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Rotundifolone‐Induced Relaxation is Mediated by BK Ca Channel Activation and Ca v Channel Inactivation
Author(s) -
Silva Darízy F.,
Araújo Islania G. A.,
Albuquerque José G. F.,
Porto Dayanne L.,
Dias Katy L. G.,
Cavalcante Karla V. M.,
Veras Robson C.,
Nunes Xirley P.,
BarbosaFilho José M.,
Araújo Demetrius A. M.,
Cruz Jader S.,
Correia Nadja A.,
De Medeiros Isac A.
Publication year - 2011
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/j.1742-7843.2011.00749.x
Subject(s) - charybdotoxin , chemistry , phenylephrine , vasodilation , tetraethylammonium , biophysics , patch clamp , vasoconstriction , agonist , mesenteric arteries , depolarization , l type calcium channel , iberiotoxin , glibenclamide , voltage dependent calcium channel , egta , pharmacology , calcium , endocrinology , medicine , membrane potential , biochemistry , artery , biology , potassium , receptor , organic chemistry , blood pressure , diabetes mellitus
Rotundifolone is the major constituent of the essential oil of Mentha x villosa Hudson. In preliminary studies, rotundifolone induced significant hypotensive, bradycardic and vasorelaxant effects in rats. Thus, to gain more insight into the pharmacology of rotundifolone, the aim of this study was to characterize the molecular mechanism of action involved in relaxation produced by rotundifolone. The relaxant effect was investigated in rat superior mesenteric arteries by using isometric tension measurements and whole‐cell patch‐clamp techniques. Rotundifolone relaxed phenylephrine‐induced contractions in a concentration‐dependent manner. Pre‐treatment with KCl (20 mM), charybdotoxin (10 −7 M) or tetraethylammonium (TEA 10 −3 or 3 × 10 −3 M) significantly attenuated the relaxation effect induced by rotundifolone. Additionally, whole‐cell patch‐clamp recordings were made in mesenteric smooth muscle cells and showed that rotundifolone significantly increased K + currents, and this effect was abolished by TEA (10 −3 M), suggesting the participation of BK Ca channels. Furthermore, rotundifolone inhibited the vasoconstriction induced by CaCl 2 in depolarizing nominally Ca 2+ ‐free medium and antagonized the contractions elicited by an L‐type Ca 2+ channel agonist, S(‐)‐Bay K 8644 (2 × 10 −7 M), indicating that the vasodilatation involved inhibition of Ca 2+ influx through L‐type voltage‐dependent calcium channels (Ca v type‐L). Additionally, rotundifolone inhibited L‐type Ca 2+ currents (I Ca L), affecting the voltage‐dependent activation of I Ca L and steady‐state inactivation. Our findings suggest that rotundifolone induces vasodilatation through two distinct but complementary mechanisms that clearly depend on the concentration range used. Rotundifolone elicits an increase in the current density of BK Ca channels and causes a shift in the steady‐state inactivation relationship for Ca v type‐L towards more hyperpolarized membrane potentials.