Activation of oestrogen receptor (ER) is neuroprotective in transient cerebral ischaemia. (Carswell et al, 2004). Vasodilatory effects of oestrogen are well documented (Pelligrino et al, 1998). Endothelial and smooth muscle cells express membrane and classic nuclear oestrogen receptors, ER-∝ and ER-β. However, it is unclear whether vasodilatory effects in cerebral arteries are mediated via membrane and/or nuclear ER or independent of both. MCA of male 3 month old Sprague Dawley rats (152 ± 2µm, n=84) were isolated and mounted on a wire myograph, the arteries were allowed to equilibrate (37○C, 20mins). Following constriction with U46619 (EC50) the relaxant potential of the following drugs was assessed: Bradykinin (Bk;1µM), 17β-estradiol (E2;0.1-100µM), selective oestrogen receptor modulators (SERMs: LY2120310 and LY362321; 0.01nM-10µM), ER-β agonist, DPN (0.1-100µM) and ER-∝ agonist, PPT (0.1-100µM). The NOS inhibitor L-NAME (100µM) was used to evaluate the role of NO in relaxation. The non-selective ER antagonist ICI 182780 (1µM) was used to assess whether the relaxation is receptor dependent. Results are expressed as % relaxation of U46619-induced tone. Data are expressed as mean ± s.e.m., n ≤ 5 and analysed using unpaired t-test. Relaxation induced by Bk (61 ± 4%) was virtually abolished by L-NAME (6 ± 4%, p<0.05). In contrast relaxation induced by E2 (87 ± 3%) was unaffected by L-NAME (93 ± 1%) or ICI 182780 (80 ± 4%). SERM LY2120310 and SERM LY362321 had no significant effect on vessel tone (-72 ± 26% v/s -72 ± 15% vehicle and -20 ± 8% v/s -25 ± 10% vehicle, respectively). Relaxation induced by DPN (60 ± 7%) and PPT (97 ± 7%) was similarly not inhibited by ICI 182780 (74 ± 2%) and (95 ± 3%), respectively. The present study shows, for the first time, the vascular actions of SERMs and agonists on the MCA. E2 does not cause relaxation via the endothelial NOS pathway. There was no relaxation induced by SERMs. However, the PPT and DPN results indicate that the acute vasodilatory effects of oestrogen in the MCA may be via activation of ER-∝ and β, possibly at the level of the plasma membrane. This is in agreement with Montgomery et al (2003) who used mesenteric arteries from male rats and who speculate that such direct membrane effects may involve inhibition of calcium entry mechanisms.