Abstract
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.
Footnotes
This work was supported by a mobility grant from Ministero degli Affari Esteri (Rome, Italy; to F.F.) and from the National Research Foundation (South Africa; to D.M.) for the project “Investigations of Isolates from the Hyacinthaceae Family for Cardiovascular Activity” [Executive program of scientific and technological co-operation between the Italian Republic and the Republic of South Africa, 2005–2007]; and by grants from the Università degli Studi di Siena [PAR Servizi 2005 and 2006].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.109.161265
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ABBREVIATIONS:
- BSA
- bovine serum albumin
- BAPTA
- 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid
- (S)-(−)-Bay K 8644
- (S)-(−)-methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)pyridine-5-carboxylate.
- Received September 4, 2009.
- Accepted November 18, 2009.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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