Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have investigated the cellular basis for the clinical and epidemiologic linkage of hypertension, left ventricular hypertrophy (LVH), obesity, and non-insulin-dependent diabetes mellitus (NIDDM) and have studied cytosolic free calcium and free magnesium levels in these syndromes. Specifically, intracellular free calcium is elevated and free magnesium is deficient in hypertension, and both are related (directly and inversely, respectively) to the ambient level of blood pressure, to LV mass index (and thus to the degree of cardiac hypertrophy), and to the hyperinsulinemia and insulin resistance of essential hypertension. Dynamically, the ability of dietary salt loading to elevate blood pressure corresponds to its ability to elevate cytosolic free calcium and reciprocally to suppress free magnesium levels. Conversely, the ability of calcium channel blockade to reverse salt-induced hypertension is related to its ability to prevent these transmembrane ionic effects. Higher steady-state free calcium or lower free magnesium, or both, are also observed in clinical states linked to hypertension, such as obesity and NIDDM. Oral glucose loading in normal subjects itself elevates free calcium and suppresses free magnesium levels, as does hyperglycemia in vitro. These data suggest an ionic hypothesis of cardiovascular and metabolic disease, in which a generalized defect in cell ion handling is present in all tissues, resulting in higher steady-state free calcium and lower free magnesium levels. In pancreatic beta cells, this would produce hyperinsulinemia; in fat and skeletal muscle, cause peripheral insulin resistance; and in renal tissue, increase proximal sodium resorption and increase urinary calcium excretion--all features of essential hypertension. In vascular smooth muscle, high cytosolic free calcium would increase smooth muscle tone and cause vasoconstriction, and in heart muscle, independent of blood pressure, would increase contractility and predispose to LVH. Therefore, what may appear clinically to be the separate syndromes of hypertension, obesity, and NIDDM may pathophysiologically be different manifestations of the same underlying cellular defect, thus explaining their frequent clinical coexistence. Therapeutically, reversal of this excess free calcium accumulation and/or free magnesium deficit with ion-specific agents, such as calcium channel blocking drugs, may thus ameliorate not only the elevated blood pressure of hypertension but also the concurrent excess morbidity and mortality of the concurrent cardiac, vascular, and metabolic aspects of the hypertensive state.
 ...
PMID:Cellular calcium and magnesium metabolism in the pathophysiology and treatment of hypertension and related metabolic disorders. 138 62

We evaluated insulin sensitivity in normotensive (blood pressure, BP, less than 135/85 mm Hg) and hypertensive (BP greater than 160/90 mm Hg) elderly subjects over 65 years old who were stratified as normal weight (body mass index, BMI, less than 27) and obese (BMI greater than 27). Obese hypertensive individuals demonstrated marked hyperinsulinemia (P less than .01) and significantly reduced (P less than .05) submaximally stimulated adipocyte 2-deoxyglucose (2-DOG) uptake (abdominal wall fat biopsy). Normal weight hypertensive subjects also demonstrated higher levels of insulinemia and lower insulin-stimulated 2-DOG uptake than nonobese controls. Adipocyte [Ca2+]i levels were elevated in all elderly subjects compared to young individuals (P less than .01). Basal and maximally stimulated 2-DOG uptake were similar in all groups. One month of therapy with a calcium channel blocker, 10 mg nitrendipine twice daily, reduced blood pressure in the hypertensive subjects, reduced plasma insulin to control values during an oral glucose tolerance test in obese hypertensive individuals (P less than .01), and restored adipocyte 2-DOG uptake at submaximally effective insulin concentration to control values in normal weight and obese hypertensive subjects. In summary, older hypertensive, and particularly older obese hypertensive, patients manifest significant insulin resistance accompanied by elevated levels of [Ca2+]i in their adipocytes.
 ...
PMID:Cytosolic calcium and insulin resistance in elderly patients with essential hypertension. 163 18

