Effect of nisoldipine on atherosclerosis in the cholesterol fed rabbit: endothelium dependent relaxation and aortic cholesterol content

STUDY OBJECTIVE--The aim was to determine the effect of the calcium channel blocker nisoldipine on the loss of endothelium dependent relaxation and the accumulation of cholesterol in the aorta produced by feeding a diet enriched with cholesterol. DESIGN--12 week old New Zealand white rabbits were assigned randomly to four groups with the following dietary and drug regimens: group A--standard diet + 2.5% cholesterol (n = 45); group B--standard diet + nisoldipine (n = 9); group C--standard diet + nisoldipine + 2.5% cholesterol (n = 9); group D--standard diet (n = 9). After 3 weeks the cholesterol supplements were stopped and all animals were given the standard rabbit diet. The animals in groups B and C were given nisoldipine (1 mg.kg-1.d-1) by mouth for the entire 7 week period. EXPERIMENTAL MATERIAL--Aortic tissue was removed for measurement of cholesterol content, endothelium dependent relaxation to acetylcholine, contractile responses to noradrenaline, relaxant responses to sodium nitrite, and sudan staining. Serum was obtained for measurement of cholesterol and triglyceride concentration. MEASUREMENTS AND MAIN RESULTS--At 7 weeks, endothelium dependent relaxation to acetylcholine was impaired in group A compared to group D, while that in group C was not. Aortic tissue cholesterol content in group A was significantly greater than in groups B, C, and D. At 15 weeks, ie, 12 weeks after reversal of the diet, endothelium dependent relaxation had recovered in the animals in group A. There was a significant reduction in the aortic cholesterol content at this stage. In two subgroups of A (groups A2 and A4) which were given nisoldipine immediately after and 4 weeks after cessation of cholesterol feeding respectively, the drug was found to have no influence upon restoration of endothelium dependent relaxation. However, the drug appeared to promote the retention of cholesterol within the aorta after cessation of cholesterol feeding. CONCLUSIONS--Nisoldipine protects against the accumulation of cholesterol and loss of endothelium dependent relaxation in the aorta of rabbits fed a diet supplemented with 2.5% cholesterol for three weeks. Administration of the drug after the lesions are established in the aorta also appears to retard the removal of cholesterol from the aorta.     

Effect of argon laser irradiation on rabbit aortic smooth muscle: evidence for endothelium independent contraction and relaxation

To study the effect of argon laser irradiation on vascular smooth muscle reactivity, ring segments of rabbit thoracic aorta were mounted isometrically in Krebs bicarbonate buffer. Laser irradiation was performed via a 200-micron core optical fibre interfaced with an argon ion gas laser. Laser irradiation at powers greater than 1.0 watt (W) (n = 34) produced contraction in each case, regardless of the duration of exposure. Conversely, irradiation at powers less than 0.1 W (n = 41) consistently produced relaxation. When the power employed ranged from 0.1 to 1.0 W (n = 100), the typical response consisted of a combination of low amplitude contraction and relaxation. At each power level, the responses observed were independent of the presence or absence of intact endothelium, assessed functionally by the response to acetylcholine and anatomically by scanning electron microscopy. Recordings of tissue temperature profiles performed during continuous-wave laser irradiation suggest that the findings observed in this study may be explained by a combination of heat induced contraction and light induced relaxation. At powers greater than 1.0 W, heat generated by laser irradiation is predominant, causing contraction. At powers less than 0.1 W, light predominates over heat, causing relaxation. When the power range is intermediate between these values, the heterogeneous response recorded reflects the combination of light and heat. In all cases, contraction and relaxation are endothelium independent.     

Effect of metformin on lipid metabolism in the rabbit aortic wall

The aim of the present study was to investigate whether metformin was capable of altering aortic lipid metabolism. Pretreatment of rabbits for 8 days with 120 mg/kg per os metformin reduced by 50--70% the incorporation of a 20 muCi tracer doseof [4(-14)C]cholesterol (given orally 24 h before) into various segments of aorta, plasma, liver, intestine and lung, as compared with control animals. However, as intestinal absorption of cholesterol was also diminished in the same proportion, it was then decided to inject the labelled cholesterol directly into the blood. Under these conditions, metformin induced the same reduction in [4(-14)C]cholesterol specific activity in the aorta, but not in other tissues. Three hours after intravenous injection of a 200 muCi tracer dose of [2(-14)C]-acetate, metformin strongly diminished the radioactivity of total lipids of the aorta, both in fed-rabbits and in rabbits on a 24 h fast, independently of the plasma radioactivity level. The inhibition of acetate incorporation into arterial lipids was observed in all lipid fractions (i.e. free and esterified cholesterol, free fatty acids, phospholipids and especially triglycerides) and the effect persisted unaltered over periods of increasing length after the injection of precursor (1/4, 1/2, 1, 3, 5, 8, 12 h). Metformin also significantly inhibited lipid biosynthesis in the liver and intestine. These properties, added to others previously described, can to a large extent explain the preventive effect of metformin on experimental atherosclerosis.     

