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The protective effects of a phosphodiesterase 5 inhibitor, sildenafil, on postresuscitation cardiac dysfunction of cardiac arrest: metabolic evidence from microdialysis.

Zhang Q, Yuan W, Wang G, Wu J, Wang M, Li C - Crit Care (2014)

Bottom Line: Advanced cardiac life support was delivered to both groups, with a 24-hour survival rate showing a promising trend in the sildenafil group (7 of 8 versus 3 of 8 survivors, P < 0.05).Compared with the SA group, the sildenafil group had a better outcome in terms of hemodynamic and oxygen metabolism parameters (P < 0.05).Myocardial tissue analysis revealed a dramatic increase in the contents of ATP, ADP and phosphocreatine in the sildenafil group versus the SA group at 24 hours after return of spontaneous circulation (ROSC; P = 0.03, P = 0.02 and P = 0.02, respectively).

View Article: PubMed Central - PubMed

Affiliation: Department of Emergency Medicine, Beijing Chao-yang Hospital, Capital Medical University, 8# Worker's Stadium South Road, Chao-yang District, Beijing, 100020, China. zqian604@163.com.

ABSTRACT

Introduction: Recent experimental and clinical studies have indicated the cardioprotective role of sildenafil during ischemia/reperfusion injury. The aim of this study was to determine, by obtaining metabolic evidence from microdialysis, if sildenafil could reduce the severity of postresuscitation myocardial dysfunction and lead to cardioprotection through beneficial effects on energy metabolism.

Methods: Twenty-four male piglets were randomly divided into three groups: sildenafil (n = 8), saline (SA; n = 8) and sham operation (n = 8). Sildenafil pretreatment consisted of 0.5 mg/kg sildenafil administered once intraperitoneally 30 minutes prior to ventricular fibrillation (VF). The myocardial interstitial fluid (ISF) concentrations of glucose, lactate, pyruvate, glutamate and glycerol were determined by microdialysis before VF. Afterward, the piglets were subjected to 8 minutes of untreated VF followed by 15 minutes of open-chest cardiopulmonary resuscitation. ISF was collected continuously, and the experiment was terminated 24 hours after resuscitation.

Results: After 8 minutes of untreated VF, the sildenafil group exhibited higher glucose and pyruvate concentrations of ISF and lower lactate and glutamate levels in comparison with the SA group, and these data reached statistical significance (P < 0.05). Advanced cardiac life support was delivered to both groups, with a 24-hour survival rate showing a promising trend in the sildenafil group (7 of 8 versus 3 of 8 survivors, P < 0.05). Compared with the SA group, the sildenafil group had a better outcome in terms of hemodynamic and oxygen metabolism parameters (P < 0.05). Myocardial tissue analysis revealed a dramatic increase in the contents of ATP, ADP and phosphocreatine in the sildenafil group versus the SA group at 24 hours after return of spontaneous circulation (ROSC; P = 0.03, P = 0.02 and P = 0.02, respectively). Furthermore, 24 hours after ROSC, the sildenafil group had marked elevations in activity of left ventricular Na(+)-K(+)-ATPase and Ca(2+)-ATPase compared with the SA group (P = 0.03, P = 0.04, respectively).

Conclusions: Sildenafil could reduce the severity of postresuscitation myocardial dysfunction, and it produced better clearance of metabolic waste in the ISF. This work might provide insights into the development of a novel strategy to treat postresuscitation myocardial dysfunction.

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The myocardial interstitial fluid concentrations of glucose, lactate, pyruvate, glycerol and glutamate as determined by microdialysis under basal conditions (before ventricular fibrillation) and after ventricular fibrillation. (A) Myocardial interstitial fluid (ISF) concentrations of glucose. (B) ISF concentrations of lactate (Lac). (C) ISF concentrations of pyruvate. (D): ISF concentrations of glycerol. (E) ISF concentrations of lactate/pyruvate (Lac/pyr). (F) ISF concentrations of glutamate. The values are reported as mean ± SD. CPR, Cardiopulmonary resuscitation; ROSC, restoration of spontaneous circulation; VF, Ventricular fibrillation. *P < 0.05 vs. sham, **P < 0.01 vs. sham, ΔP < 0.05 vs. saline (one-way repeated-measures analysis of variance).
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Fig5: The myocardial interstitial fluid concentrations of glucose, lactate, pyruvate, glycerol and glutamate as determined by microdialysis under basal conditions (before ventricular fibrillation) and after ventricular fibrillation. (A) Myocardial interstitial fluid (ISF) concentrations of glucose. (B) ISF concentrations of lactate (Lac). (C) ISF concentrations of pyruvate. (D): ISF concentrations of glycerol. (E) ISF concentrations of lactate/pyruvate (Lac/pyr). (F) ISF concentrations of glutamate. The values are reported as mean ± SD. CPR, Cardiopulmonary resuscitation; ROSC, restoration of spontaneous circulation; VF, Ventricular fibrillation. *P < 0.05 vs. sham, **P < 0.01 vs. sham, ΔP < 0.05 vs. saline (one-way repeated-measures analysis of variance).