Use of thiazide diuretics and beta-blockers in the treatment of hypertension may result in metabolic derangements and/or disturbances in the parameters of renal function, which offset the benefits of blood pressure reduction by adversely affecting other cardiovascular risk factors, particularly in special patient groups such as the elderly or those with concomitant diseases. Newer agents including calcium channel blockers, which exert potent antihypertensive effects without adversely affecting metabolic parameters unfavorably, are used with increasing frequency in hypertensive patients, but their clinical utility has been limited by the need for multiple daily dosing with attendant fluctuations in plasma levels thought to be associated with nuisance side effects and possible gaps in therapeutic protection. The Modern Approach to the Treatment of Hypertension (MATH) trial was conducted to determine the efficacy and safety of the new once-daily nifedipine gastrointestinal therapeutic system (GITS) formulation in a large cohort of mild-to-moderate hypertensive patients overall, and to identify specific effects of therapy in the presence of complicating factors such as diabetes and obesity. A total of 1155 patients from 127 centers were treated with nifedipine GITS in the MATH trial, including 157 diabetic (fasting plasma glucose greater than 120 mg/dL or on hypoglycemic therapy) and 747 nondiabetic patients. There were 458 obese patients (body mass index [BMI] greater than 30), 489 overweight patients (BMI greater than or equal to 25 less than or equal to 30), and 206 patients of normal weight (BMI less than 25).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Endocrine and renal effects of nifedipine gastrointestinal therapeutic system in patients with essential hypertension. Results of a multicenter trial. The Modern Approach to the Treatment of Hypertension Study Group. 207 20

The frequent concurrence of other cardiovascular risk factors in hypertensive patients, such as obesity and diabetes mellitus, suggests that overlapping genetic and environmental factors may contribute to the common metabolic and cardiovascular derangements observed in these populations. Hypertension and hyperglycemia accelerate atherosclerosis in diabetics, and play an important role in associated morbidity and mortality. Several abnormalities in blood pressure regulatory systems such as the renin-angiotensin system, the sympathetic nervous system, and sodium/volume control have been described in diabetes mellitus. Sodium retention and cardiovascular hyperreactivity appear to occur early in the course of diabetes mellitus, even at normal blood pressure levels and before onset of renal failure, and could set the stage for the development of hypertension. The relationship between obesity and hypertension is also well-established, and may reflect metabolic and cardiovascular adaptations in obese subjects which predispose to blood pressure elevations. Obese subjects display changes in sympathetic nervous system activity, sodium metabolism, and vascular hemodynamics. Sodium-sensitive blood pressure responses in the obese may be secondary to increased cardiac output or fluid volume, and are directly related to circulating insulin levels. Certain metabolic and vascular characteristics of obesity and diabetes mellitus are found in patients with essential hypertension. It has been suggested that insulin and insulin resistance may be the common link between these risk factors. Improved understanding of metabolic considerations in the treatment of obese and diabetic hypertensives should lead to more careful selection of medications that avoid metabolic complications. Although diuretics and beta-blockers may be useful in some patients, there are several reasons not to recommend their use as initial therapy in obese and diabetic hypertensives. On the other hand, calcium channel blockers and angiotensin converting enzyme inhibitors are highly effective, with minimal effects on metabolic parameters, and are well-suited as first-line therapy in the treatment of obese and diabetic hypertensives.
 ...
PMID:Metabolic considerations in hypertension. 207 23

Hypertension and diabetes mellitus are chronic medical conditions that frequently coexist. In the United States, it is estimated that 10 million persons suffer from diabetes mellitus, 60 million from hypertension, and 3 million from the combination of the two. There may be a causal relationship between hypertension and diabetes. Obesity may be a precipitating factor for both hypertension and non-insulin-dependent diabetes mellitus. Those with insulin-dependent diabetes mellitus generally become hypertensive only with the onset of nephropathy. Glucose tolerance, insulin resistance, and hyperinsulinemia frequently occur with essential hypertension and may be aggravated by hypertension therapy, especially with diuretics and beta-blockers. Hyperinsulinemia may be an important common factor promoting sodium retention, sympathetic nervous system stimulation, and inhibition of the sodium pump. The Working Group on Hypertension in Diabetes has outlined a flexible modified version of the stepped-care approach to the treatment of hypertension in diabetes. Management is complex because diabetes is associated with autonomic neuropathy, sexual dysfunction, hyperlipidemia, and fluid and electrolyte disorders. All these problems can be exacerbated by antihypertensive treatment. Nonpharmacologic measures, which address weight reduction and sodium restriction, are logical, but aggressive antihypertensive medication is invariably necessary. Diuretics and/or beta-blockers were the mainstay of treatment until the introduction of angiotensin-converting enzyme (ACE) inhibitors and calcium channel blockers. These newer agents have no deleterious effects on carbohydrate metabolism and are generally better tolerated. Antihypertensive therapy may slow the rate of deterioration in diabetic nephropathy. This was first shown with diuretics, beta-blockers, and hydralazine and more recently with ACE inhibitors, which provide effective blood pressure control and a significant drop in albuminuria without affecting the glomerular filtration rate adversely. ACE inhibition may also lead to increased insulin sensitivity and glucose disposal rate. Long-term trials are needed to assess the effects of these new agents on the treatment of hypertension in the diabetic population.
 ...
PMID:Diabetes mellitus and hypertension. 222 Jul 97

