The present experiment was performed to identify endothelium-derived contracting factor produced by acetylcholine stimulation in the aorta of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. The rings of the thoracic aorta were obtained from age-matched SHR and WKY rats, and changes in isometric tension were recorded. The relaxant responses to acetylcholine in the aortic rings from SHR were significantly weaker than those from WKY rats. The relaxant responses to acetylcholine were significantly enhanced by pretreatment with a cyclooxygenase inhibitor (indomethacin) or thromboxane A 2 / prostaglandin H 2 receptor antagonist (ONO-3708) in aortic rings from both SHR and WKY rats. A thromboxane A 2 synthetase inhibitor (OKY-046) did not affect the acetylcholineinduced relaxation in the aortic rings from SHR or WKY rats. In the organ bath solution, after acetylcholine stimulation, prostaglandin E 2 and 6-keto-prostaglandin F la concentrations increased but not prostaglandin F 2a and thromboxane B 2 concentrations. Exogenous prostaglandin H 2 , a stable analogue of thromboxane A 2 , and prostaglandin F 2a induced contractions of the SHR rings at a lower concentration than prostaglandin E 2 , prostaglandin D 2 , and prostaglandin I 2 . These contractile responses to various prostaglandins were markedly inhibited by pretreatment with ONO-3708. A prostacyclin synthetase inhibitor did not affect the relaxant responses to acetylcholine in the SHR rings. These results show that endotheliumderived contracting factor is produced and released by acetylcholine stimulation not only in the aorta of SHR but also in those of WKY rats and suggest that prostaglandin H 2 , a precursor of the released prostaglandins, is a strong candidate for endothelium-derived contracting factor produced by acetylcholine stimulation. (Hypertension 1990;15:475-481) A ll blood vessels are lined by the endothelium, and the important role of an organic or functional abnormality of endothelial cells in the pathogenesis and pathophysiology of various diseases has attracted attention.In 1980, Furchgott et al 1 found that acetylcholine induced endothelium-dependent relaxation in the rabbit aorta. Since then, various substances have been reported to induce endothelium-dependent relaxation in most of the blood vessels in mammals. 23Several pharmacological observations have strongly suggested that there is more than one endothelium-

We examined whether prostaglandin (PG) H2, as an endothelium-dependent contracting factor, or the disturbed production of endothelium-derived relaxing factor, impairs endothelium-dependent relaxation and whether long-term inhibition of nitric oxide (NO) synthesis aggravates atherosclerosis in hypercholesterolemic rabbits. Male New Zealand White rabbits were fed one of the following diets: (1) standard chow; (2) 2% cholesterol-supplemented chow; (3) standard chow with 80 micrograms/mL N omega-nitro-L-arginine methylester (L-NAME), an NO synthetase inhibitor, in their drinking water; or (4) 2% cholesterol-supplemented chow with 80 or 160 micrograms/mL L-NAME in their drinking water. The rabbits were fed these diets for 8 or 12 weeks. Then aortic rings were obtained, and changes in isometric tension were recorded. Intimal atherosclerotic areas of the thoracic aortas were subsequently measured by planimetry. The cholesterol-supplemented diet significantly impaired endothelium-dependent aortic relaxation to acetylcholine. Pretreatment with the thromboxane A2/PGH2 receptor antagonist ONO-3708 did not reverse this impaired response. Vessels from both normocholesterolemic and hypercholesterolemic rabbits given L-NAME showed more impaired endothelium-dependent relaxation than those from their dietary counterparts not given L-NAME. Morphometric analysis revealed marked enlargement of intimal atherosclerotic areas in aortas from L-NAME-treated hypercholesterolemic rabbits compared with those from untreated hypercholesterolemic rabbits. These findings suggest that PGH2 does not contribute to impaired endothelium-dependent relaxation and that long-term administration of L-NAME promotes atherosclerosis by inhibition of NO synthesis in the hypercholesterolemic rabbit thoracic aorta.

Objective-To assess whether the concentrations of serum advanced glycation end products (AGE) in diabetic patients with obstructive coronary artery disease diVer from those in type 2 diabetic patients without obstructive coronary artery disease. Design-Serum AGE concentrations were measured in type 2 diabetic patients and in non-diabetic patients, both with and without obstructive coronary artery disease, and the relation between these values and coronary disease severity was evaluated. Results-Mean (SD) serum AGE concentrations were higher (p < 0.0125) in type 2 diabetic patients with obstructive coronary artery disease (5.5 (2.5) mU/ml, n = 30) than in patients without obstructive coronary artery disease (2.8 (0.5) mU/ml, n = 12), and higher than in nondiabetic patients with (3.4 (1.0) mU/ml, n = 28) and without (3.2 (0.4) mU/ml, n = 13) obstructive coronary artery disease. Serum AGE was associated with the degree of coronary arteriosclerosis in type 2 diabetic patients with obstructive coronary artery disease (single vessel: n = 13, 3.4 (0.9) mU/m; two vessel: n = 6, 5.7 (1.6) mU/m; three vessel: n = 11, 7.2 (2.5) mU/ ml). Serum AGE was positively correlated with serum mean four year HbA 1C (r = 0.46, p < 0.01), but not with recent serum HbA 1C (r = 0.24). The four groups did not diVer in the other coronary risk factors. Conclusions-Serum AGE concentrations may be associated with long term poor glycaemic control and reflect the severity of coronary arteriosclerosis in type 2 diabetic patients. (Heart 2001;85:87-91)

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