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Cardiac fibrosis occurs early and involves endothelin and AT-1 receptors in hypertension due to endogenous angiotensin II

Teresa M. Seccia, MD^*, Anna S. Belloni, BSc, Reinhold Kreutz, MD, Martin Paul, MD, Gastone G. Nussdorfer, MD, Achille C. Pessina, MD, PhD and Gian Paolo Rossi, MD, FACC^,*

^* Department of Clinical Methodology and Clinical-Surgical Technologies, University of Bari, Bari, Italy
Department of Human Anatomy and Physiology (Section of Anatomy), University of Padova, Padova, Italy
Institute of Clinical Pharmacology and Toxicology, Freie University of Berlin, Berlin, Germany
Department of Clinical and Experimental Medicine, Clinica Medica 4, University of Padova, Padova, Italy

View larger version (34K): [in a new window]   Figure 1 Systolic blood pressure (SBP) values in the five experimental groups before and during the treatment with placebo (open squares), bosentan (closed circles), irbesartan (closed down triangles), BMS-182874 (open triangles), and irbesartan plus BMS-182874 (closed up triangles). Starting from the end of the first week of treatment, SBP was significantly lower (p < 0.001) in the irbesartan group compared with all other groups. In the irbesartan plus BMS-182874 group, SBP was significantly (p < 0.01) lower only at the end of the third week compared with the bosentan and BMS-182874 groups.

View larger version (157K): [in a new window]   Figure 2 Microphotographs of left ventricular myocardium stained with the collagen-specific dye Sirius red. Collagen fibers appear as red structures, and myocytes and intramyocardial vessels are yellow (magnification x40). A diffuse interstitial and a marked perivascular fibrosis is evident in placebo-treated eight-week-old TGRen2 (A). Irbesartan (B) and bosentan (C) treatment for four weeks resulted in a marked reduction of fibrosis, both in the interstitium and perivascularly. No effect of treatment with the ETA receptor antagonist BMS-182874 (D) was seen. The combined treatment with irbesartan plus BMS-182874 (E) did not reduce cardiac fibrosis compared with placebo and with BMS-182874 alone.

View larger version (37K): [in a new window]   Figure 3 Left ventricular collagen density, expressed as percent of the total area pertaining to fibrillar collagen (as visualized by the Sirius red staining) and measured by videodensitometry, was significantly decreased in bosentan- and irbesartan-treated eight-week-old TGRen2 compared with both age- and gender-matched placebo-treated TGRen2 and with BMS-182874 or BMS-182874 + irbesartan. The BMS-182874, either alone or combined with irbesartan, did not reduce collagen density compared with placebo.

View larger version (23K): [in a new window]   Figure 4 The bar graph shows total birefringence (left bars of each group) and the ratio of red-orange to greenish-yellow fibers (right bars of each group) of Sirius red–stained sections of the LV of eight-week-old TGRen2, assessed with polarization microscopy. Total birefringence is expressed as percent of the total area pertaining to the sum of red-orange and greenish-yellow fibers, which roughly correspond to collagen type I and III, respectively. Total birefringence and the ratio of red-orange to greenish-yellow fibers were lower in bosentan-treated TGRen2 compared with placebo. The TGRen2 receiving irbesartan + BMS-182874 showed a significantly higher total birefringence compared with both bosentan- and irbesartan-treated TGRen2.