Mentions: The microdialysis probes were implanted and extracted without inducing arrhythmias or other side effects. Real-time measurement of myocardial energy metabolic variables (glucose, pyruvate and glutamate), markers of injury (lactate and glycerol) and their ratios are presented in Figures 5A to 5E. No differences were noted at baseline between the groups. The mean ISF glucose levels decreased in all groups after CA and increased following CPR. The sildenafil group had a higher glucose level than the SA group during VF and the early reperfusion phase (P < 0.05) (Figure 5A). ISF lactate was elevated in all groups after VF, and the lactate levels rose further to reach a maximum after 10 minutes of VF and then declined slowly. Lactate levels in the SA group were continuously higher than in the other two groups (P < 0.05) (Figure 5B). The pyruvate levels were reduced significantly in the sildenafil and SA groups during VF; however, the levels of pyruvate were higher in the sildenafil group than in the SA group, even after CPR (Figure 5C). The glycerol level was elevated in the SA group after VF and stayed at a higher level compared with the other two groups, and the glycerol level of the sildenafil group also increased after VF and declined more significantly than in the SA group (Figure 5D). The lactate-to-pyruvate (L/P) ratios and glutamate levels in the SA group were dramatically higher than in the other two groups during and after CA (P < 0.05) (Figures 5E and 5F). Additional information is available in Additional file 1: Table S2.Figure 5


The protective effects of a phosphodiesterase 5 inhibitor, sildenafil, on postresuscitation cardiac dysfunction of cardiac arrest: metabolic evidence from microdialysis.

Zhang Q, Yuan W, Wang G, Wu J, Wang M, Li C - Crit Care (2014)

The myocardial interstitial fluid concentrations of glucose, lactate, pyruvate, glycerol and glutamate as determined by microdialysis under basal conditions (before ventricular fibrillation) and after ventricular fibrillation. (A) Myocardial interstitial fluid (ISF) concentrations of glucose. (B) ISF concentrations of lactate (Lac). (C) ISF concentrations of pyruvate. (D): ISF concentrations of glycerol. (E) ISF concentrations of lactate/pyruvate (Lac/pyr). (F) ISF concentrations of glutamate. The values are reported as mean ± SD. CPR, Cardiopulmonary resuscitation; ROSC, restoration of spontaneous circulation; VF, Ventricular fibrillation. *P < 0.05 vs. sham, **P < 0.01 vs. sham, ΔP < 0.05 vs. saline (one-way repeated-measures analysis of variance).
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4262990&req=5