In vivo detection of endothelium dependent and independent pulmonary artery relaxation in children.

BACKGROUND--In vitro studies have suggested an important role for the endothelium in the control of pulmonary vascular tone, but endothelium dependent and independent relaxation of pulmonary arteries have not been studied in children in vivo. METHODS--The response of the pulmonary circulation to graded infusions of acetylcholine (an endothelial dependent vasodilator) and to nitroprusside (a dilator not dependent on endothelium) was studied in 10 children aged four to 16 years who had normal pulmonary haemodynamics. Arterial diameter was measured by quantitative angiography, and pulmonary blood flow velocity was measured with a 3F intra-arterial Doppler catheter placed in a lower lobe segmental artery. RESULTS--There was a dose dependent increase in flow velocity in response to acetylcholine (maximum response 93%) (SEM 7%), and an increase of 51% (8%) in response to nitroprusside. By contrast, segmental artery diameter was unchanged during acetylcholine infusion in all patients, and increased only modestly in response to nitroprusside (5% (1%)). CONCLUSIONS--The most important site of action of endothelium dependent and independent pulmonary vasodilators is distal to the segmental pulmonary arteries. Despite low resting tone in the pulmonary circulation, endothelium dependent vasodilatation can be shown in vivo. This may allow study of the role of endothelial dysfunction in children with abnormal pulmonary haemodynamic secondary to congenital heart disease.     

益多脂对高甘油三酯血症患者血管内皮依赖性舒张功能的影响

目的 :观察益多脂对高甘油三酯血症患者血管内皮依赖性舒张功能的影响。方法 :30例高甘油三酯血症患者 (治疗组 )口服益多脂治疗 8周后 ,采静脉血用酶法测定甘油三酯 (TG)和总胆固醇 (TC)的浓度 ;采用高分辨率血管外超声法检测治疗前后肱动脉内皮依赖性血管舒张功能 ,并与 2 8例正常对照者 (对照组 )比较。结果 :治疗组血流介导的内皮依赖性血管舒张功能明显减弱 ,与对照组相比差异有显著性意义 [(4 .1± 0 .5 ) %∶(10 .1± 0 .8) % ],单因素相关分析发现 :血浆TG浓度与血流介导的肱动脉内皮依赖性舒张功能下降值之间呈负相关 (r =- 0 .6 3,P <0 .0 1)。治疗 8周后血流介导的内皮依赖性血管舒张功能增加 (4 .6± 1.2 ) % (P <0 .0 1) ,单因素相关分析显示 :肱动脉内皮依赖性血管舒张功能改善的程度与TG的基础值无相关性 (r =0 .2 84,P >0 .0 5 ) ,与TG的降低程度呈正相关 (r =0 .5 39,P <0 .0 1)。结论 :益多脂对高甘油三酯血症患者具有改善其血管内皮依赖性舒张功能的作用     

Effect of regenerated endothelium on lipid accumulation in the arterial wall.

We tested the hypothesis that loss of endothelium results in increased transport of lipoprotein into the arterial wall, favors accumulation of lipid, and thus predisposes to atherosclerosis. In rabbits initially fed a diet low in lipid, the aortas were de-endothlialized with an intraarterial balloon catheter; 28 days later, the animals were divided into two groups. Group I animals were continued on a diet low in lipid and sacrificed at 8, 11, 13, and 15 weeks after de-endothelialization. Group II animals were fed the same diet supplemented with 0.5% cholesterol and sacrificed at comparable intervals. Aortas of group I animals revealed proliferative fibromuscular intimal thickening in both de-endothelialized and re-endothelialized areas, with little or no fatty change in the intima. In contrast, aortas of group II animals revealed slight to marked fatty change in the intima, characterized by accumulation of oil red O-positive material with anisotropic lipid inclusions. The greatest quantity of lipid was present in intimal thickening beneath regenerated endothelium, and not in adjacent intimal thickening lacking an endothelial lining. These results do not support the hypothesis that the absence of endothelium favors accumulation of lipid and predisposes to atherosclerosis. The experiments indicate that lipid accumulates preferentially in areas of intimal thickening covered by regenerated endothelium.     

