Arteriolar wall thickening, capillary rarefaction and interstitial fibrosis in the heart of rats with renal failure

Abstract

In experimental renal failure, increased intramyocardial arteriolar wall thickness, reduced myocardial capillary density, and increased cardiac interstitium are found. The extent to which such alterations can be modified by therapeutic interventions has not been investigated to date. The purpose of this study was to examine the effects of Ramipril, Nifedipine and Moxonidine on these structural changes. Sham-operated and subtotally nephrectomized (SNX) 300-g male Sprague-Dawley rats (N = 7 to 11) were left untreated (N = 9) or treated with Ramipril (0.5 mg/kg body wt per day; N = 7), Nifedipine (30 mg/kg body wt per day; N = 9), or Moxonidine (10 mg/kg body wt per day; N = 8) for 8 wk. After perfusion fixation, heart and aorta were examined by stereological techniques. Aortic wall thickness was significantly higher in SNX than in sham-operated control rats and was similarly lowered by all three interventions. In contrast, the wall thickness of intramyocardial arterioles was significantly higher in SNX; this was prevented by Ramipril and Nifedipine, but not by Moxonidine. Intramyocardial capillary length density (Lv) was significantly lower and interstitial volume density (Vv) significantly higher in untreated SNX. Reduction of capillary length density was completely prevented by Moxonidine and in part by Ramipril. The increase in cardiac interstitial volume density was completely prevented by Ramipril and was partially prevented by Moxonidine or Nifedipine treatment. The following conclusions can be drawn from the results: (1) all agents normalize aortic wall thickness, but only calcium channel blockers and angiotensin-converting enzyme (ACE) inhibitors prevent intramyocardial arteriolar wall thickening: (2) intramyocardial arteriolar wall thickening, capillary rarefaction, and expansion of the cardiac interstitium are seen in SNX even after lowering the blood pressure to subnormal levels; i.e., changes in systemic blood pressure cannot completely explain the altered vascular structure in renal failure; (3) the effects of Ramipril, Nifedipine, and Moxonidine on cardiovascular structures in experimental renal failure are not completely accounted for by their hemodynamic actions.

Paricalcitol Downregulates Myocardial Renin-Angiotensin and Fibroblast Growth Factor Expression and Attenuates Cardiac Hypertrophy in Uremic Rats

“…The finding that cardiac hypertrophy in renal failure can be effectively prevented by the administration of either E or Pc is consistent with the notion that the RAS plays an important role in the regulation of cardiomyocytes cell size and number 6,9,33 and that these changes can be abrogated by therapeutic agents capable of modulating the RAS cascade. 6 The significant attenuation of the heart-to-body weight following E is in line with past observations that demonstrated prevention of the development and progression of LVH with ACEI treatment in uremia.…”

“…6 The significant attenuation of the heart-to-body weight following E is in line with past observations that demonstrated prevention of the development and progression of LVH with ACEI treatment in uremia. 33 Paricalcitol also significantly ameliorated myocardial hypertrophy, a novel observation in experimental uremia. Our findings differ from those of Mizobuchi et al 9 who showed only a modest and nonsignificant reduction in cardiac hypertrophy with Pc treatment in uremia.…”

Coronary artery calcium burden, carotid atherosclerotic plaque burden, and myocardial blood flow in patients with end-stage renal disease: A non-invasive imaging study combining PET/CT and 3D ultrasound

“…This finding supports the assumption that the duration of renal replacement therapy has a strong impact on myocardial perfusion, mainly due to rarefication of small intramyocardial vessels. 23 – 25 We found impaired CFR in 20% of our patients, which is less than reported in other studies 33 and most probably due to the relatively young study cohort. Prior investigations have suggested that CKD is associated with abnormal coronary vasodilator function, 26 which results from multiple mechanisms including decreased capillary density, 27 vascular remodeling, 28 and endothelial dysfunction.…”

Capillaries as a Therapeutic Target for Heart Failure

“…The hearts of experimental uremic Sprague-Dawley rats (5/6 nephrectomy (5/6 NX)) exhibited cardiac hypertrophy, interstitial fibrosis, and reduced capillary density 47) . Nephrectomy-induced capillary rarefaction in the heart was completely inhibited by the administration of moxonidine, a central sympatholytic agent, but not by the calcium antagonist nifedipine 48) . Another report showed transcript Vegfa reduced in the heart with 5/6 NX, and this was ameliorated with selective renal sympathetic denervation 49) .…”