Endothelin-1 and Vascular Tone in Subjects With Atherogenic Risk Factors

Abstract

Abstract-Endothelin-1 (ET-1) is a potent vasoconstrictor that increases vascular tone in the resistance vessels of subjects with hypertension. It is unclear whether endogenous ET-1 affects resistance-vessel function equally in patients with other cardiovascular risk factors. Vasoconstriction to ET-1 is mediated principally via the endothelin-A (ET A ) receptor on vascular smooth muscle cells. Accordingly, we used an ET A -specific antagonist, BQ-123, to test the hypothesis that endogenous ET-1 increases vascular resistance selectively in subjects with hypertension compared with other risk factors. BQ-123 was infused at 100 nmol/min for 80 minutes into the brachial artery of 10 subjects with hypertension (meanϮSEM arterial pressure, 106Ϯ5 mm Hg), 12 subjects with hypercholesterolemia (meanϮSEM total cholesterol, 7.1Ϯ0.2 mmol/L), 10 active smokers (meanϮSEM, 42Ϯ11 pack-years), and 11 healthy, age-matched individuals. ET-1 levels are elevated in patients with atherosclerosis, 10 and atherosclerotic coronary lesions exhibit enhanced ET-1-mediated vascular tone. 11,12 Risk factors for atherosclerosis are also associated with elevated plasma ET-1 levels. [13][14][15][16][17][18][19] Several studies have found that endogenous ET-1 causes vasoconstriction in the resistance vessels of subjects with hypertension. 20 -22 One group has reported that ET-1 also contributes to vascular tone in subjects with hypercholesterolemia, 23 and there are conflicting reports regarding the response to ET-1 blockade in diabetic individuals. 24,25 There have been no studies evaluating the role of endogenous ET-1 in cigarette smokers. There has also been a difference of opinion regarding the effect of ET-1 on vascular resistance in healthy individuals. 4,7,20,22,23 The fact that these observations come from several different laboratories makes it difficult to gauge whether ET-1 contributes to vascular tone equally among the various cardiac risk factors.To evaluate the relative contribution of ET-1 to vasomotor dysfunction in patients with atherogenic risk factors, we performed a single, comparative study with an ET A -selective antagonist, , to compare the activity of endogenous ET-1 in the forearm resistance vessels of subjects with hypertension, hypercholesterolemia, and cigarette smokers, relative to healthy volunteers. Methods Subject SelectionThe study population consisted of 10 subjects with hypertension (systolic blood pressure Ͼ140 mm Hg or diastolic blood pressure Ͼ90 mm Hg), 12 subjects with hypercholesterolemia (fasting cholesterol Ͼ75th percentile for age and gender), 10 active cigarette smokers (average of Ն1 pack/d for Ն3 years), and 11 healthy, age-matched controls. Subjects were recruited by advertisement in local newspapers and provided written, informed consent. Subjects were screened by history, physical examination, and routine biochemical analyses. Subjects with risk factors were excluded if they

Acute Effect of Sildenafil Is Maintained in Pulmonary Arterial Hypertension Patients Chronically Treated With Bosentan

“…On the other hand, endothelin antagonism has been reported to markedly improve NO-production/bioavailability, resulting in enhancement of the vasodilating effect in most types of atherosclerotic diseases. [18][19][20][21][22][23][24][25][26] This has also been reported in patients with PAH due to collagen diseases. 27,28) The vasodilating effect of sildenafil definitely requires cGMP-production and is also thought to be synergistically exerted in well-ventilated lung areas possessing an intact NO-cGMP system where NO is more abundant than in lung areas with ventilation disorders and/or an impaired NO-cGMP system.…”

Dyslipidemia and the Risk of Incident Hypertension in Men

“…Atherogenic lipid abnormalities clearly cause endothelial dysfunction. 4 A dysfunctional endothelium, possibly through impaired nitric oxide production and activity, as well as alterations in endothelin-1 and endothelin A and B receptor expression, 24 cannot respond to changes in intravascular conditions to constrict and dilate as needed. This vasodysregulation could lead to an inability or difficulty in vasodilatation to appropriate stimuli and eventually to increased resting BP.…”

Association of single nucleotide polymorphisms in endothelin family genes with the progression of atherosclerosis in patients with essential hypertension

“…[6][7][8][9] Endogenous ET-1, which acts via EDNRA, increases resistance-vessel tone in subjects with hypertension to a level greater than that in smokers and in subjects with hypercholesterolemia. 10 Plasma ET-1 concentrations can be reduced by resistance training and aerobic exercise. 11 Pulse wave velocity (PWV) is generally recognized as a surrogate marker for atherosclerosis.…”