Figure 2. Schematic illustration of vasodilator interactions in skeletal muscle arterioles.

A, illustration of a simplified view of endothelium-dependent induction of vasodilatation. Vasodilator agonist, such as adenosine or acetylcholine (ACh), acts on specific receptors on endothelial cells lining the luminal side of an arteriole. The receptor activation leads to the formation of compounds which cause relaxation of smooth muscle cells situated adjacent to the endothelial cells resulting in vasodilatation of the arteriole. B, detailed illustration of how vasodilator systems in the vascular wall can be activated and of proposed interactions between vasodilator systems. In vascular endothelial cells, several compounds, including acetylcholine, ATP, adenosine and bradykinin as well as mechanical signals including shear stress, activate both endothelial NO synthase (eNOS) and the arachidonic acid pathway leading to formation of prostacyclin (PGI₂) and eicosatrienoic acids (EETs). Activation of NOS and the arachidonic acid pathway occurs via an increase in intracellular calcium but eNOS activity is also regulated by protein phosphorylation at different sites. Redundancy exists between the NO and the prostacyclin systems where one described mechanism is inhibition of NOS by prostacyclin. Redundancy also exists between the NO system and cytochrome P450 2C9 (CYP 2C9), which produces 11,12-eicosatrienoic acid (11,12-EET) that can induce smooth muscle cell (SMC) relaxation by hyperpolarization. During normal conditions, NO exerts an inhibitory effect on CYP 2C9 but when NO formation is inhibited, the activity of CYP 2C9 increases. In the smooth muscle cell cyclic guanosine monophosphate (cGMP) can promote cyclic adenosine monophosphate (cAMP) levels by inhibiting phosphodiesterase III, which degrades cAMP. Abbreviations: AChR: acetylcholine receptor; AA: arachidonic acid; ATP: adenosine 5′-triphosphate; BKR: bradykinin receptor; 11, 12 EETs: 11, 12 eicosatrienoic acid; CaM: calmodulin; CaMK: calmodulin kinase; cAMP: cyclic adenosine monophosphate; cGMP: cyclic guanosine monophosphate; COX: cyclooxygenase; CYP 2C9: cytochrome P450 2C9; HR: histamine receptor; PGI₂: prostacyclin; PKA, protein kinase A; PKC: protein kinase C; P1: purinergic receptor 1; P2: purinergic receptor 2; SMC: smooth muscle cell.