Fig. 7. Schematic diagram depicting the proposed signaling pathway for propofol-induced modulation of Na⁺–Ca²⁺exchange (NCX) in diabetic cardiomyocytes. Elevated levels of intracellular Na⁺([Na⁺]ⁱ)  via reduced Na⁺–K⁺adenosine triphosphatase activity leading to a more positive membrane potential results in a reversal potential that thermodynamically slightly favors Ca²⁺efflux  via  forward mode NCX. This effectively limits sarcoplasmic reticulum (SR) Ca²⁺loading at rest. However, the NCX is dysfunctional in diabetic cardiomyocytes and therefore results in prolonged Ca²⁺removal. Propofol further exacerbates the situation via  activation of protein kinase C (PKC), which then turns on the Na⁺–H⁺exchanger or further reduces Na⁺–K⁺adenosine triphosphatase activity to further elevate [Na⁺]ⁱ. This result shifts the reversal potential to favor Ca²⁺influx at rest and effectively increases the SR Ca²⁺load. At the same time that Ca²⁺influx is favored via  reverse mode, PKC may also inhibit Ca²⁺efflux via  the forward mode NCX, resulting in an even greater prolongation in Ca²⁺removal. RyR2 = ryanodine receptor; SERCA = sarcoplasmic reticulum Ca²⁺pump.