Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.34 (lipoprotein lipase)
 7,025 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The goal of antihypertensive treatment must be not only the reduction of high blood pressure, but also the effective management of elevated cholesterol levels and other risk factors of coronary heart disease (CHD). In controlled clinical trials, doxazosin has been shown to have antihypertensive efficacy comparable with other classes of antihypertensive agents and to lower the levels of total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides while increasing the levels of high-density lipoprotein cholesterol. Doxazosin appears to inhibit the development of CHD on two fronts. First, doxazosin binds to the alpha 1-adrenoreceptor and inhibits the receptor-mediated responses to epinephrine and norepinephrine. Second, doxazosin has direct and indirect effects on lipid metabolism by increasing LDL receptor activity, decreasing intracellular LDL synthesis, reducing the synthesis and secretion of very low-density lipoprotein cholesterol, and stimulating lipoprotein lipase activity. Doxazosin may also inhibit platelet aggregation. Long-term studies will determine how these actions translate into reductions in the morbidity and mortality rates of CHD. First-year results from the Treatment of Mild Hypertension Study (TOMHS) have demonstrated expected reductions in blood pressure for all antihypertensive agents studied. The lipid changes have varied with the type of antihypertensive treatment and have been favorable for doxazosin.
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PMID:Effects of doxazosin on serum lipids: a review of the clinical data and molecular basis for altered lipid metabolism. 182 47

The sympathetic nervous system plays a major role in the pathogenesis of essential hypertension and is mediated by the alpha and beta receptors. The alpha receptor is divided into two types, alpha 1 and alpha 2, based on response to epinephrine and norepinephrine. alpha 1-Adrenergic receptors have a high affinity for drugs such as prazosin, doxazosin, and terazosin, which act to reduce blood pressure by selective blockade of the receptor. These agents provide a rational approach to the treatment of hypertension by correcting elevated total peripheral resistance, the fundamental hemodynamic abnormality in essential hypertension. In contrast, early alpha-adrenergic receptor blockers nonselectively blocked both alpha 1 and alpha 2 receptors and were unsuitable as antihypertensive agents because they induced tachycardia and patients developed a tolerance to them rapidly. alpha 1-Adrenergic blockers also have beneficial effects on plasma lipoproteins, tending to decrease levels of triglycerides and cholesterol and increase levels of high-density lipoprotein (HDL) cholesterol and the HDL cholesterol/total cholesterol ratio. beta-Adrenergic blockers, such as propranolol and atenolol, have been shown to have an adverse effect on the lipid profile by tending to increase levels of triglycerides and decrease HDL cholesterol. A number of mechanisms contribute to these effects, in particular, adrenergic modulation of lipoprotein lipase and the triglyceride secretion rate. Doxazosin has been shown to increase the activity of LDL receptors, which may be partly responsible for its beneficial effect on plasma lipids and lipoproteins.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Alpha-adrenergic blockers: mechanism of action, blood pressure control, and effects of lipoprotein metabolism. 198 Feb 36

The effects of alpha 1-adrenergic receptor inhibition with doxazosin, and beta-blockade with propranolol on tissue lipoprotein lipases and plasma lipids were studied in rats. In rats fed a normal lab chow, doxazosin increased heart lipoprotein lipase activity (+14%), while propranolol had the opposite effect (-20%). These effects were not statistically significant when compared with nontreated controls, although the difference between the doxazosin and propranolol groups was significant (p less than 0.05). There were no significant effects on adipose tissue lipoprotein lipase activity or hepatic lipase activity. In rats fed a cholesterol-enriched diet there were similar but smaller effects on heart lipoprotein lipase activity (+5% and -12%, respectively). In these rats alpha 1-inhibition also tended to increase adipose tissue lipoprotein lipase (+14%) and hepatic lipase (+13%), while beta-blockade had the opposite effect (-20% and -9%, respectively). The lipase activities were significantly different between the treatment groups in liver and heart but not in adipose tissue. Doxazosin and propranolol did not affect plasma triglyceride or total cholesterol, but high-density lipoprotein cholesterol was increased during alpha 1-blockade (+24%).
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PMID:Effects of doxazosin and propranolol administration on lipoprotein lipases in cholesterol-fed rats. 244 35

