Possible mechanism of selective inotropic activity of the n-butanolic fraction from Berberis aristata fruit.
Berberis aristata is an edible plant employed in South Asian traditional medicine; in particular, its fruit is used as a tonic remedy for liver and heart. In isolated cardiac tissues, Berberis aristata fruit extract exhibits a positive inotropic action. Activity-directed fractionation using organic solvents revealed that the cardiotonic activity is concentrated in the n-butanolic fraction (BF). The cardiac action of BF was investigated in spontaneously beating right atria and in electrically driven right ventricular strips and left atria obtained from reserpinized guinea pigs. The results show that this fraction produces a dose-dependent positive inotropic action with little effect on heart rate. To study its possible mode of action, guinea pig atria were pretreated with propranolol, a beta-adrenoceptor blocking agent. This treatment abolished the cardiotonic effect of isoprenaline, whereas the cardiotonic effect of BF remained unaltered, suggesting that this effect does not involve stimulation of beta-adrenoceptors. On the other hand, application of carbachol reverses only part of the BF-induced increase in ventricular force of contraction, indicating that besides a cyclic AMP (cAMP)-dependent mechanism, a cAMP-independent mechanism underlies the inotropic action of BF. This is in line with the observation that the dynamics of isometric twitch contractions are not significantly altered by BF. Investigations in skinned myocardial preparations showed that BF modulates the calcium-dependent interaction of actin and myosin, apparently by reducing the cooperativity of the calcium-dependent binding of myosin to actin, i.e., there is enhanced calcium activation at low to physiological intracellular calcium, and reduced calcium activation at high intracellular calcium concentrations as present, for example, in ischemic calcium overload. These data indicate that the edible plant, Berberis aristata, contains active principle(s) that cause(s) a selective inotropic effect, involving-in the form of the modulatory effect on actin myosin cooperativity-a novel mechanism of action. Further phytochemical and pharmacological studies may lead to isolation and structural identification of an attractive, new cardiotonic agent from Berberis aristata fruit.