Calcium-antagonizing activity of S-petasin, a hypotensive sesquiterpene from Petasites formosanus, on inotropic and chronotropic responses in isolated rat atria and cardiac myocytes.
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.
Wang
Guei-Jane
GJ
National Research Institute of Chinese Medicine, Taipei, Taiwan, Republic of China.
Liao
Jyh-Fei
JF
Hintz
Kadon K
KK
Chen
Wen-Pin
WP
Su
Ming-Jai
MJ
Lin
Yun-Lian
YL
Shi
Chuen-Chao
CC
Chen
Chieh-Fu
CF
Ren
Jun
J
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000378:metabolism / Q000502:physiology*; D004305:Dose-Response Relationship, Drug; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D007022:Hypotension / Q000139:chemically induced / Q000503:physiopathology; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D036901:Petasites; D051381:Rats; D017207:Rats, Sprague-Dawley; D012717:Sesquiterpenes / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D012717:Sesquiterpenes; C418727:petasin