We have suggested that the expression of various signalling intermediates and channels at the junction of endothelial and smooth muscle cells forms a unique signalling microdomain. In isolated rat mesenteric resistance arteries, we investigated how this signalling domain might influence arterial tone. Myoendothelial gap junctions occur at regular intervals in this artery, the endothelium physically projecting through the holes in the internal elastic lamina (IEL) to make contact with smooth muscle cells. Thus, potentially there is the possibility for both direct cell-cell coupling of via current spread, and heterocellular coupling of signalling molecules to include inositol trisphosphate (InsP₃). The pathways leading to hyperpolarization of smooth muscle cells due to endothelial cell-specific agonists crucially involves the activation of endothelial cell small (SK_Ca) and intermediate (IK_Ca) conductance Ca²⁺-activated K⁺ channels, both of which are found in the endothelial cell projections through the IEL in this artery. The Na⁺/K⁺-ATPase, and inwardly rectifying K⁺ channels are found close to these channels, raising the possibility of K⁺ efflux through K_Ca channels further amplify hyperpolarization. It has also been demonstrated that InsP₃ and calcium sensing receptors are expressed within this signalling microdomain, each of which can be influenced by activation of endothelial or smooth muscle cells. How these processes interact and are modulated form a new avenue of research into how arterial diameter is controlled, and should be considered in situations of compromised function.