Soluble Guanylyl Cyclase Activation Rescues Hyperoxia-Induced Dysfunction of Vascular Relaxation

Abstract

Introduction: Perioperative alterations in perfusion lead to ischemia and reperfusion injury, and supplemental oxygen is administered during surgery to limit hypoxic injury but can lead to hyperoxia. We hypothesized that hyperoxia impairs endothelium-dependent and endothelium-independent vasodilation but not the vasodilatory response to heme-independent soluble guanylyl cyclase activation. Methods: We measured the effect of oxygen on vascular reactivity in mouse aortas. Mice were ventilated with 21% (normoxia), 60% (moderate hyperoxia), or 100% (severe hyperoxia) oxygen during 30 minutes of renal ischemia and 30 minutes of reperfusion. After sacrifice, the thoracic aorta was isolated, and segments mounted on a wire myograph. We measured endothelium-dependent and endothelium-independent vasodilation with escalating concentrations of acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, and we measured the response to heme-independent soluble guanylyl cyclase activation with cinaciguat. Vasodilator responses to each agonist were quantified as the maximal theoretical response (Emax) and the effective concentration to elicit 50% relaxation (EC50) using a sigmoid model and nonlinear mixed-effects regression. Aortic superoxide was measured with dihydroethidium probe and high-performance liquid chromatography quantification of the specific superoxide product 2-hydroxyethidium. Results: Hyperoxia impaired endothelium-dependent (ACh) and endothelium-independent (SNP) vasodilation compared with normoxia and had no effect on cinaciguat-induced vasodilation. The median ACh Emax was 76.4% (95% confidence interval = 69.6 to 83.3) in the normoxia group, 53.5% (46.7 to 60.3) in the moderate hyperoxia group, and 53.1% (46.3 to 60.0) in the severe hyperoxia group (P < 0.001, effect across groups), while the ACh EC50 was not different among groups. The SNP Emax was 133.1% (122.9 to 143.3) in normoxia, 128.3% (118.1 to 138.6) in moderate hyperoxia, and 114.8% (104.6 to 125.0) in severe hyperoxia (P < 0.001, effect across groups), and the SNP EC50 was 0.38 log M greater in moderate hyperoxia than in normoxia (95% confidence interval = 0.18 to 0.58, P < 0.001). Cinaciguat Emax and EC50 were not different among oxygen treatment groups (median range Emax = 78.0% to 79.4% and EC50 = –18.0 to −18.2 log M across oxygen groups). Aorta 2-hydroxyethidium was 1419 pmol/mg of protein (25th–75th percentile = 1178–1513) in normoxia, 1993 (1831–2473) in moderate hyperoxia, and 2078 (1936–2922) in severe hyperoxia (P = 0.008, effect across groups). Conclusions: Hyperoxia, compared with normoxia, impaired endothelium-dependent and endothelium-independent vasodilation but not the response to heme-independent soluble guanylyl cyclase activation, and hyperoxia increased vascular superoxide production. Results from this study could have important implications for patients receiving high concentrations of oxygen and at risk for ischemia reperfusion-mediated organ injury.

Hyperoxia Increases Kidney Injury During Renal Ischemia and Reperfusion in Mice

“…9,10 In addition, hyperoxia impairs endothelium-dependent and endothelium-independent vascular reactivity, dysregulating tissue perfusion. 11 During major surgery, alterations in cardiac output, intravascular volume, and vascular resistance, venous congestion, hemorrhage, transfusion, and anesthetics all impact renal ischemia and reperfusion (IR) and may culminate in AKI. Thus, renal IR injury is common during major surgery, and oxygenation may affect this mechanism of kidney injury.…”

Targeting Soluble Guanylyl Cyclase during Ischemia and Reperfusion

“…In swine with induced coronary artery stenosis, for example, the administration of hyperoxia decreased coronary blood flow and led to myocardial ischemia and decreased cardiac output [61]. These changes may be mediated by endothelium-dependent vasoconstriction in response to hyperoxia [62]. Hyperoxia promotes increased oxidative stress, and oxidative stress may further contribute to hyperoxic vasoconstriction [63][64][65].…”

“…Therefore, vascular effects may mediate these renal observations. In a murine study of variable oxygen tension (PaO 2 range 104-318 mmHg) during renal IR injury, aortic responses to endothelium-dependent and -independent vasodilation were impaired in hyperoxia treated animals, while the response to the sGC activator cinaciguat was unaffected by oxygen tension [62].…”