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Objective: We sought to characterize the effects of NG-monomethyl-L-arginine (L-NMMA) and L-arginine (L-Arg) on the pressor response to the infusion of angiotensin II in rats.

Methods: L-NMMA and L-Arg were infused intraperitoneally into rats at a constant rate by means of an osmotic minipump. The L-NMMA group received an infusion of L-NMMA (3 mg/d) daily for 13 d, whereas the L-NMMA plus L-Arg group received L-NMMA (3 mg/d) daily for 4 d, followed by L-NMMA plus L-Arg (12 mg/d) daily for 9 d. Sham operated rats served as controls. The animals were anesthetized on day 13, and catheters were placed into the femoral artery and vein. After the animals had recovered from the anesthesia, the pressor response to intravenous bolus doses of angiotensin II (50, 100, 200, and 400 ng/kg) were determined after recovery from anesthesia.

Results: While the baseline mean arterial blood pressure was not affected by L-NMMA, with or without L-Arg, the pressor response to angiotensin II in the L-NMMA group was significantly increased as compared with that in the control group, at doses of 50, 100, and 200 ng/kg. The response of the L-NMMA plus L-Arg group did not differ significantly from that of the control group.

Conclusion: Results indicate that the infusion of a nitric oxide synthase inhibitor, at a dose insufficient to produce hypertension, increases the pressor response to angiotensin II.

The effects of acetylsalicylic acid (ASA) on aortic smooth muscle contractility were studied in aortic rings of male SHR and WKY rats. The rats were administered two intraperitoneal injections of 10 mg/kg of ASA per week for ten weeks. Blood pressure of each rat was monitored twice weekly prior to the i.p. injections. Twenty four hours after the last injection the aortic smooth muscles were evaluated for generation of active tension in response to KCl, Phenylephrine (PE), Clonidine and Norepinephrine (NE). In another set of experiments calcium conductance was evaluated in the presence or absence of endothelium both in ASA treated and non treated animals. We report that aortic rings from ASA-treated SHR animals were more responsive to contractile agents than rings from non-treated SHR male rats. Also, the Ca2+ conductance in vitro was enhanced appreciably in SHR aortic rings denuded of their monolayer of endothelium in response to ASA treatment. No decrease in systolic blood pressure was observed in response to ASA treatment in SHR male rats. These results suggest that acetylsalicylic acid not only may modulate aortic smooth muscle contractility through the metabolites of arachidonic acid but may repair to a great extent the hypertension associated plasma membrane permeability defect of vascular myocytes.

Methylglyoxal, a highly reactive endogenous aldehyde is formed in the tissue of humans and animals as an intermediate of glucose and fructose metabolism. N-acetyl cysteine (NAC), an analogue of the dietary amino acid cysteine, binds aldehydes thus preventing their damaging effect on physiological proteins. We measured systolic blood pressure (SBP), platelet [Ca2+]i, circulating nitric oxide levels, tissue aldehyde conjugates and renal vascular changes in chronic methyglyoxal treated Wistar-Kyoto (WKY) rats and examined the effect of NAC in the diet on these parameters. Animals, age seven weeks, were divided into three groups of six animals each and were treated as follows: WKY-control (chow diet and normal drinking water); WKY-methylglyoxal (chow diet and methyglyoxal in drinking water); WKY-methyglyoxal + NAC (1.5% NAC in diet and methylglyoxal in drinking water) for the next 18 weeks. Methylgyoxal in drinking water was given at a concentration of 0.2% during weeks 0-5; 0.4%, weeks 6-10; and 0.8%, weeks 11-18. After 18 weeks systolic blood pressure, platelet [Ca2+]i and kidney aldehyde conjugates were significantly higher and serum nitric oxide levels lower in methylglyoxal treated rats. Methylglyoxal treated rats also showed smooth muscle cell hyperplasia in the small artery and arterioles of the kidney. N-acetyl cysteine, an aldehyde binding thiol compound, prevented these changes.

