Ausência de efeito do captopril no metabolismo de uma emulsão lipídica artificial semelhante aos quilomícrons em pacientes hipertensos e hipercolesterolêmicos / Lack of effect of captopril on the metabolism of an artificial lipid emulsion similar to chylomicrons in hypertensive hypercholesterolemic patients

OBJETIVO: Avaliar o efeito do captopril, sobre o metabolismo dos quilomícrons e de seus remanescentes e as possíveis alterações nas concentrações dos lípides plasmáticos em hipertensos e hipercolesterolêmicos. MÉTODOS: O metabolismo dos quilomícrons foi testado pelo método da emulsão lipídica artificial de quilomícrons marcada com 3H-oleato de colesterol, foi injetada intravenosamente em 10 pacientes com hipertensão arterial leve-moderada antes e após 45 dias de tratamento com captopril (50 mg/dia). Após injeção, foram coletadas amostras de sangue durante 60min em intervalos de tempo pré-estabelecidos para determinar a curva de decaimento e a taxa fracional de remoção (TFR em min-1), bem como o tempo de residência no plasma, da emulsão lipídica artificial, por análise compartimental. As concentrações dos lípides do plasma também foram avaliadas antes e após o tratamento. RESULTADOS: A taxa fracional de remoção (em min-1) da emulsão lipídica antes e após o tratamento com captopril (0,012±0,003 e 0,011±0,003, respectivamente; p=0,85, n.s.) ou o tempo de permanência da emulsão no plasma (83,3±20,8 e 90,9± 22,5 min, n.s.) não se alteraram, mas os níveis de colesterol total e de LDL-c reduziram-se em 7 por cento e 10 por cento respectivamente (p=0,02). As concentrações de HDL-c, triglicérides, Lp(a) e apolipoproteínas AI e B não se modificaram. CONCLUSÃO: O tratamento com captopril, avaliado pelo método da emulsão lipídica artificial, não provoca alterações deletérias no metabolismo dos quilomícrons e seus remanescentes.

Metabolism of chylomicrons in patients with congenital lipoatrophic diabetes: a study with emulsion models of chylomicrons.

BACKGROUND: Lipoatrophic diabetes is characterized by the near absence of adipose tissue and the presence of insulin-resistant diabetes. Fasting hypertriglyceridaemia and increased postprandial lipidaemia are also present, but the metabolism of chylomicrons, the triglyceride-rich lipoproteins in the circulation that carry the dietary fats absorbed by the intestine, was not specifically investigated. Because both the activity of insulin-dependent lipoprotein lipase that catalyses the chylomicron lipolysis and the storage of the lipolysis products are affected in the disease, it is important to evaluate how those changes may ultimately affect the chylomicron lipolysis and removal of chylomicron remnants from the circulation. OBJECTIVE: The aim of the study was to evaluate the chylomicron intravascular metabolism in patients with lipoatrophic diabetes. PATIENTS: Six patients with lipoatrophic diabetes (four females, two males) aged 22.2 +/- 4.4 years, with body mass index (BMI) 21.6 +/- 3.6 kg/m(2), were compared with 12 healthy control subjects (seven females, five males) aged 24.3 +/- 2.1 years with BMI 22.5 +/- 2.7 kg/m(2). MEASUREMENTS: The plasma kinetics of intravenously injected chylomicron-like emulsions labelled with (3)H-triglycerides ((3)H-TG) and with (14)C-cholesteryl esters ((14)C-CE) were determined, the former tracing the chylomicron lipolysis by lipoprotein lipase and the latter the removal of chylomicron remnants from the plasma. RESULTS: Triglyceride values (8.3 +/- 9.2 mmol/l) in the patients were higher (P < 0.005) and high density lipoprotein (HDL) cholesterol values (0.8 +/- 0.2 mmol/l) lower (P < 0.0005) than in controls (0.7 +/- 0.2 and 1.3 +/- 0.4 mmol/l, respectively) whereas total cholesterol, apoprotein B (apo B) and apo A1 were similar. The fractional clearance rate (FCR, in min(-1)) of (3)H-TG was 0.014 +/- 0.016 and the FCR of (14)C-CE was 0.008 +/- 0.012 in the patients and 0.046 +/- 0.024 and 0.024 +/- 0.012 in the controls, respectively (P < 0.05). Thus FCRs of both emulsion labels were markedly reduced in the patients, indicating that lipolysis and remnant removal were diminished. Diminished remnant removal may be due to either deficient lipolysis or deficient removal mechanisms. CONCLUSION: The metabolism of chylomicrons tested by the emulsion method is impaired in lipoatrophic diabetes.

