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 Ca2+ 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 µM). Mechanical evaluation in isolated ventricular myocytes showed that S-petasin (0.1 to 100 µM) depressed peak myocyte contraction and intracellular Ca2+ transients concentration-dependently. The duration of myocyte contraction was not affected. Whole-cell voltage clamp analysis revealed that S-petasin inhibited the L-type Ca2+ 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 µM) and the dihydropyridine binding sites of L-type voltage-dependent Ca2+ 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 Ca2+ channel or to muscarinic receptor activation.
References
Bean BP, Cohen CJ, Tsien RW (1983) Lidocaine block of cardiac sodium channels. J Gen Physiol. 81:613–642
Brune K, Bickel D, Peskar BA (1993) Gastro-protective effects by extracts of Petasites hybridus: the role of inhibition of peptido-leukotriene synthesis. Planta Med 59:494–496
Cheng YC, Prusoff WH (1973) Relationship between the inhibition constant (K i) and the concentration of inhibitor which causes 50 percent inhibition (IC50) of an enzymatic reaction. Biochem Pharmacol 22:3099–3108
Clark RB, Bouchard RA, Giles WR (1996) Action potential duration modulates calcium influx, Na+-Ca2+ exchange, and intracellular calcium release in rat ventricular myocytes. Ann NY Acad Sci 779:417–429
Ferrari R, Cucchini F, Bolognesi R, Bachetti T, Boraso A, Bernocchi P, Gaia G, Visioli O (1994) How do calcium antagonists differ in clinical practice? Cardiovasc Drug Ther 8:565–575
Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches. Pflugers Arch 391:85–100
Huguet F, Brisac AM, Roche A, Dubray C (1992) Absence of a direct coupling of a G protein to dihydropyridine binding sites in rat heart. Biochem Pharmacol 44:1680–1682
Liao JF, Yu PC, Lin HC, Lee FY, Kuo JS, Yang MCM (1994) Study on the vascular reactivity and α1-adrenoceptors of portal hypertensive rats. Br J Pharmacol 111:439–444
Lin YL, Mei CH, Huang SL, Kuo YH (1998) Four new sesquiterpenes from Petasites formosanus. J Nat Prod 61:887–890
Mill JG, Vassallo DV, Leite CM (1992) Mechanisms underlying the genesis of post-rest contractions in cardiac muscle. Braz J Med Biol Res 25:399–408
Ren J (2000) Altered cardiac contractile responsiveness to insulin-like growth factor I in ventricular myocytes from BB spontaneous diabetic rats. Cardiovasc Res 46:162–171
Thomet OA, Wiesmann UN, Schapowal A, Bizer C, Simon HU (2001) Role of petasin in the potential anti-inflammatory activity of a plant extract of Petasites hybridus. Biochem Pharmacol 61:1041–1047
Wang GJ, Shum AYC, Lin YL, Liao JY, Wu XC, Ren J, Chen CF (2001) Calcium channel blockade by S-petasin, a hypotensive sesquiterpene from Petasites formosanus, in vascular smooth muscle cells. J Pharmacol Exp Ther 297:240–246
Wong KK (1996) Lack of calcium-antagonizing activity of dehydroevodiamine on the chronotropic and inotropic activities of mouse isolated atria. Planta Med 62:246–249
Ziolo G, Samochowiec L (1998) Study on clinical properties and mechanisms of action of Petasites in bronchial asthma and chronic obstructive bronchitis. Pharm Acta Helv 72:378–380
Acknowledgements
This research was supported in part by Grant NSC92-2320-B-077-010 from the National Science Council of the Republic of China to GJW and United States of America (North Dakota State) Experimental Program to Stimulate Competitive Research (EPSCoR) to JR. KKH was supported by the EPSCoR Science Bound Program.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Wang, GJ., Liao, JF., Hintz, K.K. et al. Calcium-antagonizing activity of S-petasin, a hypotensive sesquiterpene from Petasites formosanus, on inotropic and chronotropic responses in isolated rat atria and cardiac myocytes. Naunyn-Schmiedeberg's Arch Pharmacol 369, 322–329 (2004). https://doi.org/10.1007/s00210-003-0863-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00210-003-0863-8