Possibility of using mouse isolated aorta to evaluate the effect of vasoactive agents was demonstrated. The results suggested that aortic contraction induced by the alpha adrenoceptor agonist norepinephrine was sensitive to prazosin, and the contraction induced by the membrane depolarization agent KCl was sensitive to verapamil. Clonidine acting as a partial agonist attenuated the norepinephrine or methoxamine induced contraction. Both IBMX and nitroprusside relaxed the aortic contraction. These vascular changes induced by the above vasoactive agents in mouse isolated aorta were similar to those of rat described elsewhere. The present findings suggested that mouse isolated aorta can be used as a tool to test the effect of vasoactive agents.

Objective: We sought to determine whether the pressor response to an infusion of angiotensin II during pregnancy would be reduced by the oral administration of highly purified eicosapentaenoic acid ethyl ester (EPA-E).

Methods: We administered EPA-E orally to nine pregnant rabbits (200 mg/kg/day) from day 5 of gestation to day 5 postpartum. Pressor responses to graded doses of intravenously infused angiotensin II and norepinephrine were examined serially during pregnancy and the postpartum period.

Results: The EPA-E-treated, as well as the control pregnant rabbits (n = 6), were significantly less responsive to the vasoconstrictor effects of angiotensin II throughout pregnancy than the nonpregnant rabbits (n = 8). The vascular reactivity to infused angiotensin II in EPA-E-treated pregnant rabbits, as compared with that of control pregnant rabbits was unchanged, but reactivity to angiotensin II was lower only on the fifth postpartum day. The pressor responses to infused norepinephrine were unchanged during pregnancy and in the postpartum period, and EPA-E did not alter the response. The litters of four of the nine rabbits were partially or completely macerated.

Conclusion: EPA-E did not reduce the already blunted pressor responsiveness to angiotensin II during pregnancy in rabbits. The effect of EPA-E in a state of increased pressor responsiveness during pregnancy due to a deficiency of vasodilatory prostaglandins needs to be determined.

The hypolipidemic effect of an ethyl acetate extract of the rhizome of Curcuma comosa Roxb was investigated in mice. Intragastric administration of the extract significantly decreased plasma lipid levels of both triglyceride and cholesterol but increased liver triglyceride content. Liver weight and plasma activities of glutamic oxaloacetic transaminase and glutamic pyruvic transaminase were not affected by a single administration. Prolonged treatment did not further decrease plasma lipid level but caused further increases in liver triglyceride content and weight. The lower plasma cholesterol activity of C. comose extract was found to be essentially associated with elevation of plasma HDL cholesterol level, increased excretion of fecal cholesterol and bile salt. The increase persisted throughout the period of treatment. These results suggest that C. comosa has hypolipidemic action. It exerts hypocholesterolemic activity by accelerating mobilization of cholesterol from peripheral tissues into liver and enhancing excretion of cholesterol and bile salt into feces.

Plasma lipoproteins and clinical characteristics of non-insulin-dependent diabetic mellitus (NIDDM) patients with (n = 50) and without (n = 108) ischemic heart disease (IHD) were compared. The patients with IHD were older (64 +/- 9 vs 59 +/- 9 years, mean +/- SD, P < 0.01) and had a longer duration of diabetes (14 +/- 9 vs 11 +/- 8 years, P < 0.05). Lipids, lipoproteins and apolipoproteins were comparable in the two groups. The percent distribution of triglycerides (TG) in the very low density lipoprotein (VLDL) fraction was significantly higher (55 +/- 16 vs 50 +/- 17%, P < 0.05). The level of low density lipoprotein (LDL) (33 +/- 14 vs 39 +/- 15%, P < 0.05) and the apo E/VLDL-TG ratio (0.085 +/- 0.045 vs 0.12070.097, P < 0.01), however, was significantly lower in patients with IHD than in those without IHD. Multiple regression analysis also indicated that age, duration of diabetes, percent distribution of TG in VLDL, percent distribution of TG in LDL and the apo E/VLDL-TG ratio were significantly related to the presence of IHD. Hypertriglyceridemia, particularly when characterized by abnormalities of TG distribution, may play an important role in the development of IHD in NIDDM patients.

