CaMKII-dependent reactivation of SR Ca uptake and contractile recovery during intracellular acidosis

Nomura, Noriyuki, Hiroshi Satoh, Hajime Terada, Masaki Matsunaga, Hiroshi Watanabe, and Hideharu Hayashi. CaMKII-dependent reactivation of SR Ca2 uptake and contractile recovery during intracellular acidosis. Am J Physiol Heart Circ Physiol 283: H193–H203, 2002; 10.1152/ ajpheart.00026.2001.—In hearts, intracellular acidosis disturbs contractile performance by decreasing myofibrillar Ca2 response, but contraction recovers at prolonged acidosis. We examined the mechanism and physiological implication of the contractile recovery during acidosis in rat ventricular myocytes. During the initial 4 min of acidosis, the twitch cell shortening decreased from 2.3 0.3% of diastolic length to 0.2 0.1% (means SE, P 0.05, n 14), but in nine of these cells, contractile function spontaneously recovered to 1.5 0.3% at 10 min (P 0.05 vs. that at 4 min). During the depression phase, both the diastolic intracellular Ca2 concentration ([Ca2 ]i) and Ca2 transient (CaT) amplitude increased, and the twitch [Ca2 ]i decline prolonged significantly (P 0.05). In the cells that recovered, a further increase in CaT amplitude and a reacceleration of twitch [Ca2 ]i decline were observed. The increase in diastolic [Ca2 ]i was less extensive than the increase in the cells that did not recover (n 5). Blockade of sarcoplasmic reticulum (SR) function by ryanodine (10 M) and thapsigargin (1 M) or a selective inhibitor of Ca2 -calmodulin kinase II, 2-[N(2-hydroxyethyl)-N-(4-methoxybenzenesulfonyl)] amino-N(4-chlorocinnamyl)-N-methyl benzylamine (1 M) completely abolished the reacceleration of twitch [Ca2 ]i decline and almost eliminated the contractile recovery. We concluded that during prolonged acidosis, Ca2 -calmodulin kinase IIdependent reactivation of SR Ca2 uptake could increase SR Ca2 content and CaT amplitude. This recovery can compensate for the decreased myofibrillar Ca2 response, but may also cause Ca2 overload after returning to physiological pHi. cardiac myocyte; intracellular pH; intracellular Ca2 concentration; ATPase