辛伐他汀对不稳定型心绞痛患者血管内皮功能的影响

目的 :观察辛伐他汀对不稳定型心绞痛 (UA)患者血管内皮依赖性血管舒张功能 (FMD)的影响。方法 :4 2例UA患者随机分为常规治疗组和辛伐他汀治疗组 ,治疗 8周前后 ,采静脉血用酶法测定甘油三酯和胆固醇的浓度 ;采用高分辨率血管外超声法检测治疗前后肱动脉FMD和内皮非依赖性舒张功能 (NMD)。结果 :辛伐他汀治疗 8周后肱动脉FMD(6 .14± 0 .4 5 ) %较治疗前 (2 .4 5± 0 .2 1) %及常规治疗组 (2 .5 0± 0 .36 ) %均显著改善 (P <0 .0 5 ) ,而肱动脉NMD差异无显著性意义 (P >0 .0 5 )。结论 :辛伐他汀具有改善UA患者血管FMD的作用     

Haptoglobin-haemoglobin complex in human plasma inhibits endothelium dependent relaxation: evidence that endothelium derived relaxing factor acts as a local autocoid

Endothelium dependent relaxation of isometrically mounted rabbit aortic strip preparations was rapidly inhibited by human plasma at dilutions down to 1:1000. Gel filtration and ion exchange chromatography were used to demonstrate that this inhibitory activity was present in fractions containing haptoglobin. Purified haptoglobin itself possessed no inhibitory action against endothelium dependent relaxation, but the haptoglobin-haemoglobin complex did, consistent with the documented ability of haemoglobin to inhibit this phenomenon. The concentration of haemoglobin normally bound to haptoglobin is sufficient to account for the inhibitory properties of human plasma. This suggests that endothelium derived relaxing factor exerts no downstream intravascular effect in vivo and thus that its physiological dilator role is that of a local autocoid acting on subjacent smooth muscle.     

Age related attenuation of the endothelium dependent relaxation to noradrenaline in isolated pig coronary arteries.

STUDY OBJECTIVE--The aim was to investigate the relationship between vascular aging and endothelial regulation of the vascular tone by various agonists in isolated pig coronary arteries. EXPERIMENTAL MATERIALS AND DESIGN--Coronary artery rings from young (4-6 month old) and aged (3-4 years old) Yorkshire pigs were studied under isometric tension by organ chamber experiments. Cumulative concentration-response curves were obtained for vasorelaxing agents including noradrenaline (with beta blocker), substance P, bradykinin, and glyceryl trinitrate in rings precontracted with prostaglandin F2 alpha (PGF2 alpha). The degree of atherosclerosis of the coronary arteries was examined by light microscopy after the pharmacological experiments. MEASUREMENTS AND MAIN RESULTS--In the presence of propranolol (3 x 10(-6)M), noradrenaline (10(-8)-10(-5)M) caused endothelium dependent relaxation. The maximum relaxation was significantly greater in the young [45.4(SEM 2.5)% of the magnitude of precontraction induced by PGF2 alpha] than in the aged group [26.9(3.0)%] (p less than 0.001). However, magnitudes of relaxation to substance P, bradykinin, and glyceryl trinitrate were not significantly different between the young and the aged groups. The alpha 2 antagonist yohimbine (3 x 10(-6)M) inhibited the endothelium dependent relaxation to noradrenaline, but the alpha 1 antagonist prazosin (10(-6)M) failed to inhibit the response. Gossypol (3 x 10(-5)M) and methylene blue (10(-5)M), both inhibitors of endothelium dependent relaxation, abolished alpha 2 adrenoceptor mediated relaxation, but a cyclo-oxygenase inhibitor indomethacin (10(-5)M) did not affect the response. Histologically almost all young pig coronary arteries were free of atherosclerotic changes, whereas aged arteries had fatty streaks with slightly narrowed lumen in 22 of 38 rings (58%). The remaining aged pig coronary rings were free from atherosclerosis. Comparison of the endothelium dependent relaxation to noradrenaline between the rings with fatty streaks and those without lesions in the aged pigs suggested that the attenuated response was due both to vascular aging and to fatty streak development. CONCLUSIONS--The endothelium dependent relaxation to noradrenaline via the alpha 2 adrenoceptor was attenuated by vascular aging and also by fatty streak formation in isolated pig coronary arteries. Thus vascular aging may affect the sympathetic regulation of the coronary arterial tone by the attenuation of endothelium dependent relaxation to catecholamines via alpha 2 adrenoceptors.     

