Protective Effects of Cyclopiazonic Acid on Ischemia-Reperfusion Injury in Rabbit Hearts

Abstract

The cardioprotective effects on myocardial ischemia of the sarcoplasmic reticulum (SR) Ca2+-ATPase (SERCA) inhibitor, cyclopiazonic acid (CPA), were studied. We used the isolated arterially perfused interventricular septum of the rabbit heart submitted to 30-min global ischemia/30-min reperfusion. Mechanical [maximal increase in resting tension (MIRT), and the recovery of developed tension (RDT)], and biochemical parameters [creatine phosphokinase activity (CPK) in the effluent] were analyzed. CPA, 1 microM, perfused 30 min before the ischemia intervention significantly increased RDT by 54% and lessened MIRT by 66%. CPA also decreased CPK in the perfusate by 67.7 and 71.4% at 0-2 and 5-7 min of reperfusion, respectively. No additional benefits were shown either when the drug was perfused, both during ischemia and reperfusion, or with higher CPA concentrations (10-30 microM). The CPA cardioprotection was lost when the drug was present only during the reperfusion period. CPA exhibits functional and biochemical cardioprotective effects on myocardial ischemia. We postulated a decreased SR calcium contribution to the initial cytoplasmic calcium overload as the most probable mechanism involved.

Is reduced SERCA2a expression detrimental or beneficial to postischemic cardiac function and injury? Evidence from heterozygous SERCA2a knockout mice

“…If the rise in postischemic Ca 2ϩ i or Ca 2ϩ i oscillation is attributable to SR Ca 2ϩ content, then according to Avellanal et al (1) and du Toit et al (13) reduced SERCA2a function in SERCA2a ϩ/Ϫ hearts will decrease the rise in Ca 2ϩ i and thus improve postischemic mechanical function. However, in striking contrast, we observed the reverse findings.…”

“…Conversely, it has also been reported that pharmacological inhibition of SERCA might improve postischemic function in the stunned heart or in isolated myocardium following I/R (1,13,47). However, the results with the SERCA inhibitors thapsigargin and cyclopiazonic acid (CPA) were inconsistent in terms of effectiveness, narrow dose range, and timing of administration (1,13).…”

“…Conversely, it has also been reported that pharmacological inhibition of SERCA might improve postischemic function in the stunned heart or in isolated myocardium following I/R (1,13,47). However, the results with the SERCA inhibitors thapsigargin and cyclopiazonic acid (CPA) were inconsistent in terms of effectiveness, narrow dose range, and timing of administration (1,13). The advent of gene-modified models with either targeted deletion or transgenic overexpression of SERCA has improved the characterization of cardiac effects more directly in different experimental settings (20,32,37,43).…”

The Ca2+-ATPase (SERCA1) Is Inhibited by 4-Aminoquinoline Derivatives through Interference with Catalytic Activation by Ca2+, Whereas the ATPase E2 State Remains Functional

“…Medium affinity inhibitors such as clotrimazole (CLT, IC 50 ϳ 35 M (11)), curcumin (IC 50 ϳ 15 M (12)), and 1,3-dibromo-2,4,6-tri(methylisothiouronium)benzene (IC 50 ϳ 15 M (13)) are also known. As a point of pharmacological interest, TG derivatives have been considered for treatment of prostate cancer (14,15) and cyclopiazonic acid for myocardial ischemia (16).…”

The effect of isoflurane during reoxygenation on the sarcoplasmic reticulum and cellular injury in isolated ventricular myocytes

“…The fact that increased SR Ca 2+ content plays an important part in cellular reperfusion damage is underlined by the observation that CPA, a blocker of SERCA, has cardioprotective effects, when applied either before or after ischemia. (Avellanal et al, 1998;du Toit and Opie, 1994;Siegmund et al, 1997) Halothane, like CPA and high-affinity binding of ryanodine to the SR Ca 2+ release channel, decreases the SR content and therefore protects against cell contracture during reoxygenation. This different SR Ca 2+ handling seems to be responsible for the obvious discrepancy between our results with 0.62 mM isoflurane and those obtained by reoxygenation in the presence of 0.4 mM halothane.…”