Figure 7. The site and mechanism of action of O₂ in the hamster cheek pouch .

Schematic diagram depicting a mast cell (the proposed sensor site in the cheek pouch), a smooth muscle cell replete with receptors for cysteinyl leukotrienes (CysLTRs) and ion channels involved in arteriolar O₂ reactivity in the cheek pouch. Elevated $P_{{\mathrm{O}}_2}$ is sensed by the 5‐lipoxygenase (5‐LO) in the nuclear membrane of periarteriolar mast cells that decorate arterioles in this tissue (see Fig. 1). This results in conversion of arachidonic acid to cysteinyl leukotrienes (CysLTs) such as LTC₄, LTD₄ and LTE₄ through a process that involves presentation of the arachidonic acid to the 5‐LO by the 5‐LO‐activating protein (FLAP). This process can be inhibited by drugs such as MK 866, that blocks interaction of FLAP with the 5‐LO, or SC 43251, U 60257, nordihydroguaiaretic acid (NDGA), eicosatetraynoic acid (ETYA) or phenidone, inhibitors of the 5‐LO. The CysLTs then bind to and activate CysLTRs on vascular smooth muscle cells to induce vasoconstriction. CysLTR antagonists such as SKF 102922 or FPL 55712 can inhibit this step in the process. Activation of CysLTRs results in activation of L‐type Ca²⁺ channels (Ca_L), Ca²⁺ influx, an increase in intracellular Ca²⁺ and vasoconstriction, which can be antagonized by Ca_L blockers such as diltiazem or nifedipine. The increase in Ca²⁺ activates Ca²⁺‐activated Cl⁻ channels (Cl_Ca). The resulting efflux of Cl⁻ through these channels causes membrane depolarization, further activating Ca_L and amplifying the initial signal. Blockers of Cl_Ca channels such as niflumic acid or DIDs can inhibit this step in the process. The increase in intracellular Ca²⁺ and the membrane depolarization due to activation of Ca_L and Cl_Ca activates large conductance, Ca²⁺‐activated K⁺ channels (BK_Ca). The efflux of K⁺ through BK_Ca channels blunts the depolarizing effects of activation of Ca_L and Cl_Ca providing a degree of negative feedback, and limiting membrane depolarization. This step in the process can be inhibited by iberiotoxin or tetraethylammonium ions (TEA). Oxygen‐induced smooth muscle depolarization can be conducted along the vessel wall by gap junctions (GJ) supporting the conduction of O₂‐induced vasoconstriction that has been observed experimentally.