| Immunosuppressants have greatly improved long-term survival after organ transplantation, leading to the exponential growth of organ transplant programs. Hypertension and baroreflex dysfunction are major side effects associated with the treatment of the calcineurin inhibitors cyclosporine (CsA) and Tacrolimus (FK506). The main objective of the following research was to investigate the mechanisms of the deleterious hemodynamic effects of acute and short term immunosuppression.;The first part of this research involves establishing the effect of short term (5 day) CsA treatment in our animal model on the cardiovascular system mainly mean arterial pressure (MAP), heart rate (HR) and baroreflex sensitivity (BRS) using the traditional Oxford method.;The second part of this research involves investigating the effect of elevating plasma nonesterified fatty acids (NEFAs) via overnight fasting and intralipid/heparin infusion on the cardiovascular indices, which involved the recording and analysis of blood pressure and heart rate using data acquisition system and analysis software custom designed for this purpose. That software allowed us to measure BRS, blood pressure variability (BPV) and heart rate variability (HRV) indices using both in time domain and frequency domain analysis. The results of this work showed an inverse correlation between NEFAs and BRS in both fasting and adlib conditions. Also, elevation of NEFAs increased MAP, HR and BPV while reduced HRV indices. At the cellular level elevation of NEFAs enhanced caveolar sequestration of myocardial M2 muscarinic cholinergic receptors (M2-mAChRs) in the ventricles of the treated rats which could explain the associated attenuation of the parasympathetic system.;The third part of this research involves establishing a causal relationship between NEFAs and the deleterious changes in the cardiovascular indices. This was achieved with the use of acipimox, a nicotinic acid analogue antilipidemic drug, which inhibits lipolysis and stops the production of plasma NEFAs. Acipimox treatment in a dose dependent manner enhanced BRS and HRV while it reduced MAP, HR, BPV. It also reduced caveolar sequestration of myocardial M2-mAChR. The results of this part led to the conclusion that the changes in the cardiovascular indices due to fasting and intralipid/heparin infusion are due to NEFAs effect on the myocardial m2-mAChRs.;The last part in this study involves investigating whether the effects of CsA on the cardiovascular parameters were dose dependent and if these effects occur also with FK506 and if NEFAs elevation mediates these changes in the treated rats. The results of this part led us to conclude that the cardiovascular response to immunosuppressants involves elevation in plasma NEFAs and enhanced caveolar sequestration of myocardial M2-mAChRs. |
