Thaliporphine, a positive inotropic agent with a negative chronotropic action.
The effects of thaliporphine on contractions and electrophysiological properties of cardiac tissues were examined. In driven rat left atria and right ventricular strips, thaliporphine (1-30 microM) increased twitch tension dose-dependently. The positive inotropic effect of thaliporphine was unaffected by atenolol (3 microM) and prazosin (1 microM) but was significantly suppressed by verapamil (1 microM). An electrophysiological study revealed that thaliporphine (3-10 microM) markedly inhibited the action potential upstroke and prolonged the action potential duration (APD50) in rat and guinea pig atrial and ventricular cells. At 1-30 microM, thaliporphine reduced the transient outward current (Ito) of the rat ventricular cells in a dose-dependent manner. The peak Ito in rat ventricular cells and the delayed rectifying K+ current (Ik in guinea pig ventricular cells were reduced by thaliporphine (10 microM) to 37.3 +/- 2.1% (n = 8) and 45.3 +/- 1.8% (n = 4), respectively. In rat ventricular cells and guinea pig atrial cells, thaliporphine (1.5 microM) reduced the Na+ inward current (INa) with a negative shift (4-5 mV) relative to its half inactivation potential. For the Ca2+ inward current (ICa) in rat ventricular cells, 10 microM of thaliporphine caused a smaller increase in the peak ICa than 0.5 microM of Bay K 8644. The increase in ICa elicited by both agents was associated with a negative shift of its half activation potential from -10 +/- 2 mV to -18 +/- 2 mV (n = 6) by thaliporphine and -11 +/- 2 to -19 +/- 2 mV (n = 4) by Bay K 8644. These results indicate that thaliporphine is a weak Ca2+ channel agonist with strong Na+ and K+ channel blocking activities. The positive inotropic effect may be due to an increase in calcium entry mediated via partial activation of calcium channels or by inhibition of K+ efflux. Inhibition of K+ efflux would result in prolongation of APD50 and contribute to the negative chronotropic effect of thaliporphine.
Su
M J
MJ
Department of Pharmacology, College of Medicine, National Taiwan University, Taipei.
Chang
Y M
YM
Chi
J F
JF
Lee
S S
SS
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001060:Aporphines / Q000494:pharmacology*; D002120:Calcium Channel Agonists / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004558:Electric Stimulation; D004594:Electrophysiology; D006168:Guinea Pigs; D006339:Heart Rate / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology; D015221:Potassium Channels / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D015222:Sodium Channels / Q000187:drug effects / Q000378:metabolism
D001060:Aporphines; D002120:Calcium Channel Agonists; D002316:Cardiotonic Agents; D015221:Potassium Channels; D015222:Sodium Channels; C080702:thaliporphine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester