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To clarify whether probucol, an antioxidant, or diltiazem, a Ca2+ antagonist, favorably affect the regression of established atherosclerosis, rabbits were fed a 1% cholesterol diet for 10 weeks, then a standard diet for an additional 25 weeks (regression period). During the regression period, rabbits were grouped into a saline (S) group (n=8, 1 ml saline/d), a probucol (P) group (n=8, 1000 mg/d probucol), or a probucol and diltiazem (P+D) group (n=8, probucol 1000 mg/d in diet and diltiazem 30 mg/d). We measured cholesterol in serum, lipoprotein fractions, and serum triglyceride or phospholipid concentration and found no significant differences among the three groups at 10, 15, or 35 weeks. After 10 weeks of the atherogenic diet, the ratio of macroscopic atherosclerotic lesions in aortic intima rose to 36.6 + or - 5.6%. After the regression period, the S group developed more atherosclerotic lesions (48.6 + or - 6.4%). The P+D and P groups, however, had decreased scores of 24.3 + or - 5.5% (p<0.05 vs. S) and 32.3 + or - 5.6%, respectively. Moreover, these decreased scores were well correlated with the decrease in aortic tissue lipid compositions, but not the parameters for extracellular matrices. We concluded that P+D or P therapy might be effective in regressing established atherosclerosis by removing lipid contents but not extracellular matrices.

Hamsters were fed high fiber diets containing cellulose, wheat bran or psyllium. The psyllium was incorporated into high fiber, ready-to-eat (RTE) flakes that were used to formulate the test diet. All the diets contained 0.125% cholesterol. The study was terminated after three weeks. Food intake, weight gain and feed efficiency were not significantly different in the three groups. Serum total and HDL cholesterol levels were reduced significantly by the psyllium diet. Serum triglycerides were 26% lower in the hamsters fed psyllium but because of the large variation the difference did not reach statistical significance. Liver total cholesterol and cholesteryl ester levels were significantly lower in the hamsters fed psyllium. Liver triglycerides were highest in the psyllium-fed hamsters and liver phospholipid levels were similar in the three groups. Liver cholesterol and triglyceride levels were higher in hamsters fed cellulose than in those fed wheat bran. Psyllium formulated into an RTE cereal was effective in reducing serum and liver cholesterol levels in hamsters.

All known pathways of ethanol metabolism result in the production of acetaldehyde, a highly reactive compound. N-acetyl cysteine, an analogue of the dietary amino acid cysteine, binds acetaldehyde, thus preventing its damaging effect on physiological proteins. This study examined the effect of oral N-acetyl cysteine on the increased blood pressure, platelet cytosolic free calcium, blood acetaldehyde and adverse renal vascular changes induced by chronic ethanol treatment in rats. Twenty-four male Wistar-Kyoto (WKY) rats, age 7 weeks were divided into four groups of six animals each. Animals in group I were given water and group II 5% ethanol in water for the next 14 weeks. Animals in group III were given 5% ethanol + 1% N-acetyl cysteine for 4 weeks followed by 5% ethanol + 2% N-acetyl cysteine for the next 10 weeks. Animals in group IV were given 5% ethanol for 7 weeks; at that time ethanol was withdrawn and animals were placed on water with 2% N-acetyl cysteine for the next 7 weeks. After 14 weeks systolic blood pressure and platelet cytosolic free calcium were all significantly higher (p<0.001) in rats given ethanol as compared to rats in other groups. N-acetyl cysteine treatment, along with ethanol, significantly (p<0.001) attenuated the increased blood pressure and platelet cytosolic free calcium and adverse renal vascular changes. Discontinuation of ethanol treatment for 7 weeks along with N-acetyl cysteine supplementation also significantly lowered the blood pressure and platelet cytosolic free calcium and attenuated adverse renal vascular changes. There was no significant difference in aortic malonaldehyde among four groups. Increase in blood acetaldehyde with ethanol treatment was significantly attenuated with N-acetyl cysteine treatment. These results suggest that acetaldehyde may be the cause of ethanol-induced hypertension and elevated cytosolic free calcium and renal vascular changes.

Rats were fed a semi purified diet containing 0.5% cholesterol and 10% fiber (cellulose, pectin, psyllium seed and defatted psyllium husk). One additional group of rats was fed cholesterol (0.5%) as part of a fiber-free diet and another was fed the fiber free diet without cholesterol. Cellulose had virtually no effect on serum or liver lipids. Pectin had a lipid lowering effect. Psyllium seed exerted an effect on total serum cholesterol equal to that of pectin but gave higher levels of HDL-cholesterol. The effects of psyllium seed on liver lipids were more pronounced than those of pectin. Defatted psyllium husk feeding virtually normalized liver size and serum triglyceride levels and produced lower serum total cholesterol levels and higher HDL-cholesterol than observed in normal controls. Defatted psyllium husk feeding also yielded liver lipid values which were in the normal range. Fecal wet and dry weights were significantly higher in rats fed either psyllium preparation.

Earlier work on peptidergic fibres suggested some involvement of CGRP perivascular nerve fibres in acetylcholine-induced endothelium-dependent vascular relaxation. We have investigated the effect of blocking CGRP receptors and CGRP replacement on acetylcholine-induced endothelium-dependent vascular relaxation in the isolated perfused mesenteric arterial bed in normal Sprague-Dawley rats and in rats seven days following freeze-denervation of the superior mesenteric artery. Freeze-denervation was carried out under pentobarbital anesthesia (40 mg/Kg). It was found that the ability of acetylcholine to cause relaxation was reduced by CGRP receptor blocking with CGRP8-37 in vessels from control rats, but returned to pre-blocking levels after washout of the antagonist. Treatment with CGRP increased the relaxation due to acetylcholine in denervated vessel beds, but not in control tissues. The CGRP receptor appears to be involved in the acetylcholine-induced relaxation of blood vessels. The mechanism of action is not known, although both acetylcholine and CGRP, act through activation of K+ channels, and CGRP may facilitate the activation of K+ channels by acetylcholine.

