A Pilot Study to Assess Adenosine 5’-triphosphate Metabolism in Red Blood Cells as a Drug Target for Potential Cardiovascular Protection

Abstract

Objective: To study the effect of exercise preconditioning on adenosine 5’triphosphate (ATP) metabolism in red blood cells and cardiovascular protection against injury induced by isoproterenol in vivo. Methods: Male Sprague Dawley rats (SDR) were each exercised on a treadmill for 15 minutes at 10 m/min and 10% grade (n = 7) (LowEx), or 14 m/min and 22% grade (n = 8) (VigEx). Two hours after the exercise, each rat received a single dose of isoproterenol (30 mg/kg) by subcutaneous (sc) injection. Two separate groups of SDR were used as control: One received no exercise (n = 10) (NoEx) and the other received no exercise and no isoproterenol (n = 11) (NoIso). Serial blood samples were collected over 5 hours for measurement of ATP and its catabolites by a validated HPLC. Hemodynamic recording was collected continuously for the duration of the experiment. Data were analysed using ANOVA and t-tests and difference considered significant at p < 0.05. Results: Exercise pre-conditioning (both LowEx and VigEx) reduced mortality after isoproterenol from 50% to < 30% (p > 0.05). It attenuated the rebound in blood pressure significantly (p < 0.05 between NoEx vs VigEx), attenuated the increase of RBC adenosine 5’-monophosphate (AMP) concentrations induced by isoproterenol, and also decreased the breakdown of ATP to AMP in the RBC (p < 0.05 vs NoEx). Conclusion: Exercise pre-conditioning decreased the blood pressure rebound and also breakdown of ATP in RBC after isoproterenol which may be exploited further as a drug target for cardiovascular protection and prevention.

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

“…We have shown in an experimental rat model that preconditioning rats with acute exercise on a treadmill for 15 min at either moderate (LowEx 10 m/min and 10% gradient) or more intense levels (VigEx 14 m/min and 22% gradient) 2 h before isoproterenol reduced mortality, attenuated the rebound in blood pressure, and reduced the production of AMP secondary to breakdown of ATP in the RBC. The protective effect was more apparent in the rats preconditioned with the more vigorous exercise (VigEx) ( Figure 5 ) [ 62 ]. Thus, we hypothesize that the cardiovascular protective effect of exercise and the post-exercise effect is mediated by increased metabolism and production of ATP in RBCs and other cell types, which would preserve, either directly or indirectly, intracellular ATP concentration when encountering an insult induced by oxidative stress and/or cardiovascular injury.…”

“…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 ]. The increase of circulatory concentrations of ADO and ATP are believed to be key factors for exercise preconditioning and post-exercise hypotension, and could be a mechanism responsible for cardiovascular protection [ 27 , 43 , 61 , 62 ]. The review summarizes currently available evidence in support of ATP metabolism in the RBC as a potential systemic biomarker for cardiovascular protection and toxicities.…”

Post-Exercise Hypotension: An Alternative Management Strategy for Hypertension and Cardiovascular Disease?

“…In one study, exercise increased ATP concentrations in the red blood cells (RBCs) of healthy volunteers immediately after exercise, which may be a surrogate biomarker for increased energy metabolism in response to exercise [ 18 ]. We have also shown a similar increase in ATP concentrations in response to exercise in an experimental rat model, and this increase was associated with a cardiovascular protective effect from exercise against acute myocardial infarction [ 8 , 16 ]. The linkage between post-exercise hypotension and ATP was further supported by a recent clinical study that demonstrated a single oral dose of ATP (400 mg) given 30 min before exercise increased the effect of PEH on hypertensive women [ 19 ].…”

“…It is often attributed to a series of autonomic and metabolic events that occur following exercise, including reduced sympathetic outflow and local vasodilator mechanisms [ 14 , 15 ]. Other mechanisms that contribute to PEH include upregulation of nitric oxide synthase in the endothelium as well as the renin–angiotensin system, which occurs in response to exercise [ 13 , 16 , 17 ]. In one study, exercise increased ATP concentrations in the red blood cells (RBCs) of healthy volunteers immediately after exercise, which may be a surrogate biomarker for increased energy metabolism in response to exercise [ 18 ].…”