Abstract

Compared to other cyclooxygenase-2 inhibitors, celecoxib is associated with a lower cardiovascular risk, though the mechanism remains unclear. Angiotensin II is an important mediator of oxidative stress in the pathophysiology of vascular disease. Cyclooxygenase-2 may modify the effects of angiotensin II though this has never been studied in humans. The purpose of the study was to test the effects of selective cyclooxygenase-2 inhibition on plasma measures of oxidative stress, the vasoconstrictor endothelin-1, and nitric oxide metabolites, both at baseline and in respose to Angiotensin II challenge in healthy humans. Measures of 8-hydroxydeoxyguanosine, advanced oxidation protein products, nitrotyrosine, endothelin-1, and nitric oxide metabolites were assessed from plasma samples drawn at baseline and in response to graded angiotensin II infusion (3 ng/kg/min × 30 min, 6 ng/kg/min × 30 min) before and after 14 days of cyclooxygenase-2 inhibition in 14 healthy subjects (eight male, six female) in high salt balance, a state of maximal renin angiotensin system suppression. Angiotensin II infusion significantly increased plasma oxidative stress compared to baseline (8-hydroxydeoxyguanosine; +17%; advanced oxidation protein products; +16%), nitrotyrosine (+76%). Furthermore, levels of endothelin-1 levels were significantly increased (+115%) and nitric oxide metabolites were significantly decreased (−20%). Cycloxygenase-2 inhibition significantly limited the increase in 8-hydroxydeoxyguanosine, nitrotyrosine and the decrease in nitric oxide metabolites induced by angiotensin II infusion, though no changes in advanced oxidation protein products and endothelin-1 concentrations were observed. Cyclooxygenase-2 inhibition with celecoxib partially limited the angiotensin II-mediated increases in markers of oxidative stress in humans, offering a potential physiological pathway for the improved cardiovascular risk profile of this drug.

Highlights

  • Compared to other cyclooxygenase-2 inhibitors, celecoxib is associated with a lower cardiovascular risk (Solomon et al, 2004; Hirayama et al, 2014; Nissen et al, 2016; Gunter et al, 2017)

  • Though the mechanism is unclear, animal studies suggest that COX-2-inhibition plays a role in attenuating the effects of Angiotensin II (AngII; Wu et al, 2005; Martínez-Revelles et al, 2013) the effector molecule of the renin angiotensin system (RAS), which plays a central role in the pathophysiology of hypertension, an important risk factor for cardiovascular disease (Touyz and Schiffrin, 2004; Mehta and Griendling, 2007)

  • AngII increased all measures of oxidative stress (Table 2; 8OHdG: +17%, p = 0.02 at 90 min (Figure 1); advanced oxidation protein products (AOPP): +15 and +16%, p = 0.01 at 30 and 60 min), protein nitration (+76%, p = 0.004 at 60 min), ferric reducing antioxidant power (FRAP): −13 and −14%, p = 0.04 at 60 and 90 min)

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Summary

Introduction

Compared to other cyclooxygenase-2 inhibitors, celecoxib is associated with a lower cardiovascular risk (Solomon et al, 2004; Hirayama et al, 2014; Nissen et al, 2016; Gunter et al, 2017). Though the mechanism is unclear, animal studies suggest that COX-2-inhibition plays a role in attenuating the effects of Angiotensin II (AngII; Wu et al, 2005; Martínez-Revelles et al, 2013) the effector molecule of the renin angiotensin system (RAS), which plays a central role in the pathophysiology of hypertension, an important risk factor for cardiovascular disease (Touyz and Schiffrin, 2004; Mehta and Griendling, 2007). Animal studies suggest that cyclooxygenase-2 plays a role in attenuating these effects, mainly via the reduction of the NADPH oxidase-dependent superoxide anion generation (Martínez-Revelles et al, 2013; Wu et al, 2005), suggesting that inhibition of this enzyme could blunt the unfavorable oxidative stress effects of AngII, though this has never been studied in humans

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