Left ventricular dysfunction after acute intracranial hypertension is associated with increased hydroxyl free radical production, cardiac ryanodine hyperphosphorylation, and troponin I degradation

Background: In addition to generating free radicals, stress-induced activation of the sympathetic nervous system results in hyperphosphorylation of the cardiac ryanodine receptor (RyR2)/calcium (Ca²⁺) release channel on the sarcoplasmic reticulum, causing leaky channels. These events may contribute to cytosolic Ca²⁺ overload and activation of Ca ²⁺-dependent cytotoxic processes. Because myocardial dysfunction associated with intracranial hypertension is catecholamine mediated, we sought to determine in a rat model if hemodynamic changes are associated with an increase in oxidative stress, hyperphosphorylation of RyR2, and degradation of myofilament protein cardiac troponin I (TnI). Methods: In halothane-anesthetized rats treated with saline, dimethyl sulfoxide (DMSO), or the synthetic calpain inhibitor calpeptin (3,500 μg), a subdural balloon catheter was inflated to induce intracranial hypertension. Hearts were excised, and RyR2 phosphorylation status and TnI degradation was determined with Western blot analysis. In separate experiments, treated rats were challenged with increasing doses of dobutamine 30 minutes after subdural balloon inflation. Results: Elevating the intracranial pressure resulted in an increase in plasma catecholamines, as well as in 3,4-dihydroxybenzoic acid (DHBA), an indirect marker of HO·radical production, and left ventricular dysfunction in rats treated with saline or DMSO. There was evidence of hyperphosphorylation of RyR2 and TnI degradation (27 kD immunoreactive band). Calpeptin treatment improved left ventricular function; however, this had no effect on the phosphorylation status of RyR2 or TnI degradation levels. In addition, the myocardial responsiveness to dobutamine was augmented in rats with depressed myocardial function. Conclusion: The present findings demonstrate that hemodynamic instability after intracranial hypertension is associated with oxidative stress and post-translational changes to RyR2 and TnI degradation. Despite this, the myocardial responsiveness to β₁ adrenergic stimulation is preserved in rats with depressed myocardial function.