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Vasotropic, haemostatic and haemorheological parameters have been investigated in 17 patients suffering from migraine without aura in comparison with 11 sex and age matched healthy control subjects. NO metabolites (NO2- and NO3-), endothelin (ET-1), tissue plasminogen activator (tPA), plasminogen activator inhibitor (PAI-1), fibrinogen, D-dimer, fibrinopeptide A, beta thromboglobulin (beta-TG), blood viscosity, plasma viscosity, haematocrit (Htc) and red blood cell (RBC) filterability index (FI) were determined during headache free periods. Migraineurs NO3- and ET-1 plasma levels, compared to control values, showed a significant decrease and increase respectively; fibrinogen, beta-TG and D-dimer appeared slightly lowered in migraineurs, while Htc remained in the normal limits; tPA, PAI-1 and FI were significantly reduced, while fibrinopeptide A, blood viscosity and plasma viscosity at a low shear rate (shr) exhibited a significant rise. Data obtained support the involvement of endothelial, haemostatic and haemorheological functions in the pathogenesis of migraine.

Endothelium in aorta is known to contain releasable vasoactive agents. The purpose of the present study was to examine the effect of endothelium on the contraction induced by the membrane depolarizing agent KCl and by the alpha adrenoceptor agonist norepinephrine. It was found that the contraction induced by norepinephrine was bigger in denuded aorta at 1 x 10(-9) M and 1 x 10(-8) M norepinephrine, but the norepinephrine-induced contraction at 1 x 10(-7) M norepinephrine was not different between the denuded and control aortae. On the other hand, the contraction induced by KCl in denuded aorta was bigger at 10 mM KCl but smaller at 60 and 90 mM KCl in comparing with those determined in the presence of endothelium. These results indicate that the presence of endothelium alleviates the norepinephrine-induced contraction below 1 x 10(-7) M norepinephrine but potentiates the KCl-induced contraction at 60 mM KCl and above.

The effects of the cholesterol oxides on low density lipoprotein receptor (LDLR) gene expression were investigated. Cultured rabbit aortic smooth muscle cells were incubated with 1, 2, and 5 micrograms/ml culture medium concentrations of pure cholesterol, 25-hydroxycholesterol (25-OH), 7-ketocholesterol (7-keto), cholestane-3 beta, 5 alpha, 6 beta-triol (triol) and cholesterol-5 alpha, 6 alpha-epoxide (epoxide) for 12 hours and with vehicle only as control. Total mRNAs were extracted and electrophoresed. Northern blot hybridization analyses were performed. The results showed mRNA expressions of LDLR gene were inhibited to 16.1 +/- 4.4%, 33.8 +/- 0.6%, 42.8 +/- 1.8% and 46.9 +/- 3.9% of control by 25-OH, 7-keto, epoxide and triol respectively. Pure cholesterol showed only minimal inhibition. The inhibitions were time dependent. Although cholesterol oxides have been shown to alter many membrane-related functions and the LDLR domain are located in the cell membrane. The findings of this study suggested that the cholesterol oxides exerted their repressive actions on LDLR function primarily by down-regulating LDLR gene expression rather than directly upon cell membrane.

To test possible hypocholesterolemic and antiatherogenic effects of transdermally administered phosphatidylcholine (PC), we applied a 33% solution of PC in ethanol containing 0.01% butylated hydroxytoluene as antioxidant, to the shaved back of a strain of inbred rabbits which spontaneously developed hypercholesterolemia (serum cholesterol above 110 mg/dl) and severe atherosclerotic lesions especially in the aortic arch. After the topical application of PC, increases of choline-containing phospholipids in blood were observed, reaching a plateau in 24-48 hr. There were significant reductions in serum cholesterol and LDL cholesterol in the treated animals 2-3 weeks after the treatment. Atherosclerotic lesions in the aortic arch were clearly less severe in the animals repeatedly treated with topical PC. The hypocholesterolemic and antiatherogenic effects of topical PC could be the result of increased cholesterol efflux from extrahepatic tissues and enhanced reverse cholesterol transport.

We tested the ability of remnant-like particles (RLP) from NIDDM patients to stimulate cholesteryl ester synthesis in human monocyte-derived macrophages. Six NIDDM patients were studied together with 7 non-diabetic subjects. All had apolipoprotein (apo) E3/3 phenotype. RLP were isolated using an immunoaffinity gel mixture of anti apo B-100 and anti apo A-1 monoclonal antibodies coupled to Sepharose 4B. Plasma levels of triglyceride, total cholesterol (chol) and high density lipoprotein-chol were not statistically different, but plasma levels of RLP-chol were significantly (p < 0.05) higher in NIDDM patients (10.5 +/- 2.2 mg/dl) than in non-diabetic controls (5.0 +/- 1.7 mg/dl). The effects of RLP from NIDDM patients on macrophage cholesteryl ester synthesis were estimated. 14C-oleate incorporation into cholesteryl esters in macrophages was significantly (p < 0.01) higher in NIDDM patients with apo E3/3 (0.326 +/- 0.037 nmole/mg cell protein) than in non-diabetic controls with apo E3/3 (0.181 +/- 0.011 nmole/ mg cell protein). It is suggested that RLP from NIDDM play a role in the accumulation of cholesteryl esters and are one of the risk factors for the acceleration of atherosclerosis in NIDDM.

