Anti-Ischemia Drugs have no Effect on the In Vivo Metabolism of ATP by RBC in Normotensive Restrained Rats#

Abstract

Abstract:The objective is to determine the effect of anti-ishemia agents on metabolism of adenosine-5'-triphosphate (ATP) in red blood cell (RBC) in a normotensive rat model. Male Sprague Dawley (SD) rats weighing between 300 -400 g were used. Each rat received either saline (control), or 5 mg/kg of diltiazem (DTZ), losartan, amlodipine or dipyridamole by subcutaneous injection (sc) twice daily for 5 doses. Blood samples were collected using a "Stopping Solution" from each rat at time 0 (before the last dose), and sequentially after over 6 hours following the last dose via an indwelling carotid artery catheter. In addition, hemodynamic recordings were collected throughout the experiment. Concentrations of ATP and other purine nucleotides in the RBC were determined by a validated HPLC. Data between groups were analyzed by ANOVA and paired t-test, and differences between groups considered significant when p < 0.05. The results showed that the concentrations of ATP and the other purine nucleotides in RBC of the rats treated with the anti-ischemia drugs were not different from the control rats ( Table 1). The concentrations of ATP and guanosine-5'-triphosphate (GTP) were higher towards the end of the experiment, but the increase was significant only after amlodipine and losartan (p < 0.05). The increase of ATP and AMP concentrations correlated with decrease of diastolic blood pressure (DBP) in the rats. The study concluded that the anti-ischemia drugs tested in the current study have no effect on RBC concentrations of ATP in the restraining rat model.

Diltiazem Reduces Mortality and Breakdown of ATP in Red Blood Cell Induced by Isoproterenol in a Freely Moving Rat Model in Vivo

“…In addition to the hemodynamic effect, DTZ also decreased concentrations of ADP and AMP significantly in the RBC ( p < 0.05) and modestly increased ATP concentration ( p > 0.05) ( Table 1 ) in the rats prior to receiving isoproterenol. We have shown earlier that DTZ also increased RBC concentrations of ATP in a zebrafish model [ 23 ] and in an exercise rat model [ 24 ], but not in rats kept in a restrainer [ 25 ]. The results suggest that the effect of DTZ on ATP metabolism in RBC in vivo may be enhanced when energy demand increases in the host species, as in the current study.…”

Diltiazem Reduces Mortality and Breakdown of ATP in Red Blood Cell Induced by Isoproterenol in a Freely Moving Rat Model in Vivo

“…In addition to the hemodynamic effect, DTZ also decreased concentrations of ADP and AMP significantly in the RBC ( p < 0.05) and modestly increased ATP concentration ( p > 0.05) ( Table 1 ) in the rats prior to receiving isoproterenol. We have shown earlier that DTZ also increased RBC concentrations of ATP in a zebrafish model [ 23 ] and in an exercise rat model [ 24 ], but not in rats kept in a restrainer [ 25 ]. The results suggest that the effect of DTZ on ATP metabolism in RBC in vivo may be enhanced when energy demand increases in the host species, as in the current study.…”

Effect of acute exercise on cardiovascular hemodynamic and red blood cell concentrations of purine nucleotides in hypertensive compared with normotensives rats

“…Similarly, the mean HR was decreased by 14% after exercise in SDRs compared with the 27% decline in SHRs, although it returned to the baseline value at the end of the experiment (Table 1). Third, when the rats were not exercised and kept in a restrainer as described in an earlier communication [Yeung et al . 2011], both SBP and DBP in SHRs fell throughout the experiment ( p < 0.05).…”

Adenosine 5′-Triphosphate Metabolism in Red Blood Cells as a Potential Biomarker for Post-Exercise Hypotension and a Drug Target for Cardiovascular Protection

“…It has been suggested that ATP catabolism in the RBC may be used as biomarker to quantify myocardial and endothelial ischemia [ 1 , 52 ], and as a potential target for anti-ischemia drugs [ 54 , 55 , 56 , 57 , 58 ]. We hypothesize agents which preserve ATP concentrations in the RBC would have protective effects against ischemia and/or cardiovascular injury [ 90 ].…”

“…Based on the definition proposed by the FDA Biomarker Definition Working Group [ 51 ], a “Biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention”. It has been suggested ADO and ATP catabolism may be used as biomarkers to quantify myocardial and endothelial ischemia [ 1 , 52 , 53 ], cardiovascular toxicities [ 43 ], and as a potential target for anti-ischemia drugs [ 54 , 55 , 56 , 57 , 58 ]. On the other hand, exercise has been shown to improve cardiovascular hemodynamic and increase RBC concentrations of ATP in both humans and animal models [ 59 , 60 ].…”

