FIGURE 3.

(A) Intracellular mechanisms that may contribute to the mechanical recovery during acidosis. Acidosis produces a decrease in myofilament Ca²⁺ responsiveness which increases diastolic Ca²⁺ ([Ca²⁺]_d). Activation of NHE and direct acidosis inhibition of Na⁺-Ca²⁺ exchanger (NCX), would contribute to the increase in cytosolic Ca²⁺. Acidosis also inhibits PP1. The simultaneous increase in cytosolic Ca²⁺ and inhibition of PP1 activates CaMKII and enhances PLN phosphorylation at Thr¹⁷ site. As a consequence, there is an increase in SR Ca²⁺ uptake, able to offset the direct acidosis-induced inhibition of SERCA2a activity. This would lead to enhanced SR Ca²⁺ release and Ca²⁺ transients, which counteract the negative effect of acidosis on contractile proteins and supply the substrate for the slow mechanical recovery during acidosis. (B). Putative intracellular mechanisms of post-acidosis induced-arrhythmias. Upon returning to control pH, the inhibitory effects of acidosis are rapidly removed, favoring the increase in Ca²⁺ cycling and the contractile recovery towards control levels. However, the relief of RyR2 from the previous constrain produced by acidosis, evokes also an increase in diastolic Ca²⁺ leak from the (Ca²⁺-loaded) SR. Such release may activate inward currents through the NCX, also relieved from the inhibition evoked by acidosis. The inward Na⁺ current, if large enough, can trigger arrhythmias.