The isoflavone metabolites, O-desmethylangolensin and (S)-equol, relax isolated arteries ex vivo and decrease...

Dietary isoflavones are suggested to have positive cardiovascular effects. Their intestinal absorption is low, but they undergo extensive gastrointestinal metabolism by gut bacteria, resulting in metabolites with higher bioavailability. However, there is limited data on the effect of individual pure isoflavone metabolites on the vascular system. Therefore, four of these metabolites were first screened ex vivo for vasorelaxant properties on isolated rat aortic rings. The most potent of these metabolites, namely O-desmethylangolensin (O-DMA) and (S)-equol, had EC₅₀ values of 49.3 and 59.1 μΜ, respectively. Both O-DMA and (S)-equol also induced relaxation in two additional ex vivo models, namely rat mesenteric artery rings (EC₅₀ values of 33.3 and 8.7 μΜ, respectively) and porcine coronary artery rings (EC₅₀ values of 16.8 and 15.3 μΜ, respectively). Hence, across three different ex vivo arterial models and two different species, O-DMA and (S)-equol demonstrated vasorelaxant activity. In mechanistic studies using porcine coronary arteries that more closely mimic the human situation, endothelium-independent relaxation was observed. This vasodilatory effect was present after stimulation of Gq/11-coupled receptors (with thromboxane A₂ analogue, U46619, or serotonin), or after depolarization with excess KCl that causes Gq/11-independent vasoconstriction. The mechanism of O-DMA activity was consistent with inhibition of calcium influx via L-type channels, as shown by studies using primary cultures of human aortic artery smooth muscle cells. In vivo intravenous O-DMA and (S)-equol decreased arterial blood pressure in spontaneously hypertensive rats without affecting heart rate. These results suggest that isoflavones modulate arterial blood pressure by generating their absorbable metabolites, O-DMA and (S)-equol.