Abstract The effects of myricetin (3,3’,4’,5,5’,7-hesahy- droxyflavone), a natural flavonoid found in edible plants, were studied on vascular smooth muscle L-type Ca 2+ channels by comparing its mechanical, radioligand binding, and electrophysiological properties to those of the Ca 2+ channel agonist (S)-(-)-Bay K 8644. In rat aorta rings, both myricetin and (S)-(-)-Bay K 8644 induced contractile responses, which were dependent upon prior exposure to K + . At 15 mM K + (K15) the pEC 50 values for myricetin and (S)-(-)-Bay K 8644 were 4.43±0.03 and 7.92±0.13, respectively. Furthermore, the maximum ten- sion response to myricetin was not significantly different from that elicited by either (S)-(-)-Bay K 8644 or K60. The Ca 2+ channel blockers nifedipine, verapamil and dilti- azem antagonised and fully reverted myricetin-, (S)-(-)-Bay K 8644- as well as K60-induced contractions. Both myricetin and (S)-(-)-Bay K 8644 potentiated rat aorta ring responses to K + , shifting the K + concentration-response curve to the left. (S)-(-)-Bay K 8644, but not myricetin, inhibited in a concentration-dependent manner (+)-[ 3 H]PN200–110 bind- ing in porcine aortic membranes. Electrophysiological re- cordings from single rat tail artery myocytes, under am- photericin B-perforated as well as conventional methods, showed that both myricetin and (S)-(-)-Bay K 8644 in- creased L-type Ba 2+ current (I Ba(L) ) and shifted the maxi- mum of the current-voltage relationship by 10 mV in the hyperpolarising direction, without, however, modifying the threshold potential. Furthermore, (S)-(-)-Bay K 8644 accelerated both activation and inactivation kinetics of I Ba(L) while myricetin slowed down the activation kinetics. Finally, both (S)-(-)-Bay K 8644 and myricetin slowed down deactivation kinetics of I Ba(L) . These results suggest that myricetin induces vasoconstric- tion by activating L-type Ca 2+ channel with similar efficacy but a site of action different to that of (S)-(-)-Bay K 8644. Keywords (S)-(-)-Bay K 8644 · Myricetin · Vascular smooth muscle · Whole-cell patch-clamp · Wine polyphenols Abbreviations I Ba(L) L-type Ba 2+ current · PSS Physiological salt solution · V h Holding potential Introduction Flavonoids represent a wide group of polyphenolic com- pounds with different structural, chemical, and pharmaco- logical properties (for a review see Middleton et al. 2000). They are found in edible plants and beverages, mainly ap- ples, onions, tea, and red wine, and represent an important part of the human diet. They show pleiotropic, potentially health promoting, and disease-preventing activities that have started to be appreciated, at least in experimental sit- uations. Many flavonoids, in fact, show pharmacological effects, which allegedly appear beneficial towards the vas- cular system, though further studies on the molecular mech- anisms of their effects on vascular tissues are needed. Quercetin (3,3’,4’,5,7-pentahydroxyflavone), for instance, although inducing both endothelium-dependent (Fusi et al. 2003) and endothelium-independent vasorelaxation in vitro (Duarte et al. 1993; Herrera et al. 1996), has been re- cently demonstrated to be an effective activator of vascu- lar L-type Ca 2+ channels (Saponara et al. 2002). This ef- fect, however, is overwhelmed by its vasorelaxing proper- ties, which take place via pathways (namely PKC inhibition; see Duarte et al. 1993) more prominent than L-type Ca 2+ influx in the hierarchy of functional competencies (Fusi et al. 2003). On the other hand, myricetin (3,3’,4’,5,5’,7-hexa- hydroxyflavone; Fig. 1), which is present in red wines in concentrations as high as quercetin (McDonald et al. 1998) and which differs from quercetin for the presence of an additional hydroxy group in 5’ position, induces a bimodal Fabio Fusi · Simona Saponara · Maria Frosini · Beatrice Gorelli · Giampietro Sgaragli L-type Ca 2+ channels activation and contraction elicited by myricetin on vascular smooth muscles Naunyn-Schmiedeberg’s Arch Pharmacol (2003) 368 : 470–478 DOI 10.1007/s00210-003-0836-y Received: 16 May 2003 / Accepted: 23 September 2003 / Published online: 15 November 2003 ORIGINAL ARTICLE F. Fusi (✉) · S. Saponara · M. Frosini · B. Gorelli · G. Sgaragli Dipartimento di Scienze Anatomiche e Biomediche, Università degli Studi di Siena, via A. Moro 2, 53100 Siena, Italy Tel.: +39-0577-234438, Fax: +39-0577-234446, e-mail: fusif@unisi.it © Springer-Verlag 2003