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Bosentan prevents preglomerular alterations during angiotensin II hypertension
D Casellas1, N Bouriquet, A Herizi
1Groupe Rein et Hypertension, Institut Universitaire de Recherche Clinique, Montpellier, France. casellas@iurc1.iurc.montp.inserm.fr
Insights
Chronic angiotensin II (Ang II) infusion causes vascular lesions and impairs kidney autoregulation. Endothelin-1 blockade with bosentan prevents these harmful effects, suggesting its key role in Ang II-induced hypertension.
Area of Science:
- Nephrology
- Cardiovascular Physiology
- Hypertension Research
Background:
- Chronic angiotensin II (Ang II) infusion is a model for studying hypertension.
- Ang II-induced hypertension is associated with structural and functional vascular changes.
- The role of endothelin-1 in these alterations requires further investigation.
Purpose of the Study:
- To characterize structurofunctional alterations in preglomerular vessels during Ang II-induced hypertension.
- To assess the role of endothelin-1 in these changes using the antagonist bosentan.
- To evaluate the impact on renal autoregulatory responses.
Main Methods:
- Induction of hypertension in rats using Ang II infusion.
- Administration of bosentan, an endothelin-1 receptor antagonist.
- Isolation and analysis of preglomerular vessels (arcuate arteries, interlobular arteries, afferent arterioles).
- Assessment of vascular lesions, media thickness, lipid accumulation, and cell proliferation.
- Evaluation of autoregulatory responses using videomicroscopy in blood-perfused juxtamedullary nephron preparations.
Main Results:
- Ang II infusion significantly increased systolic blood pressure and albuminuria in rats.
- Focal vascular lesions, characterized by increased media thickness and lipid deposition, were observed in preglomerular vessels of Ang II-treated rats.
- These lesions and associated media cell proliferation were significantly reduced by bosentan treatment.
- Autoregulatory responses in interlobular arteries and afferent arterioles were impaired in Ang II-treated rats but preserved in rats receiving bosentan.
- Basal vascular tone remained unaffected by Ang II or bosentan treatment.
Conclusions:
- Chronic Ang II-induced hypertension leads to the development of vascular lesions and impaired autoregulation in preglomerular vessels, particularly in juxtamedullary nephrons.
- Endothelin-1 plays a significant role in mediating these structurofunctional alterations.
- Bosentan effectively prevents Ang II-induced vascular damage and functional impairment, highlighting endothelin-1 as a therapeutic target.
Abstract:
The present study was performed to characterize structurofunctional alterations of preglomerular vessels during chronic angiotensin II (Ang II)-induced hypertension (Ang II group: 400 ng x kg[-1] x min[-1], 10 days) and to assess the role of endothelin-1 in rats receiving Ang II and the mixed receptor antagonist bosentan (Ang II+B group: 30 mg x kg[-1] x d[-1], 10 days). Systolic blood pressure rose by 56+/-3 and 54+/-6 mm Hg in Ang II and Ang II+B rats, respectively. Albuminuria increased similarly in both Ang II-treated groups, reflecting glomerular barrier dysfunction. Preglomerular vessels were isolated after HCI maceration and comprised arcuate arteries and their branches, interlobular arteries (ILA), and afferent arterioles (AA). In the Ang II group, focal vascular lesions affected 36+/-6%, 20+/-5%, and 4+/-1% of arcuate arterial branches, ILA, and AA, respectively. They were characterized by 74% increased media thickness and accumulation of Sudan black-positive (SB+) lipid droplets, and media cell proliferation was documented through immunohistochemistry. The occurrence of SB+ lesions was strikingly reduced with bosentan. Autoregulatory responses (AR) were assessed along ILA and AA with the use of blood-perfused juxtamedullary nephron preparations. AR were elicited by raising blood perfusion pressure from 60 to 160 mm Hg and quantified through videomicroscopy as pressure-induced constrictions. AR were inhibited in Ang II-treated rats along ILA and AA; Ang II-induced AR changes were prevented by bosentan. Maximal relaxation induced by Mn2+ revealed equal basal tone in Ang II-treated, Ang II+B-treated, and control vessels. Chronic Ang II-induced hypertension is therefore associated with the development of SB+ lesions and selective impairment of AR in juxtamedullary nephrons. Endothelin-1 likely mediates the structurofunctional alterations of preglomerular vasculature during Ang II hypertension.