Mode of cardiotonic action of helenalin, a sesquiterpene lactone, on guinea pig ventricular myocardium.
We investigated the mechanisms of the direct positive inotropic effect (PIE) of helenalin, a sesquiterpene lactone isolated from the plant genus Helenium of the family Compositae in guinea pig ventricular myocardium. Helenalin (3 X 10(-4) M) produced biphasic PIEs (first and second PIE phases) on normal nonreserpinized papillary muscles, driven at 1 Hz in Krebs-Henseleit solution at 30 degrees C. The first PIE phase was abolished by reserpine treatment. Helenalin increased the force of "rested-state contraction" in a manner similar to that of other cyclic AMP-elevating substances, such as norepinephrine and IBMX (3-isobutyl-1-methylxanthine). In isometric contraction curves of the papillary muscle stimulated at 0.2 Hz, helenalin showed two clear peaks of an early and a late component. Carbachol preferentially suppressed the late component of contraction, a component that is clearly apparent in the presence of intracellular cyclic AMP-increasing substances. Helenalin potentiated the PIEs of isoproterenol and histamine but not that of dihydroouabain. In the presence of a phosphodiesterase (PDE) inhibitor (IBMX 10(-3) M), helenalin did not produce any PIE. In electrophysiological studies, helenalin prolonged the duration of transmembrane action potentials of papillary muscle. In partially depolarized muscles (external K+ = 30 mM), helenalin increased the overshoot and the duration of the slow action potential. These results led to the conclusion that helenalin produces an elevation of cyclic AMP through PDE inhibition, thereby increasing Ca2+ influx which enhances the contractility of the myocardium by increasing Ca2+ release from the SR.
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002316:Cardiotonic Agents; D000242:Cyclic AMP / Q000032:analysis; D004347:Drug Interactions; D005260:Female; D006168:Guinea Pigs; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D010210:Papillary Muscles / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors; D012717:Sesquiterpenes / Q000494:pharmacology*; D045789:Sesquiterpenes, Guaiane
D002316:Cardiotonic Agents; D010726:Phosphodiesterase Inhibitors; D012717:Sesquiterpenes; D045789:Sesquiterpenes, Guaiane; C001329:helenalin; D000242:Cyclic AMP