Doxazosin has been shown to lower serum cholesterol levels in the cholesterol-fed (0.75% in a synthetic diet that contains sucrose and cholic acid) C57BR/cdJ mouse. These studies show that the drug's main effect is to lower low-density lipoprotein (LDL) cholesterol and leave high-density lipoprotein (HDL) cholesterol levels unchanged. The drug had cholesterol-lowering effects in this model at doses down to 3 mg/kg. In order to determine if these effects are unique to selective alpha 1-inhibitors, other antihypertensives including hydralazine, papaverine, and captopril were investigated. None of the drugs has any effects on the plasma lipid metabolite levels. The effects of propranolol and polythiazide on plasma lipid levels were also examined in these mice. Propranolol had no effect, whereas the diuretic increased plasma cholesterol levels. Both propranolol and polythiazide increased plasma triglycerides. Doxazosin has been shown to inhibit cGMP phosphodiesterase in the laboratory. The effects of zaprinast, a cGMP phosphodiesterase inhibitor, were tested in order to determine if this property of the drug could be responsible for its lipid-lowering activity. The data show that there are no effects on plasma lipids in zaprinast-treated animals. Doxazosin treatment increased heparin-releasable lipoprotein lipase in fasted chow-fed mice. The drug was without effect on the activity of hepatic lipase present in the plasma after heparin release. No effects were observed on the tissue levels of either hepatic or lipoprotein lipases (heart or adipose tissue).
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PMID:Effects of doxazosin and other antihypertensives on serum lipid levels and lipoprotein lipase in the C57BR/cdJ mouse. 247 Oct 10

The effects of treatment with adrenoceptor blockers on sites regulating lipid metabolism were studied in golden hamsters. In hamsters fed a standard chow, doxazosin, propranolol, and atenolol did not affect plasma cholesterol or triglycerides. After hypercholesterolemia was induced by feeding a cholesterol-enriched diet, doxazosin lowered plasma cholesterol by 12%. Lipoprotein lipase activity in adipose tissue and in the heart was not changed by any of the treatments. Hepatic lipase activity in the liver and blood was lowered by 31% in the doxazosin-treated animals. Hepatic cholesterol synthesis, measured as acetate incorporation into cholesterol and hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase activity, was also lowered in the doxazosin-treated hamsters. After norepinephrine administration to cholesterol-fed hamsters, atenolol increased (+8%) and doxazosin decreased (-35%) plasma triglycerides. Plasma cholesterol levels and hepatic cholesterol synthesis were no longer significantly affected by doxazosin. In norepinephrine-treated animals, adipose tissue lipoprotein lipase activity was enhanced (+30%) by doxazosin. Hepatic lipase activity in plasma and liver, which was lowered by norepinephrine, was increased by doxazosin. In hamsters not treated with norepinephrine, adrenoceptor blockers had no effect on plasma insulin or thyroid hormone, but with norepinephrine, levels of both insulin and thyroid hormone were increased by doxazosin. These data indicate that selective alpha 1-inhibition with doxazosin may interfere with lipid metabolism at several regulatory sites. The effects depend to a large extent on nutritional and hormonal status. Doxazosin might exert these effects partly via influences on other hormones.
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PMID:Effects of doxazosin on lipids, lipoprotein lipases, and cholesterol synthesis in the golden hamster. 247 Oct 16

In a previous open study on the metabolic effects of doxazosin in patients with essential hypertension, subgroup analysis indicated that subjects with an accumulation of risk factors for coronary heart disease (high VLDL triglycerides, low HDL cholesterol and high fasting blood glucose) seemed to benefit most from the metabolic actions of doxazosin treatment. Those results formed the basis of this double-blind, parallel-group study undertaken to elucidate the metabolic effects of 6 months of doxazosin and enalapril treatment in patients with both essential hypertension and hypertriglyceridemia. Insulin sensitivity was measured with the euglycemic hyperinsulinemic clamp method. Hemodynamic evaluation included measurements of office and ambulatory blood pressure and ultrasonic measurements of femoral artery blood flow. Both drugs significantly reduced both office BP and 24-h ambulatory BP. Office systolic BP was significantly better reduced by enalapril. Doxazosin, in contrast to enalapril, significantly increased insulin sensitivity (by 21%, P = .02). It also reduced serum-triglycerides (by 23%, P = .01), VLDL triglycerides (by 30%, P = .008) and VLDL cholesterol (by 24%, P = .02). This lipid-lowering effect of doxazosin was accompanied by an increase in both plasma lipoprotein lipase activity and the elimination rate of an intravenous fat emulsion load. Neither treatment significantly increased femoral artery blood flow. It is speculated that without measurably increasing blood flow in conduit vessels such as the femoral artery, doxazosin, by capillary recruitment, may prolong the transit time for the blood over the muscle bed, which could explain the increased glucose disposal and increased lipoprotein lipase activity.
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PMID:Metabolic effects of doxazosin and enalapril in hypertriglyceridemic, hypertensive men. Relationship to changes in skeletal muscle blood flow. 872 35