Prostacyclin production in vitro by rabbit aortic endothelium: correction for unstirred diffusional layers

The degree of mixing in fluid layers immediately adjacent to the endothelial surface is a major variable in assessment of prostacyclin (PGI2) production by cultured endothelial cells or intact vessel endothelium in vitro. Lack of adequate mixing should lead to underestimation of true production because PGI2 immediately adjacent to endothelium would be only poorly sampled upon buffer collection. Thoracic aortas from 38 New Zealand white rabbits were therefore excised, opened longitudinally, and mounted endothelial side uppermost in a buffer-filled chamber which excluded cut tissue edges from study. Production of PGI2 under unstirred and magnetically stirred conditions was measured by radioimmunoassay (RIA) for 6-keto-PGF1 alpha. For animals pretreated with the combination of papaverine and heparin (see below), unstimulated and arachidonate-stimulated 6-keto-PGF1 alpha increased with stirring rate toward limits of 2.9 and 28.5 ng/cm2/min, respectively. Unstimulated and stimulated 6-keto PGF1 alpha measured at 650 rpm, for example, were greater than their values at 0 rpm by factors of 3.5 (2P less than .01) and 3.7 (2P less than .001), respectively. The process of vessel excision, however, produces another variable: degree of injury to endothelium caused by such factors as secondary vessel contraction and thrombin generation. Vessel contraction and thrombin generation can be minimized, respectively, by the use of a smooth muscle relaxant and heparin administered prior to killing of the animals. The rabbits were, therefore, grouped according to intravenous (IV) treatment, prior to killing, with saline, papaverine (4 mg/kg), heparin (200 U/kg) or the combination of papaverine and heparin (same doses). As compared with pretreatment with saline, papaverine alone, or heparin alone, pretreatment with the combination of papaverine and saline led to increases in stimulated 6- keto-PGF1 alpha of 1.6- to 2.8-fold. By transmission electron microscopy, endothelium from animals pretreated with saline showed ultrastructural changes, including disruption of cytoplasm, separation without detachment of most endothelial cells from subendothelium, and focal areas of denudation. In contrast, ultrastructural integrity of endothelium was preserved in aortas of animals pretreated with combined papaverine and heparin. These results support the hypothesis that unstirred diffusional layers lead, in vitro, to underestimation of PGI2 production, especially when vessels are protected from excisional injury.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of regional ischaemia, with or without reperfusion, on endothelium dependent coronary relaxation in the dog.

OBJECTIVE: The aim was to establish whether the duration of coronary ischaemia and coronary ischaemia with reperfusion selectively reduced the magnitude of relaxation mediated by endothelium dependent relaxing factor (EDRF) in response to thrombin, compared with relaxation produced by acetylcholine and calcimycin. METHODS: Adult male dogs, anaesthetised with sodium pentobarbitone (30 mg.kg-1 intravenously) were used. Coronary artery occlusions were maintained for either 15 or 45 min; in half the dogs from each timepoint, occlusion was followed by 60 min reperfusion. At the end of each in situ period, coronary arteries were removed from both ischaemic and non-ischaemic regions, cut into rings, and hung in isolated organ baths. Dose-response relationships to the EDRF dependent vasodilators thrombin, acetylcholine, and calcimycin, and to the EDRF independent vasodilator isoprenaline, were then established. RESULTS: Thrombin (0.003-0.3 units.ml-1) caused dose dependent relaxation in all tissues. Relaxant responses (E(max)) in the non-ischaemic vessels from both 15 and 45 min treatment groups were used as control data for the responses in ischaemic vessels. Maximum responses were not different in the non-ischaemic groups from either 15 or 45 min studies, at 82.7 (SEM 3.7)% after 15 min, and 82.1(2.4)% after 45 min. There was a small but significant reduction in E(max) after 15 min and 45 min ischaemia, to 74.4(3.2)% and 74.4(3.0)% respectively. Sixty minutes reperfusion provoked a further reduction in E(max) to 64.9(3.8)% after 45 min ischaemia, but not after 15 min ischaemia [70.3(4.2)%]. Neither 15 nor 45 min interventions altered E(max) of relaxation to acetylcholine or calcimycin (greater than 88.0% in each group). Similarly there were no significant differences between groups to the relaxation stimulated by isoprenaline (E(max) greater than 90.0%). CONCLUSIONS: The data suggest that loss of EDRF dependent relaxation to thrombin is more sensitive to ischaemia than the relaxation produced by either acetylcholine or calcimycin, and appears to be manifested early in the onset of ischaemic injury.     