Fig5: The myocardial interstitial fluid concentrations of glucose, lactate, pyruvate, glycerol and glutamate as determined by microdialysis under basal conditions (before ventricular fibrillation) and after ventricular fibrillation. (A) Myocardial interstitial fluid (ISF) concentrations of glucose. (B) ISF concentrations of lactate (Lac). (C) ISF concentrations of pyruvate. (D): ISF concentrations of glycerol. (E) ISF concentrations of lactate/pyruvate (Lac/pyr). (F) ISF concentrations of glutamate. The values are reported as mean ± SD. CPR, Cardiopulmonary resuscitation; ROSC, restoration of spontaneous circulation; VF, Ventricular fibrillation. *P < 0.05 vs. sham, **P < 0.01 vs. sham, ΔP < 0.05 vs. saline (one-way repeated-measures analysis of variance).
Mentions: The microdialysis probes were implanted and extracted without inducing arrhythmias or other side effects. Real-time measurement of myocardial energy metabolic variables (glucose, pyruvate and glutamate), markers of injury (lactate and glycerol) and their ratios are presented in Figures 5A to 5E. No differences were noted at baseline between the groups. The mean ISF glucose levels decreased in all groups after CA and increased following CPR. The sildenafil group had a higher glucose level than the SA group during VF and the early reperfusion phase (P < 0.05) (Figure 5A). ISF lactate was elevated in all groups after VF, and the lactate levels rose further to reach a maximum after 10 minutes of VF and then declined slowly. Lactate levels in the SA group were continuously higher than in the other two groups (P < 0.05) (Figure 5B). The pyruvate levels were reduced significantly in the sildenafil and SA groups during VF; however, the levels of pyruvate were higher in the sildenafil group than in the SA group, even after CPR (Figure 5C). The glycerol level was elevated in the SA group after VF and stayed at a higher level compared with the other two groups, and the glycerol level of the sildenafil group also increased after VF and declined more significantly than in the SA group (Figure 5D). The lactate-to-pyruvate (L/P) ratios and glutamate levels in the SA group were dramatically higher than in the other two groups during and after CA (P < 0.05) (Figures 5E and 5F). Additional information is available in Additional file 1: Table S2.Figure 5

Bottom Line: Advanced cardiac life support was delivered to both groups, with a 24-hour survival rate showing a promising trend in the sildenafil group (7 of 8 versus 3 of 8 survivors, P < 0.05).Compared with the SA group, the sildenafil group had a better outcome in terms of hemodynamic and oxygen metabolism parameters (P < 0.05).Myocardial tissue analysis revealed a dramatic increase in the contents of ATP, ADP and phosphocreatine in the sildenafil group versus the SA group at 24 hours after return of spontaneous circulation (ROSC; P = 0.03, P = 0.02 and P = 0.02, respectively).

View Article: PubMed Central - PubMed

Affiliation: Department of Emergency Medicine, Beijing Chao-yang Hospital, Capital Medical University, 8# Worker's Stadium South Road, Chao-yang District, Beijing, 100020, China. zqian604@163.com.

ABSTRACT

Introduction: Recent experimental and clinical studies have indicated the cardioprotective role of sildenafil during ischemia/reperfusion injury. The aim of this study was to determine, by obtaining metabolic evidence from microdialysis, if sildenafil could reduce the severity of postresuscitation myocardial dysfunction and lead to cardioprotection through beneficial effects on energy metabolism.

Methods: Twenty-four male piglets were randomly divided into three groups: sildenafil (n = 8), saline (SA; n = 8) and sham operation (n = 8). Sildenafil pretreatment consisted of 0.5 mg/kg sildenafil administered once intraperitoneally 30 minutes prior to ventricular fibrillation (VF). The myocardial interstitial fluid (ISF) concentrations of glucose, lactate, pyruvate, glutamate and glycerol were determined by microdialysis before VF. Afterward, the piglets were subjected to 8 minutes of untreated VF followed by 15 minutes of open-chest cardiopulmonary resuscitation. ISF was collected continuously, and the experiment was terminated 24 hours after resuscitation.

Results: After 8 minutes of untreated VF, the sildenafil group exhibited higher glucose and pyruvate concentrations of ISF and lower lactate and glutamate levels in comparison with the SA group, and these data reached statistical significance (P < 0.05). Advanced cardiac life support was delivered to both groups, with a 24-hour survival rate showing a promising trend in the sildenafil group (7 of 8 versus 3 of 8 survivors, P < 0.05). Compared with the SA group, the sildenafil group had a better outcome in terms of hemodynamic and oxygen metabolism parameters (P < 0.05). Myocardial tissue analysis revealed a dramatic increase in the contents of ATP, ADP and phosphocreatine in the sildenafil group versus the SA group at 24 hours after return of spontaneous circulation (ROSC; P = 0.03, P = 0.02 and P = 0.02, respectively). Furthermore, 24 hours after ROSC, the sildenafil group had marked elevations in activity of left ventricular Na(+)-K(+)-ATPase and Ca(2+)-ATPase compared with the SA group (P = 0.03, P = 0.04, respectively).

Conclusions: Sildenafil could reduce the severity of postresuscitation myocardial dysfunction, and it produced better clearance of metabolic waste in the ISF. This work might provide insights into the development of a novel strategy to treat postresuscitation myocardial dysfunction.

Show MeSH
Related in: MedlinePlus