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The ability of Acetylcholine (ACh) and A23187 to induce endothelium-dependent relaxation was compared in the isolated perfused mesenteric arterial bed of untreated adult rats, adult rats treated neonatally with capsaicin, and adult rats treated as adults with capsaicin. Following neonatal capsaicin treatment, the response to both agents was reduced. Following adult treatment, the response to both agents was reduced seven days following capsaicin treatment. The same results were obtained in the presence of L-arginine or indomethacin. Tissues from all rats responded equally to sodium nitroprusside. Following capsaicin treatment no change in the structural relationship of the arterial intima was detected but no perivascular nerve fibres immunoreactive to substance P (SP) or calcitonin gene-related peptide (CGRP) could be demonstrated. It is suggested that the reduced response to ACh and A23187 does not involve a change in endothelial muscarinic receptors or a structural change in the arterial intima, but is directly related to the absence of immunohistochemically demonstrable CGRP/SP-containing perivascular innervation.

We studied the morphological and contractile characteristics of rat thoracic aortic segments perfused for 3 or 6 days under pulsatile conditions. Light microscopic examination of the segments revealed the presence of an unchanged tunica media. However, the intimal surface was mostly devoid of endothelial cells. The perfused aortic segments showed a dramatic increase in spontaneous tone when compared to fresh and sham-treated aortic segments. Maximum responses to potassium and norepinephrine were reduced after 3 days of perfusion (20-40% reduction), while maximum responses to 5-hydroxytryptamine and angiotensin II were not significantly different. After 6 days of perfusion, maximum responses to all agonist were reduced (50-60%). Sensitivity to norepinephrine was not affected by the treatment, while sensitivity to 5-hydroxytryptamine was reduced. The perfused aortic segments relaxed well in response to isoproterenol. Our system provides a useful experimental model for short-term studies of hypertension- and atherosclerosis-related vascular changes. Further refinement and characterization could improve the performance of the system for longer-term studies.

Warfarin administered to patients with valve replacement at a dose of 0.1 mg/kg for 2 days after surgery, and blood levels of warfarin, TT, PT, HPT, total vitamin K and vitamin K1-epoxide were determined at various time intervals after the administration of the drug. The measurements were obtained from 15 patients: 8 patients with AVR, 6 patients with MVR, and 1 patient with DVR. The blood levels of warfarin reached a peak of 462 +/- 160 ng/ml 6 hours after the administration, TT, PT and HPT were 40% of the initial values 24 hours after the administration, and vitamin K1-epoxide was 1.28 +/- 0.30 ng/ml 24 hours after the administration. It is clear from the results that warfarin exhibits sufficient anticoagulant effects at a beginning dose of 0.1 mg/kg after surgery to prevent a sudden decrease in blood coagulation.

A proper dosage of warfarin after artificial cardiac valve replacements has been determined as an indication of coagulation activity. In some cases, the coagulation activity cannot be maintained within the therapeutic range because Prothrombin time (PT) values deviated from Thrombotest (TT) values. Here we studied each relationship between warfarin concentrations in blood, coagulation activity, vitamin Ks and other coagulation-related agents which were measured in patients administered warfarin after artificial cardiac valve replacements and whose coagulation activity was maintained within a therapeutic range, and in patients whose PT values deviated from TT values. The obtained results were interpreted as follows. 1) There was a high correlation between values from Thromborel S (a clot method) and values from Chromoquick (a method using a synthesized substrate). Since TT values had little variations compared to PT values, the former was an excellent indication of coagulation activity. 2) There was no correlation between warfarin concentrations in blood and coagulation activity in the group in which warfarin concentrations in blood vary within a day (Group B); but there was highly reverse correlation in the group in which warfarin concentrations in blood vary with days (Group A). 3) There was good correlation between warfarin concentrations and PIVKA-II concentrations in blood in Group A. Further, the concentration of Gla-Protein C was one microgram/ml or less on the fourth day from the initiation of warfarin administration. 4) For example, a patient whose PT value of 67% deviated from TT value of 19% on the eleventh day from the initiation of warfarin administration had vitamin K1-epoxide concentration of 2.68 ng/ml and MK-7 concentration of 1.26 ng/ml on the same day, respectively, which were higher levels than those in Group A.

This study shows that arterial smooth muscle cells (SMC) isolated from rats receiving atherogenic doses of the lipid emulsion, Lipofundin-S, alter their in vitro growth properties. Compared to cells from control animals, SMC isolated from Lipofundin-S-infused rats show a reduction in both saturation density and response to increasing serum concentrations, without a change in the baseline proliferation. Also, SMC isolated from lipid-treated animals and grown for five days in the presence of 30, 150, or 300 pg/ml estradiol show a 30% increase in growth vs. cells from controls. Epinephrine at 1 microM stimulates growth in SMC from control rats, while causing no growth enhancement over five days in cells from lipid-infused animals. Thus, atherogenic infusions of Lipofundin-S into rats cause phenotypic changes in arterial SMC which can be passed to successive cell generations in vitro.

We surveyed the efficacy and safety of probucol (Sinlestal) in 6,002 patients with hyperlipidemia during the past six years between Oct., 1984 and Sep., 1990. Probucol was usually administered for more than 8 weeks at a dose of 500 mg per day and effects on serum lipids and adverse drug events (ADEs) were investigated. Total cholesterol (TC), triglycerides (TG) and HDL cholesterol (HDL) significantly decreased by 16-20%, 6-9% and 15-20% respectively. Further, LDL cholesterol (LDL) decreased by 15-19%. ADEs were reported in 2.7% (161/6,002 subjects), but severity was mild or moderate. In addition to survey in 6,002 patients, the effect on regression of xanthomas and safety in long-term administration of over one year was investigated in 44 and 142 patients, respectively. Regression of xanthoma was observed in 63.6% (28/44 subjects). Probucol was well tolerated in long-term administration. These PMS results showed probucol to possess good therapeutic efficacy and safety.