Diltiazem Reduces Mortality and Breakdown of ATP in Red Blood Cell Induced by Isoproterenol in a Freely Moving Rat Model in Vivo

“…In addition to the hemodynamic effect, DTZ also decreased concentrations of ADP and AMP significantly in the RBC ( p < 0.05) and modestly increased ATP concentration ( p > 0.05) ( Table 1 ) in the rats prior to receiving isoproterenol. We have shown earlier that DTZ also increased RBC concentrations of ATP in a zebrafish model [ 23 ] and in an exercise rat model [ 24 ], but not in rats kept in a restrainer [ 25 ]. The results suggest that the effect of DTZ on ATP metabolism in RBC in vivo may be enhanced when energy demand increases in the host species, as in the current study.…”

Effect of acute exercise on cardiovascular hemodynamic and red blood cell concentrations of purine nucleotides in hypertensive compared with normotensives rats

“…Similarly, the mean HR was decreased by 14% after exercise in SDRs compared with the 27% decline in SHRs, although it returned to the baseline value at the end of the experiment (Table 1). Third, when the rats were not exercised and kept in a restrainer as described in an earlier communication [Yeung et al . 2011], both SBP and DBP in SHRs fell throughout the experiment ( p < 0.05).…”

Adenosine 5′-Triphosphate Metabolism in Red Blood Cells as a Potential Biomarker for Post-Exercise Hypotension and a Drug Target for Cardiovascular Protection

“…It has been suggested that ATP catabolism in the RBC may be used as biomarker to quantify myocardial and endothelial ischemia [ 1 , 52 ], and as a potential target for anti-ischemia drugs [ 54 , 55 , 56 , 57 , 58 ]. We hypothesize agents which preserve ATP concentrations in the RBC would have protective effects against ischemia and/or cardiovascular injury [ 90 ].…”

“…Based on the definition proposed by the FDA Biomarker Definition Working Group [ 51 ], a “Biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention”. It has been suggested ADO and ATP catabolism may be used as biomarkers to quantify myocardial and endothelial ischemia [ 1 , 52 , 53 ], cardiovascular toxicities [ 43 ], and as a potential target for anti-ischemia drugs [ 54 , 55 , 56 , 57 , 58 ]. On the other hand, exercise has been shown to improve cardiovascular hemodynamic and increase RBC concentrations of ATP in both humans and animal models [ 59 , 60 ].…”

Diltiazem Reduces Mortality and Breakdown of ATP in Red Blood Cell Induced by Isoproterenol in a Freely Moving Rat Model in Vivo

“…In addition to the hemodynamic effect, DTZ also decreased concentrations of ADP and AMP significantly in the RBC ( p < 0.05) and modestly increased ATP concentration ( p > 0.05) ( Table 1 ) in the rats prior to receiving isoproterenol. We have shown earlier that DTZ also increased RBC concentrations of ATP in a zebrafish model [ 23 ] and in an exercise rat model [ 24 ], but not in rats kept in a restrainer [ 25 ]. The results suggest that the effect of DTZ on ATP metabolism in RBC in vivo may be enhanced when energy demand increases in the host species, as in the current study.…”

Effect of acute exercise on cardiovascular hemodynamic and red blood cell concentrations of purine nucleotides in hypertensive compared with normotensives rats

“…Similarly, the mean HR was decreased by 14% after exercise in SDRs compared with the 27% decline in SHRs, although it returned to the baseline value at the end of the experiment (Table 1). Third, when the rats were not exercised and kept in a restrainer as described in an earlier communication [Yeung et al . 2011], both SBP and DBP in SHRs fell throughout the experiment ( p < 0.05).…”

Adenosine 5′-Triphosphate Metabolism in Red Blood Cells as a Potential Biomarker for Post-Exercise Hypotension and a Drug Target for Cardiovascular Protection

“…It has been suggested that ATP catabolism in the RBC may be used as biomarker to quantify myocardial and endothelial ischemia [ 1 , 52 ], and as a potential target for anti-ischemia drugs [ 54 , 55 , 56 , 57 , 58 ]. We hypothesize agents which preserve ATP concentrations in the RBC would have protective effects against ischemia and/or cardiovascular injury [ 90 ].…”

“…Based on the definition proposed by the FDA Biomarker Definition Working Group [ 51 ], a “Biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention”. It has been suggested ADO and ATP catabolism may be used as biomarkers to quantify myocardial and endothelial ischemia [ 1 , 52 , 53 ], cardiovascular toxicities [ 43 ], and as a potential target for anti-ischemia drugs [ 54 , 55 , 56 , 57 , 58 ]. On the other hand, exercise has been shown to improve cardiovascular hemodynamic and increase RBC concentrations of ATP in both humans and animal models [ 59 , 60 ].…”