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The main urinary metabolites of metoprolol‐(3H) in man, the dog and the rat were identified by gas chromatography and mass spectrometry by comparison with synthesized reference compounds. The amounts of the different metabolites in urine were determined by radio‐gas chromatography. In man metoprolol was metabolized by oxidative deamination, O‐dealkylation with subsequent oxidation and aliphatic hydroxylation into three main urinary metabolites which together accounted for 85% of the total urinary excretion. In the dog and the rat the same metabolites could be recovered but in different relative abundances. The inhibition of cardiovascular effects of isoprenaline by the metabolites and a presumed metabolite was studied and compared with the effects of metoprolol. Two of the compounds blocked the isoprenaline responses but they were 2–8 times less potent than metoprolol. The metabolites showed a significantly lower acute toxicity in mice than metoprolol.

Insulin resistance, impaired glucose tolerance, high circulating levels of free fatty acids (FFA), and postprandial hyperlipidemia are associated with the metabolic syndrome, which has been linked to increased risk of cardiovascular disease. We studied the metabolic responses to an oral glucose/triglyceride (TG) (1.7/2.0 g/kg lean body mass) load in three groups of conscious 7-h fasted Zucker rats: lean healthy controls, obese insulin-resistant/dyslipidemic controls, and obese rats treated with the dual peroxisome proliferator-activated receptor alpha/gamma agonist, tesaglitazar, 3 mumol.kg(-1).day(-1) for 4 wk. Untreated obese Zucker rats displayed marked insulin resistance, as well as glucose and lipid intolerance in response to the glucose/TG load. The 2-h postload area under the curve values were greater for glucose (+19%), insulin (+849%), FFA (+53%), and TG (+413%) compared with untreated lean controls. Treatment with tesaglitazar lowered fasting plasma glucose, improved glucose tolerance, substantially reduced fasting and postload insulin levels, and markedly lowered fasting TG and improved lipid tolerance. Fasting FFA were not affected, but postprandial FFA suppression was restored to levels seen in lean controls. Mechanisms of tesaglitazar-induced lowering of plasma TG were studied separately using the Triton WR1339 method. In anesthetized, 5-h fasted, obese Zucker rats, tesaglitazar reduced hepatic TG secretion by 47%, increased plasma TG clearance by 490%, and reduced very low-density lipoprotein (VLDL) apolipoprotein CIII content by 86%, compared with obese controls. In conclusion, the glucose/lipid tolerance test in obese Zucker rats appears to be a useful model of the metabolic syndrome that can be used to evaluate therapeutic effects on impaired postprandial glucose and lipid metabolism. The present work demonstrates that tesaglitazar ameliorates these abnormalities and enhances insulin sensitivity in this animal model.

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Objective-The dyslipidemia of insulin resistance, with high levels of albumin-bound fatty acids, is a strong cardiovascular disease risk. Human arterial smooth muscle cell (hASMC) matrix proteoglycans (PGs) contribute to the retention of apoB lipoproteins in the intima, a possible key step in atherogenesis. We investigated the effects of high NEFA levels on the PGs secreted by hASMCs and whether these effects might alter the PG affinity for low-density lipoprotein. Methods and Results-hASMC exposed for 72 hours to high concentrations (800 mol/L) of linoleate (LO) or palmitate upregulated the core protein mRNAs of the major PGs, as measured by quantitative PCR. Insulin (1 nmol/L) and the PPAR␥ agonist rosiglitazone (10 mol/L) blocked these effects. In addition, high LO increased the mRNA levels of enzymes required for glycosaminoglycan (GAG) synthesis. Exposure to NEFA increased the chondroitin sulfate:heparan sulfate ratio and the negative charge of the PGs. Because of these changes, the GAGs secreted by LO-treated cells had a higher affinity for human low-density lipoprotein than GAGs from control cells. Insulin and rosiglitazone inhibited this increase in affinity. Key Words: proteoglycans Ⅲ smooth muscle cells Ⅲ LDL Ⅲ fatty acids Ⅲ insulin I nsulin resistance (IR) and type 2 diabetes (T2D) are associated with a 2-to 4-fold increase in atherosclerotic coronary artery disease. 1,2 Changes in circulating lipoproteins, chronic high levels of albumin-bound nonesterified fatty acids (NEFA, and hyperinsulinemia are important contributors to this association. [3][4][5] Atherogenesis involves a tissue response to deposition of apoB lipoproteins and insulin signaling defects that may affect vascular cells. 6 The accelerated intimal thickening of large arteries observed in IR and diabetes includes excessive production of matrix components, such as proteoglycans (PGs) and collagens by smooth muscle cells (SMCs). 7 Cell culture experiments suggest that increased endothelial cell permeability and SMC alterations of matrix production could be caused by exposure to excessive amounts of NEFA. 8 -10 In IR, arterial cells are chronically exposed to increased levels of circulating NEFA. In addition, NEFA could be produced locally by lipolytic degradation of lipoproteins, additionally increasing their concentration in the arterial intima. 11,12 Retention of low-density lipoprotein (LDL) in the intima by chondroitin sulfate (CS)-rich PGs appears to be a key step in atherogenesis at sites of intima thickening. [13][14][15] We reported that the expression of genes for extracellular matrix proteins and PGs is increased when human arterial SMCs (hASMCs) are exposed to NEFA. Furthermore, the extracellular matrix produced by the NEFA-treated hASMC had a higher affinity for LDL. 9 In this study we describe how linoleate (LO) and palmitate (PA) increased the expression of genes encoding the core proteins of the main secreted PGs from hASMC and of the key enzymes in CS-glycosaminoglycan (GAG) biosynthesis. Exposure to LO also altered...

The oxidative modification of lipoproteins is of clinical importance because of potential contribution to atherogenesis [1, 2, 3]. An early step in the complex process of oxidation is the peroxidation of polyunsaturated fatty acids. We describe here a method for the Cu(II)-catalyzed oxidation of human low density lipoproteins with the subsequent analysis of hydroperoxides formation in a single microtitre plate. The procedure includes a modification of an iodometric peroxide assay for test tubes using a commercially available reagent. The microtitre plate method correlated well with the test tube procedure (r = 0.99) and showed comparable sensitivity and reproducibility. It was sensitive down to 0.5 nmol hydroperoxides/well and linear up to at least 20 nmol well-1. The method can handle several hundreds of samples a day with considerably less labour than the test tube procedure. It was well suited to monitor the kinetics of lipoprotein oxidation. The method was also used to test the potency of antioxidants, however, some antioxidants may interfere with the iodometric reaction and should be tested in the assay before use.

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