Cardiac and electrophysiological effects of primary and refined extracts from Leonurus cardiaca L. (Ph.Eur.).
Although several antiarrhythmic drugs of chemical origin are in clinical use since decades, their application is often limited by their adverse effects and especially by their inherited proarrhythmic risk, which can lead to a significantly increased mortality in patients receiving these compounds. On the other hand, aqueous extracts from the aerial parts of the European Lamiaceae Leonurus cardiaca (Ph.Eur.) have been used for centuries as a remedy against tachyarrhythmia and other cardiac disorders. Nevertheless, a scientific basis for the claim of direct cardiac electrophysiological, antiarrhythmic, or functional effects of Leonurus cardiacae herba (LCH) preparations has not been established until now. In order to enrich the active constituents from the primary extract which was tested as the most cardioactive, namely the aqueous Soxhlet extract, and to eliminate undesired substances such as the dichloromethanic fraction or potassium, a bioassay guided fractionation procedure was applied, resulting in the development of a Leonurus cardiaca refined extract (LCRE) which was characterised together with Leonurus crude extracts by a newly developed gradient elution HPLC fingerprint analysis for separation and quantification of six major phenolics as well as by qNMR for determining the stachydrine content. This refined extract was applied intracoronarily in isolated rabbit hearts perfused according to the Langendorff technique. Mapping experiments with 256 electrodes on the heart surface showed a reduction of left ventricular pressure and an increase of relative coronary flow at concentrations of 1.0 and 2.0 mg/mL LCRE. Furthermore, the PQ-interval was prolonged and both the basic cycle length and the activation recovery interval increased. In addition, voltage-clamp measurements were performed on the following cell models in order to characterise the electrophysiological profile of LCRE: neonatal rat ventricular cardiomyocytes to investigate the effect on I(Na) and I(Ca.L), sinoatrial node cells and ventricular myocytes isolated from adult guinea pigs to test effects on I(f) and action potential (AP) duration, as well as HERG-transfected HEK 293 cells to analyse the influence on the I (K.r). In these voltage clamp experiments LCRE exerted a calcium-antagonistic activity by I(Ca.L) blockade, reduced the repolarising current I(K.r), and prolonged the AP-duration, while I(Na) was not affected. Although LCRE displayed only weak effects on the I(f) amplitude and voltage dependence, it significantly prolonged the activation time constant of I(f). Thus, LCRE acts on multiple electrophysiological targets, specifically I(Ca.L), I(K.r), and I(f), observed both at whole organ and single cell level.
Ritter
Malte
M
Clinic for Cardiac Surgery, University of Leipzig, Leipzig, Germany.
Melichar
Kerstin
K
Strahler
Sabine
S
Kuchta
Kenny
K
Schulte
Jan
J
Sartiani
Laura
L
Cerbai
Elisabetta
E
Mugelli
Alessandro
A
Mohr
Friedrich-Wilhelm
FW
Rauwald
Hans Wilhelm
HW
Dhein
Stefan
S
D000818:Animals; D002460:Cell Line; D022062:Electrophysiologic Techniques, Cardiac; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D006801:Humans; D031332:Leonurus / Q000737:chemistry*; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010936:Plant Extracts / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats
D010936:Plant Extracts