Thaliporphine, a positive inotropic agent with a negative chronotropic action

Abstract

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 μM) increased twitch tension dose-dependently. The positive inotropic effect of thaliporphine was unaffected by atenolol (3 μM) and prazosin (1 μM) but was significantly suppressed by verapamil (1 μM). An electrophysiological study revealed that thaliporphine (3–10 μM) markedly inhibited the action potential upstroke and prolonged the action potential duration (APD 50) in rat and guinea pig atrial and ventricular cells. At 1–30 μM, thaliporphine reduced the transient outward current ( I to) of the rat ventricullar cells in a dose-dependent manner. The peak I to in rat ventricular cells and the delayed rectifying K + current ( I k in guinea pig ventricular cells were reduced by thaliporphine (10 μM) to 37.3 ± 2.1% ( n = 8) and 45.3 ± 1.8% ( n =4), respectively. In rat ventricular cells and guinea pig artial cells, thaliporphine (1.5 μM) reduced the Na + inward current ( I Na) with a negative shift (4–5 mV) relative to its half inactivation potential. For the Ca 2+ inward current ( I Ca) in rat ventricular cells, 10 μM of thaliporphine caused a smaller increase in the peak I Ca than 0.5 μM of Bay K 8644. The increase in I Ca 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 Ca 2+ 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 APD 50 and contribute to the negative chronotropic effect of thaliporphine.