Inhibition of Na+,K(+)-ATPase by flavonoids and their inotropic effect. Investigation of the structure-activity relationship.

The relationship between the structures of 39 natural flavonoids (including flavones, flavonols, flavonones, and isoflavones) and their inhibitory and positive inotropic effects have been found. It is shown that flavonoids considerably inhibit the activity of the purified preparation of pig kidney medulla Na+,K(+)-ATPase with Ki = 1.4-22.2 microM and some of the flavonoids studied exert positive inotropic effect on the papillary muscle. Flavones and flavonols, containing hydroxyl groups inside the phenyl radical in ortho- and vicinal positions, exhibit high inhibitory and positive inotropic effects. The inhibitory and positive inotropic effects of flavonoid glycosides and methoxyflavonoids are less pronounced. The presence of dimethylallyl groups in flavonones leads to the increase in the inhibitory and positive activities. Isoflavones produced virtually no effect on the enzyme and the isolated heart muscle. The effect of quercetin on the structure of Na+,K(+)-ATPase was studied by the fluorescence method.