title: Cardamonin is a bifunctional vasodilator that inhibits Ca(v)1.2 current and stimulates K(Ca)1.1 current in rat tail artery myocytes.
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 Ca(v)1.2 Ca(2+) [I(Ca(L))] or Ba(2+) [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 Ba(2+) 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.
authors.affiliation: Dipartimento di Neuroscienze, Università degli Studi di Siena, via A. Moro 2, 53100 Siena, Italy. fusif@unisi.it
authors.forename: Fabio
authors.initials: F
authors.lastname: Fusi
authors.forename: Maurizio
authors.initials: M
authors.lastname: Cavalli
authors.forename: Dulcie
authors.initials: D
authors.lastname: Mulholland
authors.forename: Neil
authors.initials: N
authors.lastname: Crouch
authors.forename: Phil
authors.initials: P
authors.lastname: Coombes
authors.forename: Gill
authors.initials: G
authors.lastname: Dawson
authors.forename: Sergio
authors.initials: S
authors.lastname: Bova
authors.forename: Giampietro
authors.initials: G
authors.lastname: Sgaragli
authors.forename: Simona
authors.initials: S
authors.lastname: Saponara
mesh_terms: D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000187:drug effects* / Q000502:physiology; D047188:Chalcones / Q000494:pharmacology*; D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits / Q000819:agonists* / Q000502:physiology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013623:Tail / Q000098:blood supply; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D020746:Calcium Channels, L-Type; D047188:Chalcones; C494842:Kcnma1 protein, rat; C419385:L-type calcium channel alpha(1C); D051037:Large-Conductance Calcium-Activated Potassium Channel alpha Subunits; D014665:Vasodilator Agents; C436747:cardamonin; D002118:Calcium