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AT(1) receptor antagonism reduces endothelial dysfunction and intimal thickening in atherosclerotic rabbits
N de las Heras1, P Aragoncillo, R Maeso
1Novartis Pharma, Basle, Switzerland.
Abstract:
The effects of angiotensin (AT)(1) receptor antagonists on functional and morphological alterations associated with atherosclerosis are not well known. The current study was performed to examine the long-term effects of valsartan (3 or 10 mg/kg per day for 10 weeks) on endothelial function and structural changes in aorta from rabbits fed with either a control diet or a cholesterol-enriched diet. Rabbits fed with the cholesterol-rich diet showed higher (P<0.05) plasma levels of cholesterol than did controls. Treatment with valsartan (3 or 10 mg/kg per day) did not alter plasma cholesterol levels or systolic arterial pressure in any group. Contractions induced by angiotensin II were comparable in both control and hypercholesterolemic rabbits and were markedly reduced by treatment with valsartan. Relaxations induced by acetylcholine were lower in hypercholesterolemic rabbits than in controls. Treatment with valsartan (3 or 10 mg/kg per day) enhanced (P<0.05) this response in hypercholesterolemic rabbits but not in controls. Lumen and media cross-sectional areas were comparable in control and hypercholesterolemic rabbits. Vessel area was higher (P<0.05) in hypercholesterolemic rabbits than in controls. Intimal lesion was 29.5+/-6% in cholesterol-fed rabbits and nonexistent in control rabbits. Treatments with 3 and 10 mg/kg per day valsartan reduced (P<0.05) intimal lesion to 2.4+/-0.7% and 2.7+/-0.9%, respectively, and increased lumen area in hypercholesterolemic rabbits. No changes in either vessel or media cross-sectional areas were observed in these animals. In summary, angiotensin II, through AT(1) receptors, appears to play a key role in the development of the vascular functional and structural changes associated with hypercholesterolemia. AT(1) receptor antagonists, besides their antihypertensive effects, could be an important therapeutic tool to reduce the development of atherosclerosis.
Insights
Valsartan treatment improved endothelial function and reduced arterial lesions in hypercholesterolemic rabbits, suggesting AT(1) receptor antagonists may combat atherosclerosis.
Area of Science:
- Cardiovascular Pharmacology
- Atherosclerosis Research
- Endothelial Function Studies
Background:
- The role of angiotensin (AT)(1) receptor antagonists in atherosclerosis-related vascular changes remains incompletely understood.
- Hypercholesterolemia is a significant risk factor for atherosclerosis, impacting vascular structure and function.
Purpose of the Study:
- To investigate the long-term effects of valsartan on endothelial function and aortic structural alterations in hypercholesterolemic rabbits.
- To determine if valsartan mitigates vascular damage associated with high cholesterol diets.
Main Methods:
- Rabbits were fed a control or cholesterol-enriched diet for 10 weeks.
- Valsartan (3 or 10 mg/kg/day) was administered to assess its impact on vascular responses and morphology.
- Measurements included plasma cholesterol, systolic blood pressure, vascular reactivity (angiotensin II and acetylcholine), and aortic structural parameters (lumen, media, vessel area, intimal lesion).
Main Results:
- Valsartan did not affect plasma cholesterol or blood pressure but significantly reduced angiotensin II-induced contractions.
- Acetylcholine-induced relaxations were impaired in hypercholesterolemic rabbits but improved with valsartan treatment.
- Valsartan significantly reduced intimal lesion size and increased lumen area in hypercholesterolemic rabbits without altering media or vessel areas.
Conclusions:
- Angiotensin II, via AT(1) receptors, plays a critical role in hypercholesterolemia-induced vascular dysfunction and structural changes.
- AT(1) receptor antagonists like valsartan show potential as therapeutic agents to inhibit atherosclerosis development, beyond their blood pressure-lowering effects.