阿托伐他汀对冠心病患者的血管舒张功能的影响

目的观察阿托伐他汀对冠心病患者血管舒张功能的作用。方法将入选60例冠心病并高胆固醇血症患者随机分为阿托伐他汀治疗组(A组)和对照组(B组)。分别测定血清胆固醇、三酰甘油、低密度脂蛋白胆固醇和高密度脂蛋白胆固醇。并应用高分辨率超声技术,检测治疗前、后两组肱动脉血流介导和硝酸甘油介导的舒张功能。结果治疗前,冠心病并高胆固醇血症患者肱动脉血流介导和硝酸甘油介导的舒张功能均低于健康对照组(P<0.01)。经阿托伐他汀治疗6个月后A组血浆总胆固醇、三酰甘油和低密度脂蛋白胆固醇显著降低(P<0.01),高密度脂蛋白胆固醇显著升高(P<0.01)。随着血脂的改善,肱动脉内皮依赖性血管舒张功能显著提高(P<0.01),但硝酸甘油介导的血管舒张功能未见改善(P>0.05)。结论冠心病并高胆固醇血症患者存在内皮依赖性血管舒张功能障碍,经阿托伐他汀调脂治疗后,受损的内皮依赖性血管舒张功能得到明显改善。     

Effect of spontaneous pathology and thrombin on leukocyte adhesion to rat aortic endothelium.

Leukocyte adhesion and other injury parameters have been studied in the aortic endothelium of Sprague-Dawley rats in two situations: (1) spontaneous pathology in conventional rats with antibodies to Mycoplasma pulmonis and/or Kilham or Sendai viruses, and (2) intravascular coagulation by thrombin administration in SPF rats. Adhesion (esterase (+) leukocytes/mm2) in SPF rats was 8 +/- 5 (n = 12). Adhesion in 38% of the conventional rats was 54 +/- 27 (n = 8), half of them being non-analyzed and the rest having antibodies to M. pulmonis and/or Kilham rat virus. In 19 rats with antibodies to M. pulmonis and/or Kilham or Sendai viruses, AgNO3 and hematoxylin staining of the aortic endothelium showed an increase in leukocyte adhesion, and the presence of argyrophilic cells, stigmata and granularity--severe endothelial lesions being observed in some cases. Adhesion in rats after 0.25, 1, 3 and 6 h of thrombin administration (30 units/100 g) was not different from controls. Adhesion after 24 h was 108 +/- 53 (n = 10) and 60 +/- 59 (n = 10), and 22 +/- 20 (n = 10) in rats treated with thrombin plus heparin or hirudin, respectively. Thrombin produced endothelial lesions at all times studied, and these included membrane blebs, platelet and erythrocyte adhesion and alterations in the pattern of endothelial esterase activity.     

Effect of intact endothelium against platelet-induced coronary artery spasm in isolated rabbit hearts

Effects of collagen-activated washed rabbit platelets on coronary arteries with and without intact endothelium were studied in a supported rabbit heart preparation using a perfluorocarbon (FC-43) as perfusate. The vascular diameter of obtuse marginal coronary arteries was determined by means of gated color arteriography (injection of patent blue dye). Endothelial denudation of the obtuse marginal artery was accomplished by scraping the lumen with a roughened plastic tubing. Injection of washed platelets (10 ml with about 500,000 platelets/μl) not treated with collagen failed to constrict coronary arteries either with intact or denuded endothelium. In contrast, injection of platelet suspension immediately after activation with collagen caused vasoconstriction of denuded obtuse marginal coronary arteries In 10 of 14 cases. In 6 preparations occlusion was complete, lasting up to 16 minutes. In arteries with intact endothelium, no coronary vasoconstriction occurred. In hearts with coronary artery spasm, total coronary vascular resistance increased significantly. This study furnishes additional evidence that endothelial lesions are a contributory factor for large coronary artery spasm and that endothelial cells possess a protective function against vasoconstrictor substances released from aggregating platelets.     