Clearance of a 3H-labeled chylomicron-like emulsion following the acute phase of myocardial infarction.

BACKGROUND: Plasma lipids may be altered during acute myocardial infarction and may not reflect patient baseline lipid profile. The metabolism of chylomicrons, the lipoproteins that carry the dietary lipids in the bloodstream has not yet been studied in acute myocardial infarction patients. METHODS: In this study, a lipidic emulsion that mimics the intravascular behavior of chylomicrons labeled with cholesteryl oleate ((3)H-CO) was injected intravenously in 17 normolipidemic patients on the seventh and on the 45th day post-non complicated acute myocardial infarction after a 12-h fast. The plasma decay curve of the emulsion label was determined from blood samples collected during 60 min. Data were also compared with a group of 10 patients with chronic coronary artery disease. RESULTS: In the acute myocardial infarction group, the plasma fractional catabolic rates of the emulsion (3)H-CO, expressed as median and confidence intervals, did not change from the seventh to the 45th day after the acute event [0.0773 (0.061, 0.1025) min(-1) vs. 0.0672 (0.00507, 0.1009) min(-1) P=0.61] and was similar to that determined in chronic coronary artery disease patients. High-density lipoprotein cholesterol and apolipoprotein AI were lower on the seventh day when compared to the 45th day post acute myocardial infarction (P=0.01 and P=0.004, respectively). No changes were found in LDL and total cholesterol as well as in plasma triglycerides in myocardial infarction group. CONCLUSIONS: No changes were found in chylomicron metabolism is in the acute phase of myocardial infarction.

Lack of effect of captopril on the metabolism of an artificial lipid emulsion similar to chylomicrons in hypertensive hypercholesterolemic patients.

OBJECTIVE: To assess the effect of captopril, an angiotensin-converting enzyme inhibitor, on the metabolism of chylomicrons and their remnants and the possible alterations in the concentrations of plasma lipids caused by the drug in hypertensive hypercholesterolemic individuals. METHODS: The metabolism of chylomicrons was tested with the method of artificial lipid emulsion of chylomicrons labeled with 3H-cholesteryl oleate. The emulsion was injected intravenously in 10 patients with mild-moderate arterial hypertension before and 45 days after treatment with captopril (50 mg/day). After injection, blood samples were collected during 60 minutes at pre-established time intervals for determining the decay curve, the fractional catabolic rate (FCR in min-1), and the plasma residence time of the artificial lipid emulsion by analyzing different compartments. The plasma concentrations of the lipids were also assessed before and after treatment. RESULTS: The fractional catabolic rate (min-1) of the lipid emulsion before and after treatment with captopril (0.012 +/- 0.003 and 0.011 +/- 0.003, respectively; p = 0.85, n.s.) and the plasma residence time of the emulsion (83.3 +/- 20.8 and 90.9 +/- 22.5 min, n.s.) did not change, but the total cholesterol and LDL-C levels decreased by 7% and 10%, respectively (p = 0.02). The concentrations of HDL-C, triglycerides, Lp(a), and apolipoproteins AI and B did not change. CONCLUSION: Treatment with captopril, evaluated with the artificial lipid emulsion method, does not cause deleterious changes in the metabolism of chylomicrons and their remnants.

Metabolism of chylomicron-like emulsions in carriers of the S447X lipoprotein lipase polymorphism.

BACKGROUND: Lipoprotein lipase catalyzes the hydrolysis of the triglycerides contained in both very-low-density lipoproteins and chylomicrons for storage in the adipose tissue and muscle of fats of both hepatic and dietary origin. The S447X-Stop lipoprotein lipase is the most common polymorphism of the enzyme, affecting roughly 20% of the population and is accompanied by normal or diminished fasting triglycerides and perhaps lower incidence of coronary artery disease (CAD). Delay in the removal of chylomicron and remnant is now an established risk factor for CAD. METHODS: Currently, the chylomicron metabolism has been evaluated in 12 normolipidemic subjects with the S447X-Stop and in 13 age- and sex-paired control subjects with no mutation. The doubly labeled chylomicron-like emulsion method was used to evaluate chylomicron metabolism. The emulsions labeled with cholesteryl-oleate (14C-CE) and tri[9,10-3H]oleate (3H-Tg) were injected intravenously and the decay curves of the labels were determined by blood sampling over 60 min followed by radioactive counting. RESULTS: The fractional clearance rate (FCR, min(-1)) of the labels was not different in the S447X carriers compared with the noncarriers (FCR 3H-Tg 0.035 +/- 0.019 and 0.030 +/- 0.009; FCR 14C-CE 0.008 +/- 0.007 and 0.009 +/- 0.007, respectively). CONCLUSIONS: The chylomicron intravascular lipolysis monitored by the 3H-Tg emulsion and the remnant removal monitored by the 14C-CE emulsion were not altered by the presence of this polymorphism of great populational impact.

