Ward, Michael E. Effect of inhibition of nitric oxide synthesis on the diaphragmatic microvascular response to hypoxia. J. Appl. Physiol. 81(4): 1633-1641, 1996.The purpose of this study was to determine the effect of inhibition of nitric oxide (NO) release on the diaphragmatic microvascular responses to hypoxia. In -chloralose-anesthetized mongrel dogs, the microcirculation of the vascularly isolated ex vivo left hemidiaphragm was studied by intravital microscopy. The diaphragm was pump perfused with blood diverted from the femoral artery through a series of membrane oxygenators. The responses to supramaximal concentrations of sodium nitroprusside, moderate hypoxia (phrenic venous PO₂ 27 Torr), and severe hypoxia (phrenic venous PO₂ 15 Torr) were recorded before and after an infusion of N^G-nitro-L-arginine (L-NNA; 6 × 10⁴ M) into the phrenic circulation for 20 min. Under control conditions, diaphragmatic blood flow was 12.4 ± 1.1 ml ^· min^{1 ·} 100 g¹. Diaphragmatic blood flows recorded during moderate and severe hypoxia were 15.6 ± 1.2 and 24.3 ± 1.5 ml ^· min^{1 ·} 100 g¹, respectively (P < 0.05 for both compared with control values). Treatment with L-NNA reduced diaphragmatic blood flow to 9.6 ± 0.8 ml ^· min^{1 ·} 100 g¹ under control conditions (P < 0.05) and caused arteriolar vasoconstriction to a degree that was dependent on vessel size (i.e., larger vessels constricted more than smaller vessels). L-NNA eliminated the increase in blood flow during moderate hypoxia and inhibited arteriolar dilation by an amount that was related to vessel size (i.e., dilation of larger vessels was inhibited more than that of smaller vessels). Inhibition of NO synthesis had no effect on the increase in diaphragmatic blood flow (23.6 ± 1.9 ml ^· min^{1 ·} 100 g¹; P > 0.05 compared with that during severe hypoxia before treatment with L-NNA) or arteriolar diameters during severe hypoxia. NO release plays a role in the diaphragmatic vascular response to hypoxia, but this role is limited to dilation of larger arterioles during hypoxia of moderate severity.