Modulatory Effects of L-Arginine on Methylxanthine-Induced Cardiotoxicity in Rats: A Differential Role for Nitric Oxide (NO)

Arunabha Ray,Kavita Gulati,Jagdish C Joshi,Md Shamsuzzaman

doi:10.31487/j.jicoa.2021.03.09

Abstract

Methylxanthines are potent bronchodilators used in obstructive airway disease like COPD and bronchial asthma, but the narrow therapeutic index and resultant adverse effect profile have restricted their use. Novel beneficial effects and modes of action are now being proposed for these pharmacoeconomically viable agents. Cardiotoxicity is a prominent adverse effect of methylxanthone and thus we investigated possible mechanisms for such toxicity with an aim to devise ameliorative strategies for counteracting such undesirable effects. In view of the cardioprotective role of nitric oxide (NO) and NO mimetics, the present study investigated the possible modulatory role of L-arginine, a NO precursor, in theophylline induced cardiotoxicity in rats, with a view to exploring strategies for facilitating the safe use of this drug. The methylxanthine, aminophylline induced cardiotoxic effects like increased heart rat, raised mean BP, inverted T-waves and prolonged QTc interval (in ECG). These were accompanied by increased levels of cardiac biomarkers like Troponin-I, CPK-MB, and ADMA. Oxidative stress markers like MDA were elevated whereas, antioxidant defence markers like GSH and SOD were suppressed. Co-administration of L-arginine (with aminophylline) had dose-related effects on cardiac function (heart rate, mean BP, ECG changes) and cardiospecific biomarkers (TnI, CPK-MB, ADMA) - the lower dose being protective whereas the higher dose potentiating some of the cardiac effects and cardiospecific/oxidative stress biomarker levels. The results indicate a biphasic involvement of NO in the cardiotoxic effect of theophylline and suggests possible interactions of NO with reactive oxygen species during such modulations of cardiotoxicity.

Highlights

Cardiotoxicity is associated with the administration of several classes of clinically relevant drugs and can present even after a single administration, or after an overdose
Administration of aminophylline for seven days resulted in increased heart rate and mean blood pressure (BP) in a dose dependent manner, with the effects seen after 150 mg/kg of the drug being most consistent
The lower doses of L-arginine (100 mg/kg) showed a cardioprotective effect and decreased heart rate, and mean BP induced by amino

Summary

Introduction

Cardiotoxicity is associated with the administration of several classes of clinically relevant drugs and can present even after a single administration, or after an overdose. Such drug induced cardiotoxicity attracts considerable attention from basic scientists to clinicians. Methylxanthines like theophylline are bronchodilators that have been effectively used therapeutically in cardiorespiratory disorders for nearly a century. Theophylline (1, 3dimethylxanthine) is a potent bronchodilator, but the narrow therapeutic index of the drug has limited its use in recent years. Neurotoxicity and cardiotoxicity are among the most prominent adverse effects associate with prolonged use of theophylline which results in morbidity and mortality. Studies reported that theophylline toxicity resulted in metabolic changes like hyperglycemia, hypokalemia, metabolic acidosis, and in severe cases, cardiac arrhythmias, seizures and death [4, 5]

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Conclusion