Involvement of cAMP and beta-adrenoceptors in the relaxing effect elicited by flavonoids on rat uterine smooth muscle.

1. The effect of the flavonoids genistein (3-100 microM), kaempferol (3-60 microM) and quercetin (1-100 microM) on KCl (60 mM)-induced tonic contraction in rat smooth muscle was assayed. In the same way, the modification of these effects in the presence of an inhibitor of protein kinase (PKA) (Rp-cAMPS), an inhibitor of phosphodiesterase (papaverine) and beta-adrenoreceptor blocking agents (propranolol and atenolol) was studied. 2. The flavonoids totally relaxed the KCl-induced tonic contraction (IC50: genistein 20.2 +/- 2.0 microM, n = 11; kaempferol 10.1 +/- 1.6 microM, n = 8; quercetin 13.2 +/- 1.2 microM, n = 8). 3. The incubation with Rp-cAMPS (10 and 100 microM) 30 min prior to KCl shifted the dose-response curve of the flavonoids to the right, increasing their IC50 up to 27.8 +/- 3.8 and 31.9 +/- 7.3 microM, respectively, for genistein; 24.7 +/- 0.2 and 19.6 +/- 4.9 microM, respectively, for kaempferol; 18.8 +/- 2.2 and 18.4 +/- 1.5 microM, respectively, for quercetin. 4. Papaverine (3-100 microM) also relaxed the contraction induced by KCl and this effect was significantly displaced to the right with Rp-cAMPS (10 microM) (IC50 12.1 +/- 2.2 vs. 16.5 +/- 3.1 microM). Papaverine (3 microM) added to the organ bath 15 min before the contractile agent increased the relaxing effect of the flavonoids and significantly decreased their IC50 (genistein 20.2 +/- 2.0 vs. 9.8 +/- 1.4 microM; kaempferol 10.1 +/- 1.6 vs. 6.6 +/- 0.7 microM; quercetin 13.2 +/- 1.2 vs. 7.8 +/- 1.4 microM). 5. The incubation with atenolol (10 microM) did not alter the relaxing effect of the flavonoids. In the same experimental conditions, propranolol (10 microM) did not modify the effect of genistein and kaempferol, but shifted the response curve of quercetin significantly to the right (13.2 +/- 1.2 vs. 17.7 +/- 3.4 microM). 6. The results suggest that genistein, kaempferol and quercetin produced the relaxation of uterine smooth muscle by increasing intracellular cAMP. Beta-adrenoceptors could also be involved in the effect of quercetin.