ABSTRACT-Nitric oxide released from vascular endothelium plays important regulatory roles in cardiovascular and pulmonary systems. Epidemiological studies suggest that diesel exhaust particles (DEP) seem to be one of the causative factors responsible for the recent increase in pulmonary diseases. To clarify the pathogenic mechanism, the effects of DEP on vascular endothelial functions were investigated in terms of endothelium-dependent relaxation. Ring preparations of rat thoracic aorta were preincubated for 10 min with a DEP suspension (1, 10, 100 pg/ml) at 37°C in organ baths and relaxed with cumulative additions of acetylcholine following precontraction with phenylephrine (10-6 M). The relaxation was attenuated by DEP-exposure in a concentration-dependentmanner. An addition of superoxide dismutase (SOD) completely abolished the inhibitory effect of DEP at lower concentrations, but only partially at the higher concentration. DEP (10 tg/ml) neither affected the contractile response to phenylephrine in intact aortic rings nor the endothelium-independent relaxation by sodium nitroprusside in denuded rings, while DEP (100 pg/ml) significantly attenuated both responses. These results suggest that 1) inhaled DEP causes pulmonary inflammation by inhibiting the endothelial formation and/or the effect of nitric oxide and 2) SOD reduces the adverse effects. Keywords: Diesel exhaust particle, Endothelium-dependent relaxation, Thoracic aorta (rat), Superoxide, Acetylcholine Several epidemiological studies indicate that patients with pulmonary diseases such as asthma and chronic bronchitis are increasing in Japan, especially in children living in urban areas. Diesel exhaust contains 2 to 20 times more nitrogen oxides and 30 to 100 times more particles than gasoline exhaust. Moreover, it has been recently reported that diesel exhaust particles (DEP) suspended in phosphate buffer generate superoxide anion radicals (02'-) and hydroxyl radicals ('OH) on incubation at 371C. Sagai et al. suggested that these active oxygen radicals would cause endothelial cell damage leading to pulmonary edema (1). It was reported that reactive oxygens (02'-, 'OH and H202) were causes of pulmonary injury (2) and that 02'-produced from dihydroxyfumarate induced pulmonary endothelial cell damage (3). The earliest stages of histologically observable lung injury occurred in the pulmonary capillary bed (4) and the endothelial cells in capillaries (5). Edward reports that injury of the pulmonary endothelial cells is the pathogenesis of acute lung injury (6). These observations imply that the endothelium plays important protective roles in the development of pulmonary injury.Since the alveolar capillary endothelium lies close to the alveolar epithelium (7), inhaled DEP may easily interact with the endothelium, blood cells and blood components by releasing reactive oxygens and some soluble materials. The endothelium releases numerous biologically important materials, one of which is endothelium-derived relaxing factor (EDRF): nitric oxide (8) or nitrosot...

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1. We examined the effects of Ginkgo biloba extract (GBE) on the development of hypertension, platelet activation and renal dysfunction in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Both DOCA-salt hypertensive rats and normotensive rats were fed a 2% GBE diet for 20 days. Blood pressure (BP) was measured by two methods, namely by the tail-cuff and telemetry methods. 2. Development of hypertension was attenuated in rats fed a 2% GBE diet. In addition, an increase in heart weight, an indicator of sustained high BP, was inhibited significantly by feeding of the GBE diet. 3. Decreases in 5-hydroxytryptamine content in platelets, a marker of platelet activation in vivo associated with hypertension, were also prevented by feeding of the GBE diet. Ginkgo biloba extract itself did not inhibit ADP- and collagen-induced platelet aggregation examined in vitro. Feeding of the GBE diet tended to inhibit increases in plasma urea nitrogen due to hypertension. 4. The telemetry study demonstrated that BP and heart rate (HR) showed a clear circadian rhythm and the antihypertensive effect of GBE was prominent in the daytime, a resting period for rats. This anti-hypertensive effect of GBE was not detected in normotensive rats. In contrast, the inhibitory effect of GBE on HR was independent of time and was observed in both normotensive and hypertensive rats. 5. These results indicate that GBE has an anti-hypertensive and bradycardiac action, which are time dependent and independent, respectively. Thus, it appears that the chronopharmacological action of GBE may be ascribed not to pharmacokinetic factors, but rather to a circadian susceptibility rhythm to GBE in DOCA-salt hypertensive rats.

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