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BACKGROUND: ATP is a pivotal mediator and regulator of numerous cellular functions and plays an important role in cardiovascular homeostasis. We investigate the feasibility of exploiting ATP metabolism in the red blood cells (RBC) as systemic biomarker for cardiovascular protection. METHODS: Sprague Dawley rats (SDR) weighing between 250 and 300g were used. Each SDR had free access to drinking water during experiment. They were randomly divided into 3 groups. Group A (n ¼ 10) received normal saline (NS), group B (n ¼ 6) received diltiazem (DTZ) 10 mg/kg by subcutaneous (sc) injection twice daily for 4 doses, and group C (n ¼ 8) received an exercise on a treadmill at 14 m/min for 15 minutes at 22% grade. One hour after the last dose of DTZ or NS or two hours after the exercise, each SDR received isoproterenol (ISO) (30 mg/kg) by sc injection. A separate control group (D) received no isoproterenol (n ¼ 11). Hemodynamic recording (SBP, DBP, and HR) was collected continuously during the experiment. Data were analysed using t-tests and difference between groups considered significant at p < 0.05. RESULTS: ISO induced 50% mortality within 5 hours after injection in the control group A (p < 0.05). It decreased SBP and DBP immediately after the injection (< 15 min) by -64 AE 20 and -61 AE 19 mmHg, respectively, but increased HR by +70 AE 53 bpm which was further increased to +157 AE 56 bpm by the end of the experiment (p < 0.05). Both SBP and DBP rebounded to pre-treatment level after 1-2 hours following injection (p < 0.05), and then continued to fall for the remaining of the experiment. Mortality was <20% (1 out of 6) in B, and 25% (2 out of 8) in the exercise group C, and none in group D. There was significant breakdown of ATP in the RBC in the NS treated group A (AUC of AMP/ATP ¼ 0.12 AE 0.12 in A vs 0.03 AE 0.02 in D). Both exercise and DTZ (i.e. B and C) attenuated the breakdown of ATP induced by ISO (p < 0.05), but only exercise significantly reduced the rebound of blood pressure.