A multicenter, randomized, controlled, double-blind U.S. trial is comparing the combined effects of diet treatment and 1 of 5 active drug regimens with diet treatment alone, for the long-term management of middle-aged adults with "mild" hypertension. Factors stimulating this trial are data documenting the high prevalence of mild hypertension in the adult population; mild hypertension's responsibility for a high proportion of morbidity and mortality attributable to hypertension overall; data from long-term hypertension intervention trials showing reduced morbidity and mortality of people with mild hypertension with use of either diuretics or beta blockers as step-1 therapy, and other trials that failed to demonstrate beneficial impact on morbidity and mortality, possibly due to residual questions concerning aspects of benefit to risk ratios with these medications; recent data from trials showing long-term control of mild hypertension and other risk factors by nutritional means; lack of data from long-term trials on benefit to risk ratios with newer drugs such as selective alpha 1 inhibitors, angiotensin converting enzyme inhibitors and calcium channel blockers; paucity of data from trials on long-term combined effects of diet and drug therapy, and of diet alone, for people with mild hypertension. During the next few years, phase 1 of the trial will study 6 groups of drugs. The step-1 drugs are angiotensin converting enzyme inhibitor (enalapril), alpha 1 inhibitor (doxazosin), beta blocker (acebutolol), calcium channel blocker (amlodipine), diuretic (chlorthalidone) and placebo. All participants are to receive vigorous sustained nutritional counseling to reduce obesity, moderate sodium intake and avoid heavy use of alcohol. Key endpoints for phase 1 of the study are the need for additional medication to control mild hypertension, side effects (i.e., clinical and biochemical) and consequent need to discontinue drug and quality of life. Phase-1 data are to be used to complete the phase-2 design, with the ultimate aim to assess effects on morbidity and mortality.
 ...
PMID:Background and design of the new U.S. trial on diet and drug treatment of "mild" hypertension (TOMHS). 329 21

It has been shown that in vitro calcium channel blockers may regulate insulin secretion, and in vivo studies have demonstrated that they can reduce the degree of hyperinsulinemia and ameliorate the insulin-resistant state in subjects (particularly men) with obesity and hypertension. It is also commonly accepted that hyperinsulinemia may be an important factor responsible for the development of hyperandrogenism in obese women with polycystic ovarian syndrome (PCOS). We, therefore, investigated whether the administration of nitrendipine, a widely used calcium channel blocker, may improve both insulin levels and hyperandrogenism in a group of seven insulin-resistant hyperinsulinemic women with obesity and PCOS. They were treated for 7-8 days with oral nitrendipine (10 mg, twice daily) or placebo using a double blind, cross-over design. Before and after treatment, blood samples were obtained for androgen and sex hormone-binding globulin determinations, and an oral glucose tolerance test was performed, measuring glucose and insulin. Both nitrendipine and placebo failed to decrease basal and stimulated insulin levels. Moreover, no significant variations in testosterone, dehydroepiandrosterone sulfate, or sex hormone-binding globulin concentrations were observed after either treatment. Therefore, these data fail to support previous suggestions that calcium channel blockers may play a role in the treatment of hyperandrogenism and hyperinsulinemia in obese women with PCOS.
 ...
PMID:Nitrendipine treatment in women with polycystic ovarian syndrome: evidence for a lack of effects of calcium channel blockers on insulin, androgens, and sex hormone-binding globulin. 759 49