Although collar-induced atherosclerosis continues to be used as an investigative tool, the underlying mechanism has not been established. Two primary mechanisms suggested are adventitial ischemia due to reduction in vasa vasorum, and perivascular denervation. We have examined the effect of injuring the common carotid artery in the pattern produced by the ends of a silastic collar, and have correlated the effect on innervation with change in intima/media ratios in normal and cholesterol-fed rabbits. The serum cholesterol of cholesterol-fed rabbits was significantly elevated by 10 days following initiation of cholesterol feeding, and further elevated at 21 days. No structural difference was detected between the uninjured carotid arteries of control and cholesterol-fed rabbits. At the site of injury in freeze injured carotid arteries there was a thickening of the intima which was increased in cholesterol-fed rabbits. The intima at the site of injury was composed of lipid-laden cells embedded in a matrix of collagen and elastin fibres. In carotid artery segments, between two sites of freeze injury, denervation was established by immunohistochemistry and electron microscopy. The denervated segments were not morphologically different from uninjured carotid arteries in either control or cholesterol-fed rabbits. While injury induced intimal thickening and foam cell development, denervation did not. It is concluded that perivascular denervation is a consequence of silastic collar application and is not involved in the induction of atherosclerosis.

This study was undertaken to determine; 1) the effect of cholesterol enriched diet on prebeta-migrating (prebeta) HDL levels, 2) the effect of the diet on plasma proteins and/or activities likely associated with prebeta HDL (cholesteryl transfer protein (CETP), lecithin-cholesterol acyltransferase (LCAT) and apolipoprotein (apo)A-I), 3) the effect of the diet on the corresponding hepatic mRNAs and 4) the correlation between the hepatic mRNAs and prebeta HDL. Rabbits were fed 0.1% (low) cholesterol (LC group, n = 6) or 0.5% (high) cholesterol diet (HC group, n = 6) for 6 weeks. Plasma CETP activities, plasma total apoA-I and prebeta apoA-I concentrations in the HC group were significantly increased (58.95 +/- 2.37%, 191.52 +/- 13.93 mg/dl, 44.21 +/- 1.14 mg/dl, respectively) compared with the LC group (39.36 +/- 3.62%, 152.85 +/- 8.61 mg/dl, 30.12 +/- 2.79 mg/dl, respectively)(p < 0.05). Plasma LCAT activities did not differ significantly (56.65 +/- 7.19 vs 57.41 +/- 8.21; HC vs LC). Hepatic CETP, LCAT and apoA-I mRNA levels were determined using reverse transcription polymerase chain reaction (RT-PCR). Hepatic CETP mRNA levels, compared to GAPDH mRNA levels as a control, were increased in the HC group (2.226 +/- 0.115) compared with the LC group (1.649 +/- 0.170) (p < 0.05), while hepatic LCAT and apoA-I mRNA levels were unchanged. Thus, plasma concentration of prebeta HDL, CETP activity and the amount of hepatic CETP mRNA were increased in response to the dietary intake of cholesterol. Multiple regression analyses showed that only hepatic CETP mRNA levels had a positive correlation with plasma prebeta HDL concentration (p = 0.04). These results indicate that individual variations in hepatic CETP mRNA levels in rabbits fed a cholesterol diet probably has a major influence on the determination of plasma prebeta HDL concentration.

Plasma lipoproteins and clinical characteristics of type 2 diabetic patients with (n = 50) and without (n = 108) ischemic heart disease (IHD) were compared. The patients with IHD were older (64 +/- 9 vs 59 +/- 9 years, mean +/- SD, p < 0.01) and had a longer duration of diabetes (14 +/- 9 vs 11 +/- 8 years, p < 0.05). Lipids, lipoproteins and apolipoproteins were comparable in the two groups. The percent distribution of triglycerides (TG) in the very low density lipoprotein (VLDL) fraction was significantly higher (55 +/- 16 vs 50 +/- 17%, p < 0.05). The level of low density lipoprotein (LDL) (33 +/- 14 vs 39 +/- 15%, p < 0.05) and the apo E/VLDL-TG ratio (0.085 +/- 0.045 vs 0.120 +/- 0.097, p < 0.01), however, was significantly lower in patients with IHD than in those without IHD. Multiple regression analysis also indicated that age, duration of diabetes, percent distribution of TG in VLDL, percent distribution of TG in LDL and the apo E/VLDL-TG ratio were significantly related to the presence of IHD. Hypertriglyceridemia, particularly when characterized by abnormalities of TG distribution, may play an important role in the development of IHD in type 2 diabetic patients.