological adjunct to implanted cardioverter/defibrillator usage.
Masonic Medical Research Laboratory, Utica, NY 13501-1787, USA. fish@mmrl.edu
Jeffrey M
JM
Fish
Daniel R
DR
Welchons
Young-Sup
YS
Kim
Suk-Ho
SH
Lee
Won-Kyung
WK
Ho
Charles
C
Antzelevitch
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000209:etiology / Q000517:prevention & control*; D001692:Biological Transport / Q000187:drug effects; D002121:Calcium Channel Blockers / Q000633:toxicity; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D004365:Drugs, Chinese Herbal / Q000302:isolation & purification / Q000627:therapeutic use*; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D062554:NAV1.5 Voltage-Gated Sodium Channel; D020110:Pinacidil / Q000633:toxicity; D010936:Plant Extracts / Q000302:isolation & purification / Q000627:therapeutic use*; D018517:Plant Roots / Q000737:chemistry; D015221:Potassium Channels / Q000819:agonists; D027561:Salvia miltiorrhiza / Q000737:chemistry*; D012964:Sodium / Q000378:metabolism; D062687:Sodium Channel Agonists; D026941:Sodium Channel Blockers / Q000633:toxicity; D015222:Sodium Channels / Q000502:physiology; D013268:Stimulation, Chemical; D016593:Terfenadine / Q000633:toxicity; D014700:Verapamil / Q000633:toxicity
D002121:Calcium Channel Blockers; D004365:Drugs, Chinese Herbal; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010936:Plant Extracts; D015221:Potassium Channels; D062687:Sodium Channel Agonists; D026941:Sodium Channel Blockers; D015222:Sodium Channels; C509610:dimethyl lithospermate B; D020110:Pinacidil; D016593:Terfenadine; D012964:Sodium; D014700:Verapamil