Abstract
Okadaic acid is a monocarboxylic acid with a unique molecular structure of C44H66O13. Okadaic acid, at concentrations above 10(-5) M, caused a dose-dependent increase of contractile force in guinea-pig isolated ventricular muscles. The increase of contractile force by okadaic acid (1-4 X 10(-5) M) was accompanied by a prolongation of action potential duration (a.p.d.), while a.p.d. was shortened by okadaic acid at above 10(-4) M. The okadaic-acid-induced changes in contractile force and a.p.d. were abolished by pre-treatment with verapamil (2 X 10(-6 M) or nifedipine (10(-6) M). In a low-Ca2+ medium (0.12 mM), the contractile response to okadaic acid (4 X 10(-5) M) was inhibited, whereas the a.p.d. was more prolonged by the drug than in a control medium (containing 1.2 mM-Ca2+). In a low-Na+ (70 mM) medium or in a low-Na+ (70 mM) and low-Ca2+ (0.12 mM) medium both the contractile force and a.p.d. were unaffected by okadaic acid (4 X 10(-5) M). The positive inotropic effect of okadaic acid (4 X 10(-5) M) was not inhibited by treatment with tetrodotoxin (TTX, 2 X 10(-6) M) or with ryanodine (2 X 10(-6) M). In voltage-clamp experiments using a single sucrose-gap technique, okadaic acid (4 X 10(-5) M), caused a significant increase of slow inward current, while it did not affect the net outward current. These findings suggest that okadaic acid has a positive inotropic effect on the heart, probably due to the enhancement of slow Ca2+ and/or Na+ inward current through the cell membrane.