What is the clinical evidence from this study?

Study design: Other. Population: Angiotensin II-induced hypertension and end-organ damage (n=75). Intervention: Pyrrolidine dithiocarbamate (PDTC) vs. Vehicle (0.9% NaCl) or untreated. Primary outcome: Systolic blood pressure (p=0.02).

January 18, 2002Open Access

Angiotensin II induced inflammation in the kidney and in the heart of double transgenic rats

Key Result

Chronic treatment with the antioxidant PDTC decreased blood pressure to 162 mm Hg compared to 190 mm Hg in untreated rats, and significantly reduced cardiac hypertrophy and albuminuria.

Structured PICO

Does PDTC reduce angiotensin II-induced end-organ damage and inflammation in double transgenic rats?

Population

75 four-week-old male double transgenic and Sprague Dawley rats followed for 3 weeks to assess the effects of PDTC on Angiotensin II-induced end-organ damage.

Intervention

PDTC (pyrrolidine dithiocarbamate) 200 mg/kg subcutaneous once daily for 3 weeks

Comparator

Vehicle (0.9% NaCl) or untreated

Outcome

Blood pressure, cardiac hypertrophy, albuminuria, mortality, and NF-kB binding activity at 7 weeks of agesurrogate

Inhibition of NF-kB by PDTC markedly reduces inflammation, end-organ damage, and mortality in a rat model of angiotensin II-induced hypertension.

Main Result

Absolute Event Rate: 162% vs 190%

p-value: p=0.02

Limitations

The precise mechanism for the biological effects of PDTC is still controversial
Animal model findings may not directly translate to human pathology

Abstract

BACKGROUND: We are investigating a double transgenic rat (dTGR) model, in which rats transgenic for the human angiotensinogen and renin genes are crossed. These rats develop moderately severe hypertension but die of end-organ cardiac and renal damage by week 7. The heart shows necrosis and fibrosis, whereas the kidneys resemble the hemolytic-uremic syndrome vasculopathy. Surface adhesion molecules (ICAM-1 and VCAM-1) are expressed early on the endothelium, while the corresponding ligands are found on circulating leukocytes. Leukocyte infiltration in the vascular wall accompanies PAI-1, MCP-1, iNOS and Tissue Factor expression. Furthermore we show evidence that Ang II causes the upregulation of NF-kB in our model. METHODS: We started PDTC-treatment on four weeks old dTGR (200 mg/kg sc) and age-matched SD rats. Blood-pressure- and albuminuria- measurements were monitored during the treatment period (four weeks). The seven weeks old animals were killed, hearts and kidneys were isolated and used for immunohistochemical-and electromobility shift assay analysis. RESULTS: Chronic treatment with the antioxidant PDTC decreased blood pressure (162 plus minus 8 vs. 190 plus minus 7 mm Hg, p = 0.02). Cardiac hypertrophy index was significantly reduced (4.90 plus minus 0.1 vs. 5.77 plus minus 0.1 mg/g, p < 0.001) compared to dTGR. PDTC reduced 24 h albuminuria by 85 % (2.7 plus minus 0.5 vs. 18.0 plus minus 3.4 mg/d, p < 0.001) and prevented death significantly. Vascular injury was ameliorated in small renal and cardiac vessels. PDTC inhibited NF-kappaB binding activity in heart and kidney. Immunohistochemical analysis shows increased expression of the p65 NF-kappaB subunit in the endothelium, smooth muscles cells of damaged small vessels, infiltrated cells, glomeruli, tubuli and collecting ducts of dTGR. PDTC markedly reduced the immunoreactivity of p65. CONCLUSION: Our data show that inhibition of NF-kappaB by PDTC markedly reduces inflammation, iNOS expression in the dTGR most likely leading to decreased cytotoxicity, and cell proliferation. Thus, NF-kappaB activation plays an important role in ANG II-induced end-organ damage.

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