Vasoconstrictors activate phospholipase C (PLC) which hydrolyses phosphatidylinositol 4,5-bisphosphate (PIP₂) leading to calcium mobilisation, protein kinase C activation and contraction. Our aim was to investigate whether PLC₁, a PLC isoform implicated in ₁-adrenoreceptor signalling and the pathogenesis of hypertension, is involved in noradrenaline (NA) or endothelin (ET-1) induced PIP₂ hydrolysis and contraction. Rat mesenteric small arteries were studied. Contractility was measured by pressure myography, phospholipids or inositol phosphates were measured by radiolabelling with ³³Pi or [³H]-myo-inositol and caveolae/rafts prepared by discontinuous sucrose density centrifugation. PLC₁ was localised by immunoblot analysis and neutralised by delivery of PLC₁ antibody. The PLC inhibitor U73122 but not the negative control U73342 markedly inhibited NA and ET-1 contraction but had no effect on potassium or phorbol ester contraction implicating PLC activity in receptor-mediated smooth muscle contraction. PLC₁ was present in caveolae/rafts and NA but not ET-1 stimulated a rapid two-fold increase in PLC1 levels in these domains. PLC1 is calcium dependent and removal of extracellular calcium prevented its association with caveolae/rafts in response to NA, concomitantly reducing NA-induced [³³P]-PIP₂ hydrolysis and [³H]-inositol phosphate formation but with no effect on ET-1-induced [³³P]-PIP₂ hydrolysis. Neutralisation of PLC₁ by PLC₁ antibody prevented its caveolae/raft association and attenuated the sustained contractile response to NA when compared to control antibodies. In contrast, ET-1-induced contraction was not affected by PLC₁ antibody. These results indicate the novel and selective role of caveolae/raft localised PLC₁ in NA-induced PIP₂ hydrolysis and sustained contraction in intact vascular tissue.