Angiotensin-converting enzyme inhibitor limits pulse-wave velocity and aortic calcification in a rat model of cystic renal disease

Abstract

The effect of angiotensin-converting enzyme inhibition on function and structure of the aorta was studied in the Lewis polycystic kidney (LPK) rat model of cystic renal disease and Lewis controls. Pulse-wave velocity (PWV) was recorded under urethane anesthesia (1.3 g/kg ip) in mixed-sex animals aged 6 and 12 wk and in 12-wk-old animals treated with perindopril (3 mg·kg(-1)·day(-1) po) from age 6-12 wk. Tail-cuff systolic pressures were recorded over the treatment period. After PWV measurements, animals were euthanized and the aorta was removed for histomorphological and calcium analysis. Hypertension in LPK at 6 and 12 wk was associated with a shift of the PWV curve upward and to the right, indicating a decrease in aortic compliance, which was significantly reduced by perindopril. LPK demonstrated greater aortic calcification (6 wk: 123 ± 19 vs. 65 ± 7 and 12 wk: 406 ± 6 vs. 67 ± 6 μmol/g, P < 0.001, LPK vs. Lewis, respectively). This was reduced by treatment with perindopril (172 ± 48 μmol/g, 12 wk LPK P < 0.001). Medial cross-sectional area and elastic modulus/wall stress of the aorta were greater in LPK vs. Lewis control animals at 6 and 12 wk of age and showed an age-related increase that was prevented by treatment with perindopril (P < 0.001). Perindopril also ameliorated the degradation of elastin, increase in collagen content, and medial elastocalcinosis seen in 12-wk LPK. Overall, perindopril improved the structural and functional indices of aortic stiffness in the LPK rats, demonstrating a capacity for angiotensin-converting enzyme inhibition to limit vascular remodeling in chronic kidney disease.

Long-Term Angiotensin II Receptor Blockade Limits Hypertension, Aortic Dysfunction, and Structural Remodeling in a Rat Model of Chronic Kidney Disease

“…These findings are comparable to our previous results with the ACE inhibitor perindopril [16], with both drugs causing a significant improvement in vascular hypertrophy, lamellae elastin density and calcium deposition alongside comparable declines in BP. Unlike perindopril treatment, however, valsartan did not result in an improvement in the collagen density in the aorta.…”

“…They further demonstrate progressive aortic endothelial dysfunction as a result of impaired NO synthase (NOS) activity, which is significantly correlated with the decline in renal function. Measures of vascular hypertrophy and pulse wave velocity in LPK are consistent with increased aortic stiffness, and treatment with an angiotensin-converting enzyme (ACE) inhibitor ameliorated these parameters [16,17]. ACE inhibitors block the actions of Ang II on both AT 1 and AT 2 receptors, and can result in a nonselective increase in plasma bradykinin [18], which may cause non-Ang II-related effects.…”

“…Therefore, the aim of the present study was to use an AT 1 receptor antagonist to examine the hypothesis that Ang II drives aortic dysfunction and structural remodeling in the LPK rat. We additionally studied aortic calcification to ascertain if our previous positive response to ACE inhibition [16] can be reproduced with the more specific AT 1 receptor antagonism. In order to assess mechanistic pathways, we examined the expression of nuclear factor kappa B (NFκB) as an indicator of inflammation, and matrix metalloproteinase 9 (MMP9), cathepsin D, and cathepsin L as indicators of proteolysis [20,21].…”

The effect of losartan on differential reflex control of sympathetic nerve activity in chronic kidney disease

“…The LPK model exhibits reduced plasma angiotensin II levels and plasma renin activity [49]; yet, despite this, chronic ACE inhibition can significantly reduce SBP [50]. In conjunction with the findings of the current study, this suggests that angiotensin II is both tonically involved in the processing of autonomic reflexes in the LPK rats and contributes to the maintenance of the hypertensive state.…”

Vascular Calcification in Type 2 Diabetes: A Role for Allopurinol?

“…ACE inhibitors have been successfully used for control of blood pressure and microalbuminuria in type 2 diabetes, however, their use in prevention of VC is limited due to conflicting evidence from experimental studies with some demonstrating beneficial effects [59] and some not [60]. In people with advanced kidney disease, non-calcific phosphate binders such as lanthanum carbonate has been shown to have beneficial effects on progression of coronary calcification in a recent small study [61], however, another pilot study [62] which examined sevelemer, another preferred non-calcific phosphate binder and Rosuvastatin, did not show any significant benefit on coronary calcification with either of these agents.…”