We have shown previously that parenterally-administered lipid emulsions can be utilized to induce early atherosclerosis in the aortas of Sprague-Dawley rats. In order to evaluate the effect of obesity on lipid-induced atherogenesis, we have utilized this same approach in the present study to demonstrate that i.v. infusions of the parenteral lipid emulsion, Lipofundin-S, will induce in the genetically obese Zucker rat and its lean littermate aortic endothelial and myofibroelastic changes indicative of early atherogenesis. Four groups of rats were used: 1) obese controls, 2) obese lipid-infused, 3) lean littermate controls, and 4) lean littermate lipid-infused. Observations were made with light and transmission electron microscopy (TEM), using qualitative morphological criteria to evaluate the results. Based on the fact that both untreated control and Lipofundin-S-induced atherosclerosis was more frequent and generally more advanced in the obese animals than in their respective lean counterparts, it appears that the obese Zucker rat is more susceptible to both spontaneous and hyperlipidemia-induced atherosclerosis than its respective lean littermate. Thus, obesity in these animals, as might be the case in humans, could potentiate an atherogenic process already enhanced by hyperlipidemia.

Blood plasma LCAT (lecithin: cholesterol acyltransferase, EC 2.3.1.43) was studied in cockerels fed an atherogenic diet to determine if attenuation of aortic atherogenesis, as a result of simultaneous treatment of the birds with diazepam, might be related to modulation of enzyme activity by the drug. Administration of diazepam (0.6 mg/kg) did not influence LCAT. It was observed that no relationship could be established between enzyme activity and the extent of aortic atherogenesis. In contrast, addition of diazepam in vitro to cockerel plasma caused a concentration-dependent inhibition of LCAT activity. The effect was most pronounced when diazepam was present at a concentration of 50-200 microM, where inhibition of enzyme activity was 25-65%. Thus, pharmacologic doses of diazepam do not appear to affect LCAT in vivo. It is concluded that diazepam attenuates aortic atherogenesis in cockerels fed an atherogenic diet by a mechanism independent of LCAT.

We measured the lactate production, oxygen uptake and ATP in aortic endothelial cells cultured from young Wistar female rats. For these experiments, thoracic aortae were removed from the animals, minced into small pieces and transferred onto culture plates, to which a growth factor was added. When the endothelial cells had proliferated, the original pieces were removed from the culture and the remaining cells were subcultured until the 3rd passage. Regarding the growth curves of the 3rd passage, a logarithmic growth phase (Pg) was found from the 2nd to the 7th days and a stationary phase (Ps) followed thereafter. The ATP levels in the Pg and Ps were unchanged. Rates of lactate production and oxygen uptake were higher in the Pg than in the Ps. Only in the Ps was an interrelationship between these estimations found, suggesting that the confluent state exhibits metabolic cooperation between the cells in culture.

Thirty subjects, 5 normotriglyceridemic (NTG) with low HDL cholesterol (HDL-C < 35 mg/dl) and 25 hypertriglyceridemic (HTG) with low and high HDL-C (HDL-C > 35 mg/dl) were selected fo this study. They were treated with gemfibrozil (600 mg BID) for 12 weeks. In both groups, gemfibrozil significantly reduced serum TG levels (p < 0.005), yet HDL-C increased significantly only in HTG patients (p < 0.005). The changes in HDL-C levels were highly variable (-40 to 50%) and appeared to be dependent on the levels of serum TG achieved during treatment. Based on post-treatment serum TG, the HTG patients were divided into 2 groups. Group 1 with serum TG of < 100 mg/dL and Group 2 with serum TG levels > 100 mg/dl. Significant post treatment increases in HDL-C were seen only in Group 1 (p < 0.005). The two groups had similar pretreatment serum TG and HDL-C levels but the LDL-C was significantly higher in Group 1 (p < 0.025). Pretreatment serum LDL-C also correlated positively with the increases in HDL-C during treatment (r = 0.51, p < 0.01, n = 25). Consequently, the patients were divided into three groups based on their initial serum LDL-C levels (Group 1: LDL-C < 130 mg/dl. Group 2: LDL-C, 130-159 mg/dl and Group 3: LDL-C > 160 mg/dl). The HDL-C levels increased significantly upon treatment only in Group 3. Pretreatment levels of serum TG and HDL-C were not significantly different among the three groups. Initial body weight (r = -0.43 p < 0.025, n = 30) and percent change in body weight during treatment (r = -0.47, p < 0.025, n = 30) correlated negatively with the percent reduction in serum TG. The change in body weight also showed significant negative correlation with the changes in HDL cholesterol (r = -0.48, p < 0.25, n = 30). We conclude that gemfibrozil is most effective in reducing serum triglycerides, LDL-C and increasing serum HDL-cholesterol in HTG patients who also have comparatively high initial LDL cholesterol levels (Fredrickson's type IIb phenotype). For effective improvement of HDL-cholesterol in most HTG patients, serum TG levels need to be lowered below 100 mg/dl. Furthermore, the benefit of gemfibrozil therapy may be significantly enhanced by weight loss during treatment.