AT ₁ Receptor Antagonism Reduces Endothelial Dysfunction and Intimal Thickening in Atherosclerotic Rabbits

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.

Selective Angiotensin Receptor Antagonism with Valsartan Decreases Arterial Stiffness Independently of Blood Pressure Lowering in Hypertensive Patients

“…Furthermore, sustained angiotensin II receptor blockade for 24 weeks significantly enhanced the decrease in baPWV in response to BP lowering. This observation is consistent with the report of a significant slowing of the progression of aortic atherosclerosis by long-acting ARB (18). In a recent study, treatment with valsartan limited to 3 months in duration was more effective in decreasing baPWV than the calcium channel blocker, nifedipine (19).…”

Effect of Valsartan on Angiotensin II–Induced Plasminogen Activator Inhibitor-1 Biosynthesis in Arterial Smooth Muscle Cells

“…18,29,30 This drug, beyond its blood pressure-lowering activity, improves heart failure in rats with myocardial infarction, reduces endothelial dysfunction and intimal thickening in atherosclerotic rabbits, and induces a significant regression of left ventricular hypertrophy in patients with essential hypertension. 18,[31][32][33] The effects of AT 1 antagonists on fibrinolytic balance, and in particular on PAI-1 and tPA plasma levels, in normal subjects as well as in patients with cardiovascular disease, are still controversial. 34 Moreover, no clinical data on valsartan, which possesses greater specificity and selectivity for the AT 1 receptor than losartan, 35 are yet available.…”

Angiotensin Receptor Blockade With Candesartan Attenuates Atherosclerosis, Plaque Disruption, and Macrophage Accumulation Within the Plaque in a Rabbit Model

“…More recently, angiotensin II has been shown to contribute to atherogenesis. 1 Angiotensin II results in impaired endothelium-dependent vasodilation, 2 monocyte recruitment and activation, 3 and vascular smooth muscle cell growth and migration, 4,5 as well as increased oxidation of LDL, with subsequent uptake of oxidized LDL by macrophages. 6 The effect of angiotensin II on the vasculature is mediated by 2 plasma membrane receptors, angiotensin II receptor type 1 and angiotensin II receptor type 2 (AT 1 and AT 2 , respectively).…”