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Background and purpose. The aim of this study was to investigate, in vascular smooth muscle cells, the mechanical and electrophysiological effects of (+/−)‐naringenin. Experimental approach. Aorta ring preparations and single tail artery myocytes were employed for functional and patch‐clamp experiments, respectively. Key results. (+/−)‐Naringenin induced concentration‐dependent relaxation in endothelium‐denuded rat aortic rings pre‐contracted with either 20 mM KCl or noradrenaline (pIC50 values of 4.74 and 4.68, respectively). Tetraethylammonium, iberiotoxin, 4‐aminopyridine and 60 mM KCl antagonised (+/−)‐naringenin‐induced vasorelaxation, while glibenclamide did not produce any significant antagonism. Naringin [(+/−)‐naringenin 7‐β‐neohesperidoside] caused a concentration‐dependent relaxation of rings pre‐contracted with 20 mM KCl, although its potency and efficacy were significantly lower than those of (+/−)‐naringenin. In rat tail artery myocytes, (+/−)‐naringenin increased large conductance Ca2+‐activated K+ (BKCa) currents in a concentration‐dependent manner; this stimulation was iberiotoxin‐sensitive and fully reversible upon drug wash‐out. (+/−)‐Naringenin accelerated the activation kinetics of BKCa current, shifted, by 22 mV, the voltage dependence of the activation curve to more negative potentials, and decreased the slope of activation. (+/−)‐Naringenin‐induced stimulation of BKCa current was insensitive either to changes in the intracellular Ca2+ concentration or to the presence, in the pipette solution, of the fast Ca2+ chelator BAPTA. However, such stimulation was diminished when the K+ gradient across the membrane was reduced. Conclusions and Implications. The vasorelaxant effect of the naturally‐occurring flavonoid (+/−)‐naringenin on endothelium‐denuded vessels was due to the activation of BKCa channels in myocytes. British Journal of Pharmacology (2006) 149, 1013–1021. doi:

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We report the discovery of compound 4a, a potent β-lactam-based monoacylglycerol lipase (MGL) inhibitor characterized by an irreversible and stereoselective mechanism of action, high membrane permeability, high brain penetration evaluated using a human in vitro blood-brain barrier model, high selectivity in binding and affinity-based proteomic profiling assays, and low in vitro toxicity. Mode-of-action studies demonstrate that 4a, by blocking MGL, increases 2-arachidonoylglycerol and behaves as a cannabinoid (CB1/CB2) receptor indirect agonist. Administration of 4a in mice suffering from experimental autoimmune encephalitis ameliorates the severity of the clinical symptoms in a CB1/CB2-dependent manner. Moreover, 4a produced analgesic effects in a rodent model of acute inflammatory pain, which was antagonized by CB1 and CB2 receptor antagonists/inverse agonists. 4a also relieves the neuropathic hypersensitivity induced by oxaliplatin. Given these evidence, 4a, as MGL selective inhibitor, could represent a valuable lead for the future development of therapeutic options for multiple sclerosis and chronic pain

1 The aim of this study was to investigate the e ects of quercetin, a natural polyphenolic¯avonoid, on voltage-dependent Ca 2+ channels of smooth muscle cells freshly isolated from the rat tail artery, using either the conventional or the amphotericin B-perforated whole-cell patch-clamp method. 2 Quercetin increased L-type Ca 2+ current [I Ca(L) ] in a concentration-(pEC 50 =5.09+0.05) and voltage-dependent manner and shifted the maximum of the current-voltage relationship by 10 mV in the hyperpolarizing direction, without, however, modifying the threshold and the equilibrium potential for Ca 2+ . Quercetin-induced I Ca(L) stimulation was reversible upon wash-out. T-type Ca 2+ current was not a ected by quercetin. 3 Quercetin shifted the voltage dependence of the steady-state inactivation and activation curves to more negative potentials by about 5.5 and 7.5 mV respectively, in the mid-potential of the curves as well as increasing the slope of activation. Quercetin slowed both the activation and the deactivation kinetics of the I Ca(L) . The inactivation time course was also slowed but only at voltages higher than 10 mV. Moreover quercetin slowed the rate of recovery from inactivation. 4 These results prove quercetin to be a naturally-occurring L-type Ca 2+ channel activator.