Abstract
Although cardiotoxicity has been recognized as an adverse effect of cyclosporine A (CSA), no information exists regarding sex specificity of CSA cardiotoxicity. We tested the hypothesis that left ventricular (LV) and electrocardiographic (ECG) effects of CSA and related inflammatory/histopathological derangements are sex related. CSA reduced the LV slope of end-systolic pressure volume relationship and increased isovolumic relaxation constant. These effects were more pronounced in male compared to female rats, suggesting LV systolic and diastolic dysfunction. ECG recordings showed elevated ST segments and increased QTc and T peak trend intervals in CSA-treated male rats, markers of LV ischemia and arrhythmogenesis. In female rats, CSA delayed AV conduction, as reflected by prolonged PR interval. Other sex-related effects for CSA included (i) increased blood cholesterol, and reduced rates of rise and fall in LV pressure and nuclear factor kappa B and angiotensin receptors type 1 expressions in male rats, and (ii) increased LV adiponectin in females. Histopatholgically, CSA caused vascular congestion, blood extravasation, and pyknotic or even absent nuclei in both sexes. In conclusion, rats exhibit sex-independent susceptibility to negative LV and histopathological influences of CSA. These effects become more intensified in male rats, perhaps on account of aggravated ischemic and inflammatory milieus.
Highlights
Of the renin-angiotensin system (RAS) and angiotensin AT1 receptors is predisposed to cardiac cellular oxidative stress generation[11] and the blockade of these receptors protects against Cyclosporine A (CSA) nephrotoxicity[12]
CSA administration significantly decreased the rate at which LV pressure rose and fell in male rats but had no effect in female rats (Fig. 1B,D)
CSA had no effect on heart rate (HR) in either of the two rat sexes and caused significant increases in systolic and diastolic blood pressure (BP) in female rats only (Table 1)
Summary
Compared with vehicle-treated values, CSA significantly increased the cardiac levels of the inflammatory proteins NFκB and AT1 receptors in cardiac tissues of male rats by 70% and 100%, respectively. This is in stark contrast to the effect of CSA in female rats where it elicited elevations of around 20% in cardiac NFκB but had no effect on AT1 receptors (Fig. 3). CSA administration was associated with vascular congestion, blood extravasation, and a marked degeneration of cardiac muscle as indicated by the shrinkage of cardiac muscles and absence or pyknosis of cardiac muscle nuclei These effects of CSA were demonstrated in both male and female rats (Fig. 5)
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