Calcium-antagonizing activity of S -petasin, a hypotensive sesquiterpene from Petasites formosanus , on inotropic and chronotropic responses in isolated rat atria and cardiac myocytes

Abstract

Petasites formosanus, an indigenous species of Petasites, has been used to treat cardiovascular diseases such as hypertension for years. We have suggested recently that S-petasin, a major sesquiterpene from P. formosanus, inhibits vascular smooth muscle contraction through inhibition of voltage-dependent Ca(2+) channels, a phenomenon possibly responsible for the hypotensive effect of P. formosanus. This study was designed to examine the chronotropic and inotropic actions of S-petasin in the heart in vivo and in vitro. Administration of S-petasin (0.1-1.5 mg/kg i.v.) in anesthetized rats reduced heart rate dose-dependently. This response was consistent with significant suppression of both contractile amplitude and spontaneous firing rate of isolated atria, responses that were not antagonized by atropine (1 microM). Mechanical evaluation in isolated ventricular myocytes showed that S-petasin (0.1 to 100 microM) depressed peak myocyte contraction and intracellular Ca(2+) transients concentration-dependently. The duration of myocyte contraction was not affected. Whole-cell voltage clamp analysis revealed that S-petasin inhibited the L-type Ca(2+) current ( I(Ca,L)) concentration-dependently and shifted the steady-state inactivation curve of I(Ca,L) to more negative potentials. However, a receptor-binding assay failed to identify any significant interaction between S-petasin (0.1-300 microM) and the dihydropyridine binding sites of L-type voltage-dependent Ca(2+) channels. Taken together, these data show that the negative chronotropic and inotropic properties of S-petasin that can be ascribed mainly to I(Ca,L) inhibition, but not to blockade of dihydropyridine binding sites of L-type Ca(2+) channel or to muscarinic receptor activation.

Blood Pressure-lowering and Vascular Modulator Effects of Acorus calamus Extract Are Mediated Through Multiple Pathways

“…Additionally, alkaloids have also been found to exhibit a vasoconstrictive 42 effect mediated through the release of Ca +243 and through endotheliumdependent pathway. 44 Glucosides and sesquiterpenes 45 are also known to possess an inhibitory effect on cardiovascular system. The current findings on the cardiovascular activities of Acorus calamus can be possibly correlated to its chemical constituents, particularly alkaloids in addition to glucosides and sesquiterpenes, which might be responsible for the antihypertensive and vasomodulatory effects because the other chemical constituents such as acorine and asarone are not known to possess effects related to the cardiovascular system.…”

Mechanisms underlying the antihypertensive properties of Urtica dioica

“…Previous studies show that plant derived alkaloids have vasorelaxant properties through multiple pathways like inhibition of calcium release from Ca 2+ stores [28] and NO pathways [36]. Glucosides [37] and sesquiterpenes [38] also have an inhibitory effect on the cardiovascular system. We assume that these constituents might be the active constituents responsible for the antihypertensive effect of U. dioica .…”

Use-Dependent Block of Voltage-Gated Cav2.1 Ca2+Channels by Petasins and Eudesmol Isomers

“…Petasins comprise at least 20% of the constituents in the preparations of P. hybridus used in clinical trials, suggesting that these sesquiterpenes represent the active principle. Low micromolar concentrations of petasins have been shown to inhibit L-type VGCCs in smooth and cardiac muscle (Wang et al, 2001(Wang et al, , 2002(Wang et al, , 2004Esberg et al, 2003). Therefore, it is possible that they are also inhibitors of neuronal Ca v 2.1 channels.…”