Although proliferation of smooth muscle cells is a key event in the pathogenesis of atherosclerosis, the signals which regulate this proliferation are not fully understood. It is likely that proliferation is regulated by cytokines released by cells found in the plaque, such as T cells. In this study we report that the T cell-derived cytokine, interleukin-4 (IL-4), can inhibit proliferation of cultured human umbilical artery smooth muscle cells. Maximum inhibitory effect was achieved at IL-4 concentrations of 20 U/ml or greater. In addition, the data showed that IL-4 acted early in the G1 phase of the cell cycle, thereby preventing cells from entering S phase. The mechanism of IL-4 inhibition did not appear to involve stimulation of prostanoid synthesis since similar data were obtained when experiments were performed in the presence of a cyclooxygenase inhibitor. We propose that IL-4 may act as a protective factor released by T-cells in an atherosclerotic lesion in order to minimise the size of the plaque.

We examined the effect of 5% deuterium oxide (D20) in drinking water on systolic blood pressure, platelet cytosolic free calcium, aortic calcium uptake and plasma insulin, glucose and triglycerides in rats with fructose-induced hypertension. Eighteen male Wistar-Kyoto (WKY) rats, age 8 weeks, were divided into 3 groups of 6 animals each. Animals in group I were given water; group II, 8% fructose and group III, 8% fructose + 5% D20 as their drinking water for the next 15 weeks. Systolic blood pressure in the fructose treated rats was significantly higher (p < 0.01) than in animals on water after 2 weeks and remained higher throughout the study. At 15 weeks, systolic blood pressure, platelet cytosolic calcium, aortic calcium uptake and plasma glucose, insulin and triglycerides were significantly higher (p < 0.01) in the fructose treated rats compared with rats from other groups. Deuterium oxide given together with fructose prevented development of high blood pressure and the associated increase in platelet cytosolic calcium, aortic calcium uptake and plasma triglycerides. D20 treatment did not prevent fructose induced increases in plasma insulin and glucose. The parallel increase in systolic blood pressure, cytosolic free calcium, and in vascular calcium uptake suggests that an increased cytosolic free calcium is involved in the pathophysiology of hypertension. D20 prevents this hypertension by normalizing cytosolic free calcium.

Comparison between isolated rat and guinea pig aortae in response to drugs was made. The data indicated that the norepinephrine and KCl concentration effect curves determined in rat aortae were on the left of those determined in guinea pig aortae. When aortae were preconstricted with 60 mM KCl, the relaxation induced by nitroprusside or 3-isobutyl-1-methyl-xanthine was more potent than those in guinea pig aortae. Although bethanechol and isoproterenol were effective to relax rat aortae preconstricted with 1 x 10(-5) M norepinephrine, yet guinea pig aortae preconstricted with norepinephrine were not responsive to bethanechol and isoproterenol in similar concentrations tested. The above results suggested a difference between rat and guinea pig aortae in response to drugs.

Increased calcium uptake in vascular tissue, leading to elevated cytosolic free calcium has been implicated in the pathophysiology of hypertension. This study examined the effect of oral low molecular weight heparin (Logiparin) on systolic blood pressure, platelet cytosolic free calcium and aortic calcium uptake in spontaneously hypertensive rats. Starting at age 12 weeks, spontaneously hypertensive rats were divided into three groups of six animals each. The drinking water of groups 1, 2 and 3 was replaced by 100% H2O, 0.5 mg (low dose) or 1 mg (high dose) low molecular weight heparin/ml H2O, respectively, for next 11 weeks. Six normotensive Wistar-Kyoto rats (age 12 weeks) on H2O and six on low dose heparin in H2O were used as controls. At age 23 weeks, increase in systolic blood pressure, platelet cytosolic free calcium and aortic calcium uptake in spontaneously hypertensive rats was significantly lowered by low dose LMW heparin as compared to spontaneously hypertensive rats on H2O, but was significantly higher than Wistar-Kyoto rats on H2O and LMW heparin. This dose of heparin did not have any effect on these parameters in normotensive Wistar-Kyoto rats. High dose LMW heparin normalized the elevated platelet cytosolic free calcium, aortic calcium uptake and systolic blood pressure in spontaneously hypertensive rats, but it had a limited effect on adverse renal vascular changes. Oral low molecular weight heparin did not cause any abnormal hematological, biochemical or pathological changes in rats.

Using L-NAME and the potassium channel blocker apamin we have investigated the component of acetylcholine-induced vascular relaxation lost when the mesenteric arterial bed is denervated. We have confirmed that vascular denervation produces a reduction of up to 35% in the ability of ACh to cause relaxation in the presence of the alpha agonists methoxamine and cirazoline. A single 30 minute exposure to L-NAME reduced the relaxation to ACh by up to 44% in control vascular preparations and by 85% in denervated preparations. In control preparations, prolonged exposure to L-NAME reduced the relaxation to ACh by up to 66% and by 77% in the presence of apamin. In denervated preparations prolonged exposure to L-NAME reduced the relaxation to ACh by 96%. The almost complete loss of acetylcholine-induced relaxation following prolonged exposure to L-NAME (96.6% in methoxamine and 93.9% in cirazoline) in denervated preparations suggests that innervation is involved in the expression of the L-NAME-resistant relaxation to acetylcholine in the superior mesenteric arterial bed of the rat.