Ca²⁺-permeable cation channels not only control excitability of vascular myocytes but also form an important Ca²⁺ channeling route. Several mammalian homologues of Drosophila transient receptor potential (TRP) proteins are strong candidates for such channels (Beech, 2005). Recent studies of novel melastatin TRPM8 channels have focused on their role in cold transduction in sensory neurones. However, there are now reports that these receptors are present in blood vessels and may be active in vascular tone (Yang et al., 2006). We have examined this possibility in detail using functional and molecular techniques. Vascular tissue was taken from humanely-dispatched Wistar rats (12 weeks). Sections of precontracted proximal tail artery and thoracic aorta with endothelia removed were mounted in Krebs for isometric contraction study. Vasoconstrictions induced by KCl (60 mM; tail: 0.85±0.13 g, n=7; aorta: 0.88±0.09 g, n=6) were inhibited (paired Student’s t-test, performed on absolute data) by addition of selective TRPM8 channel agonists, menthol (300 μM; tail: 43±9 % control, P< 0.01; aorta: 61±10 %, P< 0.01) or icilin (50 μM; tail: 39±16 % control, n=3, P< 0.05; aorta: 42±7 %, n=3, P< 0.05). Similar results were obtained with contractions evoked by noradrenaline (2 μM). Sympathetically-evoked constrictions (0.6±0.32 g, n=3) in tail artery were significantly reduced by menthol (56±9 % control, P< 0.05). Single vascular smooth muscle cells (VSMCs) were isolated from proximal tail artery for patch-clamp recordings. With high K⁺ (125 mM) and low intracellular Ca²⁺ buffering (0.3 mM EGTA in the pipette solution), STOCs discharge (reflecting BKCa channel activation due to spontaneous localised Ca²⁺ release events) was observed at 1.4-4.4 Hz at holding potentials from -40 to -10 mV. These STOCs were significantly accelerated by 100 μM menthol application (75±19% frequency increase, P<0.01, n=4), while the amplitude of these currents was markedly reduced. Eventually (1-2 min after menthol application) STOCs discharge was terminated. PCR studies in VSMCs from thoracic aorta, tail, femoral, renal and mesenteric arteries with endothelia removed all showed the presence of mRNA for TRPM8 receptor proteins. We conclude that TRPM8 channels are present and functional in a range of different blood vessels. Since they can be localised not only in the plasma membrane, but also in the SR membrane (Abeele et al., 2006) Ca²⁺ store release and depletion evidenced by STOCs initial acceleration and eventual suppression seems the most likely mechanism of vasoconstrictor inhibition by TRPM8 agonists.