The purpose of this study was to evaluate the effects of the alpha 1-blocking agent terazosin on blood pressure (BP) and blood lipids in a large, variant population of patients with hypertension. A total of 16,917 patients with hypertension were evaluated at 2214 primary and community care facilities; 7808 of these patients had not been treated previously for hypertension; 3928 were switched to terazosin from another antihypertensive agent; and 5181 received terazosin in addition to an agent that had not controlled their hypertension. Terazosin produced highly significant reductions in systolic (-18.2 +/- 0.2 mm Hg) and diastolic (-13.2 +/- 0.1 mm Hg) BP when used as monotherapy (mean dose, 3.1 mg; range, 2 to 10 mg) without causing a significant increase in heart rate. Equal antihypertensive efficacy was demonstrated in men, women, blacks, and whites of all ages, with particular benefit to elderly patients (> or = 65 years of age) with systolic hypertension. Comparative studies indicated that terazosin had equal antihypertensive efficacy in combination with diuretics, beta-blockers, calcium channel blockers, and angiotensin-converting enzyme (ACE) inhibitors. Patients who had not responded to monotherapy with one of these classes of antihypertensive drugs showed significant reductions of BP after terazosin, in the following average doses, was added to diuretics, 3.1 mg; beta-blockers, 3.4 mg; calcium channel blockers, 3.3 mg; and ACE inhibitors, 3.4 mg. Terazosin produced highly significant reductions in blood levels of total cholesterol (-5.0%), triglycerides (-6.1%), and low-density lipoprotein cholesterol (-7.6%) without change in high-density lipoprotein cholesterol when used as monotherapy. Similar favorable effects on blood lipid levels were demonstrated when terazosin was used in combination with all other classes of antihypertensive drugs. The greatest reductions in blood cholesterol (-9.2%) were observed among patients with hyperlipidemia (total cholesterol > or = 240 mg/dL). Terazosin maintained its antihypertensive efficacy and was well tolerated by patients with a variety of concomitant diseases, including congestive heart failure, peripheral vascular disease, chronic obstructive pulmonary disease, benign prostatic hyperplasia, diabetes, and obesity. Adverse effects occurred in 17.9% of patients and caused 2.2% to drop out of the study. The most frequent adverse effects were dizziness (4.8%), headache (2.5%), and asthenia (2.4%). Only 0.4% suffered syncope and 0.2% impotence. These data demonstrate the usefulness of terazosin as monotherapy or add-on therapy for treatment of hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Alpha 1-blockade for the treatment of hypertension: a megastudy of terazosin in 2214 clinical practice settings. 792 16

Insulin resistance has been implicated in the pathogenesis of essential hypertension. Studies from other countries discovered insulin resistance; in people with essential hypertension in was also associated with obesity, however, insulin resistance was found in lean people too. In obesity, insulin resistance occurs secondarily to many physiopathological states and circulating factors which adversely affects insulin action. The metabolic abnormality in this action was mainly found in relation to abdominal fat; in other cases, insulin resistance was found to be inherited. Hyperinsulinaemia can actually increase blood pressure and is associated with venous and arterial thrombosis and it also rises lipid levels. It is interesting too that insulin resistance and hyperinsulinaemia are associated with impaired fibrinolysis through high levels of fibrinogen and plasminogen activator inhibitor of endothelial type and in identifying individuals prone to myocardial infarction. Some antihypertensive drugs like beta-blockers, methyl-dopa and diuretics increase insulin resistance, while angiotensin converting enzyme-inhibitors have not shown any adverse metabolic affects. Alfa-1-blocker were beneficial and alfa-2-agonists were neutral, whereas calcium channel-antagonists are still in controversy. Treatment should be designed to improve the metabolic state; physical exercise, a diet rich in fruit, vegetable and rott vegetables, the reduction of abdominal fat and, finally, the use of antihypertensive drugs which decrease insulin resistance would be expected to reverse hyperinsulinaemia. Biguanides like metformin have also been found to reduce insulin resistance.
 ...
PMID:[Insulin resistance: an etiological factor in essential arterial hypertension and coronary cardiopathy]. 792 20

The clinical coincidence of hypertension, obesity and non insulin diabetes mellitus (NIDDM) has long been recognized. Increasing interest has also been recently focused on the possible role of insulin and insulin resistance in mediating this association. There is also evidence that hyperglycemia per se may have a role in the pathogenesis of hypertension and atherosclerosis in NIDDM patients. Glucose is a determinant to cellular ion homeostasis, promoting an increase of intracellular calcium and suppressing intracellular free magnesium and pH. Moreover, hyperglycemia promotes glycosilation of proteins and the consequent accumulation of advanced glycosilation end products in tissues. It has recently been suggested that iter is a cellular ionic basis for the clinical and epidemiological linkage of hypertension, left ventricular hypertrophy (LVH), obesity and non insulin dependent diabetes mellitus (NIDDM). These clinical conditions may be different expressions of a common underlying defect in ion handling, displayed by elevated cytosolic free calcium and suppressed free magnesium levels. Therapeutically, reversal of this excess free calcium accumulation and/or free magnesium deficit with ion specific agents, such as calcium channel blocker drugs, may thus ameliorate not only the elevated blood pressure of hypertension but also the concurrent cardiac, vascular and metabolic aspects of the hypertensive states.
 ...
PMID:Diabetes, hypertension and atherosclerosis: pathophysiological role of intracellular ions. 820 15


1 2 3 4 5 6 7 8 9 10 Next >>