Effects of Inflammation and Non-Steroidal Anti-Inflammatory Drugs on Renin-Angiotensin System and Cytochrome P450 Metabolites of Arachidonic Acid

  • Author / Creator
    Asghar, Muhammad Waheed
  • Patients suffering from inflammatory disorders are at higher risk of cardiovascular (CV) morbidity and mortality compared to general population. Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat pain and inflammation associated with inflammatory disorders such as rheumatoid arthritis (RA). However, since the withdrawal of rofecoxib from the market, due to reports of life threatening CV incidents in its users, other NSAIDs are also suspected for such risks. Combined effects of inflammation and NSAIDs use on CV/renal risks are not well understood. However, many hypotheses have been suggested to explain the mechanisms behind these risks, yet none is conclusive and further pharmacological and pharmacokinetic explanations are needed to be explored. The renin angiotensin system (RAS) and cytochrome P450 (CYP) metabolites of arachidonic acid (ArA) are two major systems responsible for maintaining CV homeostasis in the body. Both systems contain distinct components in their pathways which physiologically oppose each other enabling a naturel balance. RAS component includes angiotensin converting enzymes (ACE, ACE2), physiologically active peptides (Ang-II, Ang-(1-7)) and angiotensin receptors (AT1R, AT2R Mas). The ACE/Ang-II/AT1R are group into what is called as cardiotoxic axis and ACE2/Ang-(1-7)/Mas are group into what is called as cardioprotective axis. Similarly, CYP pathway consists of CYP-enzymes and their arachidonic acid (ArA) metabolites (i.e., 20-hydroxyeicosatetraenoic acid; 20-HETE and epoxyeicosatrienoic acids; EETs, respectively). They are grouped into hydroxylase pathway (i.e., CYP-hydroxylases and 20-HETE) which is cardiotoxic in nature and epoxygenase pathway (i.e., CYP-epoxygenases and EETs) which is cardioprotective in nature. Constitutively, a balance exists between these components. However, under inflammatory conditions as well as in CV diseases this balance is altered indicating cardiotoxicity. We hypothesized that NSAIDs induced CV/renal risks involve their effects on RAS and ArA systems in the heart and kidney tissues. Also the extent of tissue exposure to NSAIDs may govern such risks. To test these hypotheses we first performed a systematic review of randomized control trials and observational studies. Looking for published evidence that NSAIDs differ in their extent of CV/renal risks. Based on these findings we choose four NSAIDs (rofecoxib, celecoxib, meloxicam, and flurbiprofen) to be dosed in Sprague Dawley rats, to investigate their extent of tissue accumulation and how it affects RAS and ArA pathways in adjuvant arthritis (AA) rat model of inflammation. Our results suggest that rofecoxib have highest while meloxicam and celecoxib have least potential of causing CV toxicity in population. Rofecoxib and flurbiprofen were also found to have higher tissue accumulation compared to meloxicam which minimally distributes in heart and kidney tissues. Celecoxib was an exception, which have high tissues accumulation yet possess less CV risks. Our results in AA rats showed that inflammation results in lower ACE2/Ang-(1-7)/Mas the cardioprotective axis, over ACE/Ang-II/ AT1R cardiotoxic axis. NSAIDs restored the constitutive balance, perhaps due to their anti-inflammatory properties. However, difference exists in terms of NSAIDS effects on ArA metabolism. Rofecoxib and flurbiprofen when dosed in inflamed rats, further increased 20-HETE/EETs cardiotoxic/cardioprotective metabolites concentration in the plasma and heart of AA rats. But meloxicam and celecoxib were devoid of these effects. These findings also correspond to higher tissue accumulation and higher CV risk reported for rofecoxib and flurbiprofen compared to meloxicam. We concluded that inflammation has detrimental effects on both RAS and ArA metabolism. NSAIDs effects on RAS are anti-inflammatory and beneficial in nature, however, some NSAIDs alter ArA metabolism resulting in higher concentration of cardiotoxic metabolites in the body. Moreover, NSAIDs with higher tissue distribution (e.g., rofecoxib, flurbiprofen) are more likely to interfere with ArA metabolism and may pose higher CV risks. While, NSAIDs which minimally distributes (e.g., meloxicam) into heart and kidney tissues poses significantly safer cadiorenal profiles. We also found that plasma and heart profiles of ArA metabolites of are very similar to each other, thus plasma ArA metabolites can serve as surrogate biomarkers of NSAIDs induced cardiotoxicity.

  • Subjects / Keywords
  • Graduation date
    Spring 2016
  • Type of Item
  • Degree
    Doctor of Philosophy
  • DOI
  • License
    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.
  • Language
  • Institution
    University of Alberta
  • Degree level
  • Department
  • Specialization
    • Pharmaceutical Sciences
  • Supervisor / co-supervisor and their department(s)
  • Examining committee members and their departments
    • Velazquez, Carlos (Pharmaceutical Sciences)
    • Schulz, Richard (Pediatrics & Pharmacology)
    • Lavasanifar, Afsaneh (Pharmaceutical Sciences)
    • Siraki, Arno (Pharmaceutical Sciences)