Effect of Insulin Resistance on Endothelial Vasodilator in Normal Subjects, Hypertensive Patients and Hypercholesterolemic Patients

This study is currently recruiting patients.

Sponsored by

National Heart, Lung, and Blood Institute (NHLBI) 

Purpose

In the last decade, in our laboratory, a great deal of work has focused on the investigation of endothelial function in patients with essential hypertension and patients with hypercholesterolemia. Our first studies demonstrated the presence of endothelial dysfunction in patients with essential hypertension and in patients with hypercholesterolemia, and pointed out distinctions between the mechanisms leading to this vascular abnormality in these patients. In recent years, the availability of new experimental drugs, the endothelin receptors blockers, has led us to a better understanding of the balance between endothelium-derived vasoconstricting and vasodilating substances in healthy subjects, both in basal condition and during insulin fusion; in patients with essential hypertension; and in patients with hypercholesterolemia. We have found, in contrast with previously published data, that in normal subjects, endothelin-1 does not contribute to basal vascular tone; furthermore, during insulin infusion, in the same subjects, we have shown that insulin stimulates both ET-1 and NO activity. On the other hand, in essential hypertensive patients and in hypercholesterolemic patients, our data indicate an increased vascular endothelin activity. Since the publication of the data of the San Antonio Heart Study, the link between metabolic and cardiovascular disorders has increasingly been recognized, as well as the features these disorders have in common: insulin resistance and vascular endothelial dysfunction. Although a number of studies have been performed, the vascular effects of local and systemic insulin action and the relation between insulin resistance and endothelial dysfunction in various diseases (essential hypertension, hypercholesterolemia, NIDDM), are still unclear. Recent studies have shown that isolated essential hypertension and isolated hypercholesterolemia per se are not insulin-resistant states. However, the prevalence rate of insulin resistance in patients with either one of these conditions is about 30%. Based on our recent findings of increased endothelin tone in patients with essential hypertension, in patients with hypercholesterolemia, and in subjects with experimental hyperinsulinemic states, we plan to investigate the hypothesis that insulin resistance is associated with increased vascular endothelin activity in these conditions. As a secondary aim we will determine whether hyperinsulinemia associated with insulin resistance stimulates endothelium derived NO activity in normal controls, hypertensive patients, and hypercholesterolemic patients. Hyperinsulinemic euglycemic glucose clamp procedure and forearm blood flow measurement will be used to assess both insulin sensitivity and vascular reactivity.

Study Type: Natural History

Official Title: Effect of Insulin Resistance on Endothelial Vasodilator in Normal Subjects, Hypertensive Patients and Hypercholesterolemic Patients

Further Study Details: In the last decade, in our laboratory, a great deal of work has focused on the investigation of endothelial function in patients with essential hypertension and patients with hypercholesterolemia. Our first studies demonstrated the presence of endothelial dysfunction in patients with essential hypertension and in patients with hypercholesterolemia, and pointed out distinctions between the mechanisms leading to this vascular abnormality in these patients. In recent years, the availability of new experimental drugs, the endothelin receptors blockers, has led us to a better understanding of the balance between endothelium-derived vasoconstricting and vasodilating substances in healthy subjects, both in basal condition and during insulin fusion; in patients with essential hypertension; and in patients with hypercholesterolemia. We have found, in contrast with previously published data, that in normal subjects, endothelin-1 does not contribute to basal vascular tone; furthermore, during insulin infusion, in the same subjects, we have shown that insulin stimulates both ET-1 and NO activity. On the other hand, in essential hypertensive patients and in hypercholesterolemic patients, our data indicate an increased vascular endothelin activity.  Since the publication of the data of the San Antonio Heart Study, the link between metabolic and cardiovascular disorders has increasingly been recognized, as well as the features these disorders have in common: insulin resistance and vascular endothelial dysfunction. Although a number of studies have been performed, the vascular effects of local and systemic insulin action and the relation between insulin resistance and endothelial dysfunction in various diseases (essential hypertension, hypercholesterolemia, NIDDM), are still unclear. Recent studies have shown that isolated essential hypertension and isolated hypercholesterolemia per se are not insulin-resistant states. However, the prevalence rate of insulin resistance in patients with either one of these conditions is about 30%.  Based on our recent findings of increased endothelin tone in patients with essential hypertension, in patients with hypercholesterolemia, and in subjects with experimental hyperinsulinemic states, we plan to investigate the hypothesis that insulin resistance is associated with increased vascular endothelin activity in these conditions. As a secondary aim we will determine whether hyperinsulinemia associated with insulin resistance stimulates endothelium derived NO activity in normal controls, hypertensive patients, and hypercholesterolemic patients. Hyperinsulinemic euglycemic glucose clamp procedure and forearm blood flow measurement will be used to assess both insulin sensitivity and vascular reactivity.  

Eligibility

Genders Eligible for Study:  Both Criteria

Must have blood pressure greater than or equal to 145/95 mm/Hg on at least three separate days.

Must have consistently elevated blood pressure readings.

Must not have renovascular hypertension or other etiologies for elevated blood pressure.

Must have a serum cholesterol value greater than 240 mg/dl.

Normal volunteers must not have any cardiovascular or other systemic conditions.

Normal volunteers must not be taking any kind of medications, including vitamins and antioxidants.

Normal volunteers must not have a history of diabetes, peripheral vascular disease, coagulopathy, or any other disease predisposing to vasculitis or Raynaud's phenomenon.

Normal volunteers must not have a body mass index greater than or equal to 28.

Patients will be excluded and treated appropriately if there is definite evidence for accelerated or malignant hypertension (diastolic pressures above 115 mmHg, with associated encephalopathic changes, papilledema, progressive renal failure, or congestive heart failure), or serious intercurrent illness.

Location and Contact Information

Maryland

National Heart, Lung and Blood Institute (NHLBI), 9000 Rockville Pike   Bethesda,   Maryland,    20892,   United States; Recruiting

PRPL     Warren G. Magnuson Clinical Center National Institutes of Health   Bethesda,    Maryland,   20892-4754,   United States  1-800-411-1222    prpl@mail.cc.nih.gov  

More Information

Detailed Web Page

Publications that lead up to this study

Gryglewski. 1988. Mediators produced by the endothelial cell, Hypertension, Vol. 12, p. 530

Vane. 1990. Regulatory functions of the vascular endothelium, N Engl J Med, Vol. 323, p. 27

Kiowski. 1991. Endothelin-1-induced vasoconstriction in humans Reversal by calcium channel blockade but not by nitrovasodilators or endothelium-derived relaxing factor, Circulation, Vol. 83, p. 469

Study ID Numbers  99-H-0066

NLM Identifier  NCT00001882

Date study started March 17, 1999

Recruitment status verified  February 28, 2000

Last Updated  February 28, 2000

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