The migration and proliferation of vascular smooth muscle cells (SMC) into the neointima are important early events in the development of atherosclerosis and post-angioplasty restenosis. The stimulation of SMC migration by platelet derived growth factor (PDGF) involves the induction of protein kinase C activity. Using immunoblot techniques, we demonstrated that rat aortic SMC express a pattern of PKC isoforms which includes PKC-alpha, delta, epsilon, zeta and eta. Upon exposure to PDGF-BB, a fraction of PKC-delta was rapidly translocated from the cytosol to the post-nuclear particulate fraction at 15 seconds and reached an apparent maximum at 30 minutes. In contrast, PKC-alpha and zeta were not translocated by PDGF-BB, TGF-beta 1, which inhibits PDGF-induced DNA synthesis and chemotaxis, reduced the immunoreactive levels of PKC-delta and blocked the PDGF-induced translocation of PKC-delta to the particulate fraction. This suggests that the activation of PKC-delta by translocation to the particulate fraction may play an important role in the control of vascular smooth muscle cell migration by PDGF and TGF-beta 1.

While estrogen is known to retard the development of atherosclerosis, the exact mechanism is unknown. The migration of monocytes into the arterial intima is important in the pathogenesis of atherosclerosis. Monocyte chemotactic protein 1 (MCP-1) is suggested to be a real chemotactic factor that is released from monocytes, endothelial cells, and smooth muscle cells. We investigated the effect of 17 beta-estradiol on the migration of human monocytes in response to MCP-1, using a modified Boyden chamber. A physiological concentration of 17 beta-estradiol (10(12) - 10(4)M) inhibited the migration of monocytes exposed to MCP-1. Two estrogen receptor antagonists, tamoxifen and clomiphene, each restored monocyte chemotaxis to MCP-1 to control level, even in the presence of 17 beta-estradiol, suggesting that estrogen receptors are related to the effect of 17 beta-estradiol. Progesterone and testosterone had no measurable effect on monocyte migration. These findings suggest that inhibition of the chemotactic response of monocytes exposed to MCP-1 may be one mechanism for the anti-atherogenic effect of 17 beta-estradiol.

Short-term (2 weeks) effects of a high-sucrose diet on plasma lipids, lipoproteins, tissue lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activities were investigated in rats. Three days of sucrose feeding significantly increased plasma TG (42 +/- 3 mg/dl vs. 56 +/- 2 mg/dl, p = 0.032), while TC increased significantly after 10 days of the diet (50 +/- 2 mg/dl vs. 62 +/- 2 mg/dl, p = 0.0001). HDL-C increased significantly after 3 days of sucrose feeding (36.2 +/- 0.9 mg/dl vs. 42.4 +/- 2.7 mg/dl, p = 0.011). Although LDL-C tended to decrease on days 3, 7 and 10, these changes were not significant. The plasma glucose level did not change during the study. Increased LPL activity in adipose tissue and decreased enzyme activities in skeletal and heart muscles were observed. Adipose tissue LPL returned to the baseline value after 14 days of the diet treatment, while LPL in skeletal and heart muscles remained at the decreased level. HTGL and HTGL/total liver lipase activities were significantly increased after 14 days of the diet. The different responses of lipase activities in various tissues may help to regulate serum lipid and lipoprotein levels in sucrose-fed rats.

The present study examined responses to norepinephrine and bethanechol in isolated aortae from 2-month diabetic rabbits induced by alloxan. Alloxan (100 mg/kg) was administered intravenously into the ear vein, and the blood glucose levels were estimated weekly for a duration of 2 months. The aortae from 2-month diabetic rabbits were removed and the aortic responses to norepinephrine and bethanechol were tested in vitro. The data showed that the aortic response to norepinephrine was increased but the aortic response to bethanechol was decreased in diabetic aortae; however, changes of responses were insignificant in comparing with those of the age-matched control aortae. It was speculated that a longer duration of diabetic development should be helpful to ensure a significant change of aortic response to vasoactive agents.

A significant increase of diabetic aortic response to a single vasoactive agent usually occurs after 3 months of streptozocin-induced diabetes. The present study was to evaluate if a significant increase of aortic response to a combination of norepinephrine and KCl in vitro in 1- and 2-month diabetic rats. The results showed that the aortic response to a combination of norepinephrine and KCl was significantly increased in 2-month diabetic aorta than in age matched control aorta, even though the aortic contraction induced by norepinephrine or KCl alone is insignificant. These data suggest that the earliest time to demonstrate a functional change in vascular reactivity after the streptozocin administration is more than one month of diabetic development.