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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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Left ventricular function evaluation based on invasive hemodynamic variables and oxygen metabolism. (A) Heart rate (HR). (B) Cardiac output (CO). (C) Mean aortic pressure (MAP). (D) Coronary perfusion pressure (CPP). (E) Mean pulmonary arterial pressure (MPAP). (F) Oxygen delivery (DO2). (G) Oxygen consumption (VO2). (H) Lactate (Lac). The values are reported as mean ± SD. ROSC, restoration of spontaneous circulation; SA, saline. *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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Fig4: Left ventricular function evaluation based on invasive hemodynamic variables and oxygen metabolism. (A) Heart rate (HR). (B) Cardiac output (CO). (C) Mean aortic pressure (MAP). (D) Coronary perfusion pressure (CPP). (E) Mean pulmonary arterial pressure (MPAP). (F) Oxygen delivery (DO2). (G) Oxygen consumption (VO2). (H) Lactate (Lac). The values are reported as mean ± SD. ROSC, restoration of spontaneous circulation; SA, saline. *P < 0.05 vs. sham, **P < 0.01 vs. sham, ΔP < 0.05 vs. saline (one-way repeated-measures analysis of variance).

Mentions: After ROSC, HR was significantly lower in the sildenafil group compared with the SA group at 1 and 2 hours after ROSC (P = 0.04, P = 0.03, respectively); however, there were no significant differences between the two groups at any other time points (Figure 4A). The CO values were significantly higher in the sildenafil group than in the SA group at 4 hours and 6 hours after ROSC (P = 0.02, P = 0.04, respectively) (Figure 4B). The MAP and CPP values were significantly increased in the sildenafil group compared with the SA group at baseline and 30 minutes after ROSC (P < 0.05 for both) (Figures 4C and 4D). These values were similar between the groups at other time points. Notably, MPAP was elevated in the sildenafil group and the SA group after CA, and the values of MPAP in the sildenafil group were continuously lower than in the SA group at most time points (P < 0.05, respectively) (Figure 4E). Oxygen metabolism measurements were compared among the three groups. DO2 was significantly higher in the sildenafil group than in the SA group at 2, 4 and 6 hours after ROSC (P = 0.03, P = 0.02 and P = 0.04, respectively), and VO2 was significantly higher in the sildenafil group than in the SA group at 30 minutes and 1, 2, 4 and 6 hours after ROSC (P = 0.02, P = 0.03, P = 0.007, P = 0.03 and P = 0.04, respectively) (Figures 4F and 4G). Serum lactate concentrations were significantly increased throughout the study time points after ROSC compared with baseline values in two groups (the SA and sildenafil groups) (P < 0.05) (Figure 4H). However, the lactate concentrations were lower in the sildenafil group than in the SA group at 30 minutes and 1 and 2 hours after ROSC (P = 0.02, P = 0.03, P = 0.01, respectively) (see Additional file 1: Table S1 for details).Figure 4


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)

Left ventricular function evaluation based on invasive hemodynamic variables and oxygen metabolism. (A) Heart rate (HR). (B) Cardiac output (CO). (C) Mean aortic pressure (MAP). (D) Coronary perfusion pressure (CPP). (E) Mean pulmonary arterial pressure (MPAP). (F) Oxygen delivery (DO2). (G) Oxygen consumption (VO2). (H) Lactate (Lac). The values are reported as mean ± SD. ROSC, restoration of spontaneous circulation; SA, saline. *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
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getmorefigures.php?uid=PMC4262990&req=5

Fig4: Left ventricular function evaluation based on invasive hemodynamic variables and oxygen metabolism. (A) Heart rate (HR). (B) Cardiac output (CO). (C) Mean aortic pressure (MAP). (D) Coronary perfusion pressure (CPP). (E) Mean pulmonary arterial pressure (MPAP). (F) Oxygen delivery (DO2). (G) Oxygen consumption (VO2). (H) Lactate (Lac). The values are reported as mean ± SD. ROSC, restoration of spontaneous circulation; SA, saline. *P < 0.05 vs. sham, **P < 0.01 vs. sham, ΔP < 0.05 vs. saline (one-way repeated-measures analysis of variance).
Mentions: After ROSC, HR was significantly lower in the sildenafil group compared with the SA group at 1 and 2 hours after ROSC (P = 0.04, P = 0.03, respectively); however, there were no significant differences between the two groups at any other time points (Figure 4A). The CO values were significantly higher in the sildenafil group than in the SA group at 4 hours and 6 hours after ROSC (P = 0.02, P = 0.04, respectively) (Figure 4B). The MAP and CPP values were significantly increased in the sildenafil group compared with the SA group at baseline and 30 minutes after ROSC (P < 0.05 for both) (Figures 4C and 4D). These values were similar between the groups at other time points. Notably, MPAP was elevated in the sildenafil group and the SA group after CA, and the values of MPAP in the sildenafil group were continuously lower than in the SA group at most time points (P < 0.05, respectively) (Figure 4E). Oxygen metabolism measurements were compared among the three groups. DO2 was significantly higher in the sildenafil group than in the SA group at 2, 4 and 6 hours after ROSC (P = 0.03, P = 0.02 and P = 0.04, respectively), and VO2 was significantly higher in the sildenafil group than in the SA group at 30 minutes and 1, 2, 4 and 6 hours after ROSC (P = 0.02, P = 0.03, P = 0.007, P = 0.03 and P = 0.04, respectively) (Figures 4F and 4G). Serum lactate concentrations were significantly increased throughout the study time points after ROSC compared with baseline values in two groups (the SA and sildenafil groups) (P < 0.05) (Figure 4H). However, the lactate concentrations were lower in the sildenafil group than in the SA group at 30 minutes and 1 and 2 hours after ROSC (P = 0.02, P = 0.03, P = 0.01, respectively) (see Additional file 1: Table S1 for details).Figure 4

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