Vol. 304, Issue 3, 985-993, March 2003

Soy-Derived Isoflavones Exert Opposing Actions on Guinea Pig Ventricular Myocytes

Reginald Liew, J. Koudy Williams, Peter Collins and Kenneth T. MacLeod

Cardiac Medicine, National Heart and Lung Institute, Imperial College London, United Kingdom (R.L., P.C., K.T.M.); and Wake Forest University School of Medicine, Winston-Salem, North Carolina (J.K.W.)

Soy-derived isoflavones appear to possess cardioprotective properties, although the precise nature of this protection and the particular isoflavones responsible remain unclear. We hypothesized that isoflavones may differ in their cardiac actions in view of their varying affinities for the estrogen receptor and differences in ability to inhibit tyrosine kinase. We investigated the direct effects of three closely related isoflavones, genistein, daidzein, and equol (a metabolite of daidzein formed by gut microflora), on the contractile function of isolated guinea pig ventricular myocytes. Genistein (10 and 40 µM) significantly increased cell shortening and the Ca²⁺ transient (measured using indo-1). In contrast, equivalent concentrations of equol produced the opposite effect, decreasing cell shortening and the Ca²⁺ transient, whereas daidzein was without effect. The opposing actions of genistein and equol were still observed in the presence of the specific estrogen receptor antagonist ICI 182,780 (10 µM). However, the stimulatory actions of genistein were markedly reduced in the presence of the potent phosphotyrosine phosphatase inhibitor, bpV(phen). Both genistein and equol significantly inhibited the peak L-type Ca²⁺ current. We conclude that genistein and equol affect the contractile function of ventricular myocytes in opposing ways despite a common initial action of Ca²⁺ current antagonism. These differences occur independently of the estrogen receptor but may be partly related to the unique actions of genistein as a tyrosine kinase inhibitor. Furthermore, isoflavone metabolites, such as equol, may be more biologically active than their precursors and have a greater role in cardioprotection than previously realized.