IMPAIRMENT OF THE RYANODINE-SENSITIVE CALCIUM RELEASE CHANNELS IN THE CARDIAC SARCOPLASMIC RETICULUM AND ITS UNDERLYING MECHANISM DURING THE HYPODYNAMIC PHASE OF SEPSIS

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Abstract

ABSTRACT—

Changes in Ca2+-induced Ca2+ release in cardiac sarcoplasmic reticulum (SR) during different phases of sepsis were studied. Sepsis was induced by cecal ligation and puncture (CLP). The 45Ca2+ release studies show that the amount of Ca2+ released from the passively and the actively loaded SR vesicles was unaffected during the early sepsis (9 h after CLP), but it was significantly decreased during the late phase (18 h after CLP) of sepsis. The [3H]ryanodine binding assays reveal that the Bmax for ryanodine binding was unaffected during the early phase, but was decreased by 32.1% during the late phase of sepsis. The affinity of ryanodine receptor for Ca2+ remained unchanged during sepsis. ATP, AMP-PCP, and caffeine stimulated binding, while MgCI2 and ruthenium red inhibited [3H]ryanodine binding in control, early sepsis, and late sepsis groups. The EC50 and IC50 values for these regulators were unaffected during the progression of sepsis. Digestion of control SR with phospholipase A2 decreased [3H]ryanodine binding and the decrease was reversible by the addition of phosphatidylcholine (PC), phosphatidylethanolamine (PE), or phosphatidylserine (PS). Addition of PC, PE, or PS to the SR isolated from septic rats stimulated [3H]ryanodine binding. These data demonstrate that Ca2+-induced Ca2+ release from cardiac SR remained relatively unaffected during the early phase, but was significantly impaired during the late phase of sepsis. The sepsis-induced impairment in SR Ca2+ release is a result of a quantitative reduction in the number of Ca2+ release channels. Furthermore, the reduction is associated with a mechanism involving a modification of membrane lipid profile in response to certain stimuli such as activation of phospholipase A2+.

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