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Changes in the cardiovascular nitric oxide pathway in cyclosporin-A treated rats
M R Rao1, A E Hutcheson, A K Markov
1Department of Medicine, University of Mississippi Medical Center, Jackson, USA.
Abstract:
Cyclosporin A (CsA), an immunosuppressive agent is known to induce cellular toxic effects by alerting calcium homeostasis. Nitric oxide (NO) has been implicated in a number of physiologic roles in the mammalian cardiovascular system (CVS). The aim of our present study is to investigate the effects of CsA on the rat CV NO pathway. We measured iNOS and cNOS activities in the 100,000 g soluble fraction of ventricles and serum nitrite (NO2-) and nitrite (NO3-) levels in rats treated with 25 mg/kg or 50 mg/kg body weight of CsA/24 hr in olive oil. CsA inhibited cNOS activity of rat ventricles and failed to bring about changes in their iNOS activity. Serum NO2-/NO3- levels were elevated in CsA treated tars. Most of these changes were found to be statistically significant (P < 0.01) at 50 mg/kg body wt of CsA. It is likely that elevation of serum NO2-/NO3- levels may cause myocardial toxicity by alerting rat CV NO pathway.
Insights
Cyclosporin A (CsA) alters the cardiovascular nitric oxide (NO) pathway in rats, inhibiting cNOS activity and increasing serum nitrite/nitrate levels, potentially leading to myocardial toxicity.
Area of Science:
- Cardiovascular Physiology
- Pharmacology
- Immunology
Background:
- Cyclosporin A (CsA) is an immunosuppressant known to cause cellular toxicity by disrupting calcium homeostasis.
- Nitric oxide (NO) plays crucial physiological roles in the mammalian cardiovascular system (CVS).
Purpose of the Study:
- To investigate the impact of Cyclosporin A (CsA) on the rat cardiovascular nitric oxide (NO) pathway.
- To assess the effects of CsA on inducible nitric oxide synthase (iNOS) and constitutive nitric oxide synthase (cNOS) activities and serum nitrite/nitrate levels.
Main Methods:
- Rats were administered CsA at doses of 25 mg/kg or 50 mg/kg body weight daily.
- Ventricle soluble fractions were analyzed for iNOS and cNOS activity.
- Serum levels of nitrite (NO2-) and nitrate (NO3-) were measured.
Main Results:
- CsA significantly inhibited cNOS activity in rat ventricles.
- CsA did not alter iNOS activity in rat ventricles.
- Serum NO2-/NO3- levels were elevated in CsA-treated rats, particularly at the 50 mg/kg dose (P < 0.01).
Conclusions:
- Cyclosporin A interferes with the cardiovascular NO pathway in rats.
- Elevated serum nitrite/nitrate levels resulting from CsA treatment may contribute to myocardial toxicity.
- The findings suggest a mechanism for CsA-induced cardiovascular adverse effects via NO pathway dysregulation.
