RT Journal Article
SR Electronic
T1 Cardamonin Is a Bifunctional Vasodilator that Inhibits Cav1.2 Current and Stimulates KCa1.1 Current in Rat Tail Artery Myocytes
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 531
OP 540
DO 10.1124/jpet.109.161265
VO 332
IS 2
A1 Fabio Fusi
A1 Maurizio Cavalli
A1 Dulcie Mulholland
A1 Neil Crouch
A1 Phil Coombes
A1 Gill Dawson
A1 Sergio Bova
A1 Giampietro Sgaragli
A1 Simona Saponara
YR 2010
UL http://jpet.aspetjournals.org/content/332/2/531.abstract
AB 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 Cav1.2 Ca2+ [ICa(L)] or Ba2+ [IBa(L)] current as well as KCa1.1 currents in single myocytes and by measuring contractile responses in endothelium-denuded isolated rings. At a holding potential (Vh) of −80 mV, cardamonin decreased both IBa(L) and ICa(L) in a concentration-dependent manner with similar pIC50 values. The maximum of the IBa(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 IBa(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 IBa(L) was frequency-dependent, and rate of recovery from inactivation was slowed. Cardamonin increased KCa1.1 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 ICa(L) and stimulating KCa1.1 current, may represent a scaffold for the design of novel drugs of potential interest for treatment of systemic hypertension. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics