Impairment of endothelium-dependent relaxation: an early marker for atherosclerosis in the rabbit.

1. Cholesterol feeding of rabbits impairs the endothelium-dependent relaxation (EDR) evoked by acetylcholine (ACh) in the aorta. The experiments described in this paper were undertaken to examine the influence of age upon this phenomenon. 2. Rabbits aged 8 weeks and 46 weeks were fed a diet containing 2% cholesterol and other lipids for 4 weeks. Age-matched control animals were fed a standard rabbit diet. The concentrations of cholesterol and triglycerides in plasma were measured and the extent of atherosclerosis was estimated by staining the aortae with Sudan Red. Light and electron microscopy were undertaken also. 3. Rings of aorta were prepared for recording isometric tension. They were contracted with noradrenaline (NA) and EDR elicited by adding ACh. 4. The young rabbits showed weight gain, hypercholesterolaemia, prominent Sudan Red staining, together with scanning and transmission electron microscopic (SEM and TEM) features of cholesterol-induced atherosclerosis. The older animals showed significant weight loss and hypercholesterolaemia. The aortae of these animals showed no significant sudanophilia or light microscopic features of atherosclerosis. The SEM appearances were similar to the young animals fed cholesterol. 5. EDR to ACh was significantly impaired in both groups of cholesterol-fed rabbits. The maximal relaxations to ACh in young control and cholesterol-fed rabbits were 46.4 +/- 2.9% and 24.0 +/- 4.3% (mean +/- s.e. mean, n = 8, P less than 0.05) of the contractile response to NA (1 mumol 1(-1]. The corresponding results in the age control and cholesterol-fed rabbits were 31.8 +/- 3.9% and 9.1 +/- 1.5% (n = 9, P less than 0.05). 6. The young rabbits were far more susceptible to cholesterol-induced atherosclerosis than older animals and these changes were accompanied by loss of EDR. In the older animals and these changes were accompanied by loss of EDR. In the older animals the loss of the latter property was not accompanied by a significant degree of atherosclerosis although hypercholesterolaemia was present.