Figure 1.
Figure 1. Systolic blood pressure and vasoconstriction is significantly elevated in mice given both L-NAME and NSAIDs. (A) In vivo inhibition of COX-2 using celecoxib. Twenty-four–hour urine samples were obtained from mice administered celecoxib ± L-NAME for 3 days and analyzed using GC/MS for PGI metabolite (2,3-Dinor-6-KetoPGF1α) urinary excretion. (B) No inhibition of COX-1 in vivo using celecoxib. Twenty-four–hour urine samples were obtained as for panel A and analyzed using GC/MS for TX urinary metabolite (11-dehydroTxB2) urinary excretion (for both panels, n = 3-4 cages per group with 3 mice per cage, mean ± SEM). (C) Blood pressure elevations following celecoxib and L-NAME administration. Ten- to 12-week-old male C57BL/6 mice were administered L-NAME, celecoxib, or both. Systolic blood pressure was monitored daily. ▪, control mice; ○, L-NAME; ▵, celecoxib; ▴, celecoxib and L-NAME. (D) Blood pressure elevations following indomethacin and L-NAME administration. Ten- to 12-week-old male C57BL/6 mice were administered L-NAME, indomethacin, or both. Systolic blood pressure was monitored daily. ▪ indicates control mice; ○, L-NAME; ▵, indo; ▴, indo and L-NAME (for all blood pressure determinations, n = 5 animals per group, mean ± SEM, *P < .05 compared with day 0; using ANOVA test with Dunnett Post-Hoc Test to isolate differences). (E) Effect of celecoxib on in vitro constriction dose response. Aortic ring constriction responses to phenylephrine were determined (n = 5-9 per group). Control (▪), L-NAME (300 μM; ○), celecoxib (10 μM; ▵), or L-NAME (300 μM) and celecoxib (10 μM; ▴). (F) Effect of indomethacin on constriction dose response. Aortic ring constriction responses to phenylephrine were determined (n = 5-9 per group). Control (▪), L-NAME (300 μM; ○), indomethacin (10 μM; ▵), or L-NAME (300 μM) and indomethacin (10 μM; ▴) (G) Effect of aspirin on constriction dose response. Aortic ring constriction responses to phenylephrine were determined (n = 5-9 per group). Control (▪), L-NAME (300 μM; ○), indomethacin (10 μM; ▵), or L-NAME (300 μM) and aspirin (100 μM; ▴). (H) Effect of COX-2 deletion on constriction dose response. Aortic ring constriction responses to phenylephrine were determined (n = 5-9 per group). WT (▪), COX2–/– (○), WT + L-NAME (300 μM; ▵), and COX-2–/– + L-NAME (300 μM; ▴). (I) Aortic rings spontaneously constrict in the presence of SMTC and celecoxib. Aortic ring tone was determined using myography after 15 minutes of incubation (n = 4-6 per group) with SMTC (100 μM) with or without celecoxib (10 μM). Inset shows representative trace from myograph. (J) Exogenous NO abolishes the vasoconstrictive effect of celecoxib. Aortic ring constriction responses to phenylephrine were determined (n = 6 per group). WT + L-NAME (300 μM) + DETA NONOate (30 μM; ▾)WT + L-NAME + DETA NONOate + celecoxib (10 μM; ▴). For all aortic ring myography scans, data are expressed as mean ± SEM. *P < .05 compared with WT group, using 2-way ANOVA to isolate differences between groups.

Systolic blood pressure and vasoconstriction is significantly elevated in mice given both L-NAME and NSAIDs. (A) In vivo inhibition of COX-2 using celecoxib. Twenty-four–hour urine samples were obtained from mice administered celecoxib ± L-NAME for 3 days and analyzed using GC/MS for PGI metabolite (2,3-Dinor-6-KetoPGF1α) urinary excretion. (B) No inhibition of COX-1 in vivo using celecoxib. Twenty-four–hour urine samples were obtained as for panel A and analyzed using GC/MS for TX urinary metabolite (11-dehydroTxB2) urinary excretion (for both panels, n = 3-4 cages per group with 3 mice per cage, mean ± SEM). (C) Blood pressure elevations following celecoxib and L-NAME administration. Ten- to 12-week-old male C57BL/6 mice were administered L-NAME, celecoxib, or both. Systolic blood pressure was monitored daily. ▪, control mice; ○, L-NAME; ▵, celecoxib; ▴, celecoxib and L-NAME. (D) Blood pressure elevations following indomethacin and L-NAME administration. Ten- to 12-week-old male C57BL/6 mice were administered L-NAME, indomethacin, or both. Systolic blood pressure was monitored daily. ▪ indicates control mice; ○, L-NAME; ▵, indo; ▴, indo and L-NAME (for all blood pressure determinations, n = 5 animals per group, mean ± SEM, *P < .05 compared with day 0; using ANOVA test with Dunnett Post-Hoc Test to isolate differences). (E) Effect of celecoxib on in vitro constriction dose response. Aortic ring constriction responses to phenylephrine were determined (n = 5-9 per group). Control (▪), L-NAME (300 μM; ○), celecoxib (10 μM; ▵), or L-NAME (300 μM) and celecoxib (10 μM; ▴). (F) Effect of indomethacin on constriction dose response. Aortic ring constriction responses to phenylephrine were determined (n = 5-9 per group). Control (▪), L-NAME (300 μM; ○), indomethacin (10 μM; ▵), or L-NAME (300 μM) and indomethacin (10 μM; ▴) (G) Effect of aspirin on constriction dose response. Aortic ring constriction responses to phenylephrine were determined (n = 5-9 per group). Control (▪), L-NAME (300 μM; ○), indomethacin (10 μM; ▵), or L-NAME (300 μM) and aspirin (100 μM; ▴). (H) Effect of COX-2 deletion on constriction dose response. Aortic ring constriction responses to phenylephrine were determined (n = 5-9 per group). WT (▪), COX2–/– (○), WT + L-NAME (300 μM; ▵), and COX-2–/– + L-NAME (300 μM; ▴). (I) Aortic rings spontaneously constrict in the presence of SMTC and celecoxib. Aortic ring tone was determined using myography after 15 minutes of incubation (n = 4-6 per group) with SMTC (100 μM) with or without celecoxib (10 μM). Inset shows representative trace from myograph. (J) Exogenous NO abolishes the vasoconstrictive effect of celecoxib. Aortic ring constriction responses to phenylephrine were determined (n = 6 per group). WT + L-NAME (300 μM) + DETA NONOate (30 μM; ▾)WT + L-NAME + DETA NONOate + celecoxib (10 μM; ▴). For all aortic ring myography scans, data are expressed as mean ± SEM. *P < .05 compared with WT group, using 2-way ANOVA to isolate differences between groups.

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