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 mu M) increased twit ch tension dose-dependently. The positive inotropic effect of thalipor phine was unaffected by atenolol (3 mu M) and prazosin (1 mu M) but wa s significantly suppressed by verapamil (1 mu M). An electrophysiologi cal study revealed that thaliporphine (3-10 mu M) markedly inhibited t he action potential upstroke and prolonged the action potential durati on (APD(50)) in rat and guinea pig atrial and ventricular cells. At 1- 30 mu M, thaliporphine reduced the transient outward current (I-to) of ventricular cells in a dose-dependent manner. The peak I-to in rat ve ntricular cells and the delayed rectifying K+ current (I-k in guinea p ig ventricular cells were reduced by thaliporphine (10 mu M) to 37.3 /- 2.1% (n = 8) and 45.3 +/- 1.8% (n = 4), respectively. In rat ventri cular cells and guinea pig artial cells, thaliporphine (1.5 mu M) redu ced the Na+ inward current (I-Na) with a negative shift (4-5 mV) relat ive to its half inactivation potential. For the Ca2+ inward current (I -Ca) in rat ventricular cells, 10 mu M of thaliporphine caused a small er increase in the peak I-Ca than 0.5 mu M 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 Ca2+ channe l agonist with strong Na+ and K+ channel blocking activities. The posi tive inotropic effect may be due to an increase in calcium entry media ted via partial activation of calcium channels or by inhibition of Kefflux. Inhibition of K+ efflux would result in prolongation of APD(50 ) and contribute to the negative chronotropic effect of thaliporphine.