Abstract-High-cholesterol alimentation is associated with an induction of angiotensin-converting enzyme and angiotensin II receptor expression within the vascular wall of the aorta. Despite an enhanced pressure response to angiotensin II in atherosclerotic conscious rabbits, angiotensin II-induced contraction was reduced in isolated vascular rings from the aorta and unchanged in those from the iliac artery. We, therefore, investigated whether cholesterol-induced atherosclerosis enhances overall vascular responsiveness to angiotensin II in intact animals and whether an altered arterial baroreflex sensitivity can explain the discrepancy between experiments in intact animals and isolated blood vessels. Rabbits were maintained on a high-cholesterol diet (2 g/d cholesterol plus 20 mL/d sunflower seed oil, nϭ11) or on a standard diet (nϭ12) for 12 weeks. Total serum lipids markedly increased (PϽ0.05). Tissue examinations 6 weeks after termination of the high-cholesterol diet revealed distinct atherosclerosis and elevated cholesterol content in the aorta (PϽ0.05). A high-cholesterol diet did not change baseline hemodynamic parameters. However, angiotensin II-induced increases in total peripheral resistance were larger in the atherosclerotic animals (86.3Ϯ13.0 versus 41.9Ϯ9.7 mm Hg ⅐ L Ϫ1 ⅐ min, PϽ0.05). In addition, the blood pressure pulse interval relationship was markedly reduced (slope: 0.80Ϯ0.14 versus 0.49Ϯ0.06 ms/mm Hg, PϽ0.05), which suggested that the baroreflex blunted the angiotensin II response to a lesser extent in atherosclerotic animals. In conclusion, the overall vascular responsiveness to angiotensin II is increased in the atherosclerotic rabbit as indicated by the larger increase in total peripheral resistance. An attenuation of the arterial baroreflex sensitivity may contribute to this effect.
Atherosclerosis is associated with increased angiotensin II AT1-receptor expression and vascular hyperresponsiveness to angiotensin II. Nevertheless, atherosclerosis is often not accompanied by hypertension. We studied if the hypertensive effect of angiotensin II is more pronounced in atherosclerosis. Rabbits were fed a high-cholesterol diet (n = 10) for 12 weeks, followed by a standard diet for another 6 weeks. Control animals received the standard diet (n = 8) for 18 weeks. After 18 weeks, haemodynamic measurements were performed during a baseline recording and during an intravenous infusion of angiotensin II (0.4 microg kg-1 min-1). Atherosclerosis in the high-cholesterol group was verified by histological and lipidchemical tissue examinations. During angiotensin II infusion, total peripheral resistance (TPR) increased more in the high-cholesterol group than in controls (+81.6 +/- 12.4 vs. +40.6 +/- 9.7 mmHg min L-1, P < 0.05). While cardiac output and stroke volume (SV) decreased more in the high-cholesterol group (P < 0.05), reflex bradycardia was stronger in the control group (P < 0.05), indicating a reduced baroreceptor reflex sensitivity in atherosclerosis. Despite the larger increase in TPR and the reduced baroreceptor reflex sensitivity in the high-cholesterol group, maximum blood pressure response to angiotensin II was similar in both groups. The lack of a greater blood pressure response to angiotensin II in the high-cholesterol group could be the result of the early stages of heart failure. Under resting conditions, heart failure seems to be fully compensated, as baseline haemodynamic parameters were similar in the high-cholesterol group and in controls. However, during angiotensin II infusion, the compensatory mechanisms do not prevent a stronger fall in cardiac output and SV. Therefore, the blood pressure response to angiotensin II is not exaggerated in atherosclerotic animals, as vascular hyperresponsiveness to angiotensin II is opposed by the stronger fall in cardiac output and SV.
The study shows that reduced acetylcholine-induced dilatation is related to the presence of atherosclerosis in old ApoB mice. Remarkably, the impaired vessel reactivity to phenylephrine already in young ApoB mice indicates early changes in vascular function in this model.
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