Lovastatin prevents the impairment of endothelium dependent relaxation and inhibits accumulation of cholesterol in the aorta in experimental atherosclerosis in rabbits

STUDY OBJECTIVE--The aim was to determine the effect of the HMG CoA reductase inhibitor, lovastatin, on the loss of endothelium dependent relaxation and the accumulation of cholesterol in the aorta produced by feeding a diet enriched with cholesterol. DESIGN--The study was conducted in two stages. In stage 1, New Zealand white rabbits were randomised into four groups. Group 1 (n = 15) was fed standard rabbit diet for 6 weeks. Groups 2 (n = 15), 3 (n = 12), and 4 (n = 12) were fed standard rabbit diet supplemented with 2% cholesterol for 2 weeks followed by standard rabbit diet only for the next 4 weeks. In addition, lovastatin (4 mg.kg-1.d-1) was given for the entire 6 weeks in group 3 and for the first 2 weeks only in group 4. In stage 2 a second group of animals was fed a diet supplemented with 0.5% cholesterol for 2 weeks in order to match the serum cholesterol levels in groups 3 and 4 of stage 1. EXPERIMENTAL MATERIAL--Aortic tissue was removed for measurement of cholesterol content, endothelium dependent relaxation (to acetylcholine), contractile responses (to noradrenaline), relaxant responses (to sodium nitrite), and sudan staining. Serum was obtained for measurement of cholesterol and triglyceride concentrations. MEASUREMENTS AND MAIN RESULTS--In stage 1, at the end of 2 weeks, the serum cholesterol was significantly lower in groups 3 and 4 than in group 2. At 6 weeks, endothelium dependent relaxation to acetylcholine (-6.0 log mol.litre-1) was impaired in group 2 compared to the other groups: group 1 78.5(SEM 5.0); group 2 43.5(7.8)%; group 3 79.4(4.6)%; group 4 84.7(3.4)%. The relaxant response to sodium nitrite was not impaired in group 2. Further, the aortic tissue cholesterol concentration in group 2 was significantly greater than that in group 1, at 355(65) v 105(10) nmol.mg-1 protein. In groups 3 and 4, the aortic cholesterol concentrations were significantly lower than those in group 2, at 74(4) and 94(17) nmol.mg-1 protein respectively. In stage 2, the serum cholesterol values were matched to those in groups 3 and 4 of stage 1. In these animals, after a further 4 weeks the aortic cholesterol was significantly greater than in group 3. CONCLUSIONS--Lovastatin attenuates the accumulation of cholesterol and preserves endothelium dependent relaxation in this model of experimental atherosclerosis. It is likely that the latter is a secondary phenomenon.     

Effect of rosuvastatin on expression of angiotensin Ⅱ receptors in rat aortic endothelium after balloon injury

background It’s established that Angiotensin Ⅱ and its receptors are involved in intimal hyperplasia after balloon injury and stent restenosis. Recent evidence also suggests that statins have some anti-intimal hyperplasia effects. In this study, the effect of Rosuvastatin on expression of angiotensin Ⅱ receptors in rat aortic endothelium after balloon injury is therefore investigated. Methods All 52 Wistar Kyoto rats were established to aorta injury models by 2F balloon catheter, then were randomly divided ...     

Effect of hypoxia on cholesterol accumulation in cultured rabbit aortic smooth muscle cells

We studied the effect of hypoxia on cholesterol accumulation in cultured rabbit aortic smooth muscle cells, which were incubated in a medium with normolipemic rabbit serum (NRS) or hyperlipemic rabbit serum (HRS). The cells were incubated in a humidified atmosphere of either 20% O2, 75% N2 and 5% CO2 (control cells) or 2% O2, 93% N2 and 5% CO2 (hypoxic cells). In a medium containing 20% NRS, the free cholesterol level of hypoxic cells was only a little higher than that of control cells, and there was no significant difference in esterified cholesterol content. On the other hand, in a medium containing 20% HRS, the free cholesterol level was slightly higher and the esterified cholesterol level was markedly higher in hypoxic cells compared with control cells. These results show that hypoxia promotes the accumulation of cholesterol, especially as ester, in smooth muscle cells cultured with hyperlipemic serum. These in vitro experiments indicate that hypoxia in the arterial wall associated with hyperlipidemia may play an important role in atherogenesis, although the precise mechanism remains unclear.     

Clustering of replicating cells in aortic endothelium.

Cell division in the aortic endothelium of the rat is not randomly distributed. Maps of the aortic surface show focal areas where the daily rate of replication may be in excess of 50%. This implies the existence of focal areas of rapid cell growth or rapid cell turnover and other areas where growth or turnover is largely absent.