Cardamonin Is a Bifunctional Vasodilator that Inhibits Cav1.2 Current and Stimulates KCa1.1 Current in Rat Tail Artery Myocytes

An in-depth analysis of the effects of cardamonin, 2',4'-dihydroxy-6'-methoxychalcone, on rat tail artery preparations was performed by means of whole-cell patch-clamp recordings of Ca(v)1.2 Ca2+ [I-Ca(L)] or Ba2+ [I-Ba(L)] current as well as K(Ca)1.1 currents in single myocytes and by measuring contractile responses in endothelium-denuded isolated rings. At a holding potential (V-h) of -80 mV, cardamonin decreased both I-Ba(L) and I-Ca(L) in a concentration-dependent manner with similar pIC(50) values. The maximum of the I-Ba(L)-voltage relationship was shifted by 10 mV in the hyperpolarizing direction, but threshold remained unaffected. Cardamonin modified both the activation and the inactivation kinetics of I-Ba(L) and shifted the voltage dependence of both inactivation and activation curves to more negative potentials by 19 and 7 mV, respectively, thus markedly decreasing the Ba2+ window current. Block of I-Ba(L) was frequency-dependent, and rate of recovery from inactivation was slowed. Cardamonin increased K(Ca)1.1 currents in a concentration-dependent manner; this stimulation was iberiotoxin-and BAPTA [1,2-bis(2-aminophenoxy)ethane- N,N,N',N'-tetraacetic acid]-sensitive. On the contrary, iberiotoxin did not modify cardamonin-induced relaxation of rings precontracted either with phenylephrine or with (S)-(-)-methyl-1,4-dihydro-2,6-dimethyl-3-nitro- 4-(2-trifluoromethylphenyl)pyridine-5-carboxylate [(S)-(-)-Bay K 8644]. The overall effects of cardamonin were incompletely reversed by washout. In conclusion, cardamonin is a naturally occurring, bifunctional vasodilator that, by simultaneously inhibiting I-Ca(L) and stimulating K(Ca)1.1 current, may represent a scaffold for the design of novel drugs of potential interest for treatment of systemic hypertension.