Atorvastatin enhances the plasma clearance of chylomicron-like emulsions in subjects with atherogenic dyslipidemia: relevance to the in vivo metabolism of triglyceride-rich lipoproteins.

Delayed chylomicron clearance is a characteristic of patients with coronary artery disease. In vivo study of the clearance of labeled chylomicron-like emulsions constitutes a valid model system for evaluation of chylomicron catabolism. The effects of atorvastatin at low (10 mg) and high (40 mg) dose upon the intravascular metabolism and plasma kinetics of chylomicron-like emulsions were evaluated in fasting hyperlipidemic subjects (n=45). Subjects were randomized to a 6-week treatment period with placebo (n=15), low dose or high dose atorvastatin (10 mg/day, n=17 and 40 mg/day, n=13). The chylomicron-like emulsion, double-labeled with 14C-Cholesteryl oleate (14C-CE) and 3H-triolein (3H-TG), was injected in a bolus after a 12-h fast, and blood samples were collected up to 60 min. Plasma decay curves were determined for labeled emulsion CE and TG and residence times (RT) calculated by the occupancy principle. The 14C-CE RT was decreased by 50% after low dose atorvastatin and by 73% after atorvastatin at high dose in comparison to placebo (P<0.05). The 3H-TG RT was significantly reduced (-55%) after high dose atorvastatin, but in contrast was not significantly reduced after placebo or low dose statin. By compartmental analysis, both doses of atorvastatin led to marked elevation in the slow removal component of emulsion remnant particles (10 mg/day=107%; 40 mg/day=195%, P=0.01). Equally, the rapid removal component was increased (+99%) at high dose (P=0.015). Recirculation of 3H-fatty acids was significantly reduced at both statin doses (43 and 83%, respectively) in comparison to placebo (P=0.01). In conclusion, atorvastatin treatment accelerates the plasma clearance of chylomicron-like emulsions and reduces recirculation of fatty acids in subjects with atherogenic hyperlipidemia. Such effect might implicate in reduction of cardiovascular risk.

Uptake of a cholesterol-rich emulsion by breast cancer.

OBJECTIVE: Overexpression of low-density lipoprotein (LDL) receptors occurs in several cancer cell lines and offers a unique strategy for drug targeting by using LDL as vehicle. However, the native lipoprotein is difficult to obtain and handle. Previously, we showed that a lipidic emulsion (LDE) similar to the lipid structure of native LDL may bind to LDL receptors and be taken up by acute myelocytic leukemia cells. We also showed that LDE can also concentrate in ovarian cancer tissue. In this study, we tested whether LDE is taken up by breast carcinoma. METHODS: LDE labeled with (99m)Tc was injected into 18 breast cancer patients, and nuclear medicine images of the tumor and metastatic sites were acquired. Subsequently, LDE labeled with [3H]cholesteryl oleate was intravenously injected into 14 breast cancer patients 24-30 h before total mastectomy procedure. Fragments of normal and of breast cancer tissue excised during surgery were lipid extracted with chloroform/methanol and their radioactivity was measured in a scintillation solution. RESULTS: (99m)Tc-LDE images of the primary tumor and of metastasis sites were obtained in all 18 breast cancer patients. As directly measured in the tumor and in the normal mammary tissue, the amount of the emulsion radioactive label in the tumor was 4.5 times greater than in the normal tissue (range 1.2- to 8.8-fold). CONCLUSION: LDE concentrates much more in malignant breast tumor tissue than in the normal tissue. Thus it has potential to carry drugs or radionuclides directed against mammary carcinoma cells for diagnostic or therapeutic purposes.