Endothelin Antagonism Uncovers Insulin-Mediated Vasorelaxation In Vitro and In Vivo (original) (raw)
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Insulin Stimulates Both Endothelin and Nitric Oxide Activity in the Human Forearm
Circulation, 1999
Background-The mechanism of the hemodynamic effect of insulin in the skeletal muscle circulation has not been fully elucidated. The purpose of this study was to assess whether the hemodynamic response to insulin involves the concurrent release of endothelin (ET-1) and nitric oxide (NO), 2 substances with opposing vasoactive properties. Methods and Results-Bioactivity of ET-1 and NO was assessed without insulin and during insulin infusion in the forearm circulation of healthy subjects by use of blockers of ET-1 receptors and by NO synthesis inhibition. In the absence of hyperinsulinemia, ET-1 receptor blockade did not result in any significant change in forearm blood flow from baseline (Pϭ0.29). Intra-arterial insulin administration did not significantly modify forearm blood flow (Pϭ0.88). However, in the presence of hyperinsulinemia, ET-1 receptor antagonism was associated with a significant vasodilator response (PϽ0.001). In the presence of ET-1 receptor blockade, the vasoconstrictor response to NO inhibition by N G -monomethyl-L-arginine was significantly higher after insulin infusion than in the absence of hyperinsulinemia (Pϭ0.006). Conclusions-These findings suggest that in the skeletal muscle circulation, insulin stimulates both ET-1 and NO activity.
AJP: Heart and Circulatory Physiology, 2007
Regulation of vascular tone and blood flow involves interactions between numerous local and systemic vascular control signals, many of which are altered by Type 2 diabetes (T2D). Vascular responses to endothelin-1 (ET-1) are mediated by endothelin type A (ETA) and type B (ETB) receptors that have been implicated in cross talk with α1-adrenoceptors (α1-AR). ETA and ETB receptor expression and plasma ET-1 levels are elevated in T2D; however, whether this influences coronary α1-AR function has not been examined. Therefore, we examined the effect of ETA and ETB receptor inhibition on coronary vasoconstriction to ET-1 and α1-AR activation in a mouse model of T2D. Coronary vascular responses were examined in isolated mouse hearts from control and diet-induced T2D C57BL/6J mice. Responses to ET-1 and the selective α1-AR agonist phenylephrine (PE) were examined alone and in the presence of the nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester (l-NAME) alone or in combination ...
Review: Insulin and endothelin: an interplay contributing to hypertension development?
The Journal of clinical endocrinology and metabolism, 2007
The aim of this article was to review the existing data on the interactions among insulin, insulin resistance, and endothelin and how those contribute to the development of hypertension in insulin-resistant states. A literature search of MEDLINE database was performed to identify English-language articles published during the last 20 yr. Search terms used were endothelin, insulin, insulin resistance, and hyperinsulinemia in combination with blood pressure and hypertension. Reference lists of retrieved articles were also evaluated for relevant information. Several mechanisms connect insulin resistance and compensatory hyperinsulinemia with blood pressure elevation in the context of the metabolic syndrome, i.e. sodium retention, sympathetic activation, and impairment of endothelial nitric oxide production. Accumulating evidence suggests that activation of the endothelin system seems to be another important, yet less discussed, mechanism. In vitro studies have shown that insulin stimul...
AJP: Heart and Circulatory Physiology, 2003
Insulin resistance is a risk factor for atherosclerosis, and is associated with hyperinsulinemia, abnormal lipid profile and hypertension. Whether hyperinsulinemia affects vascular function independent of insulin resistance or other metabolic risk factors is unknown. This investigation aimed to assess the effects of hyperinsulinemia on endothelial function in subjects with a spectrum of insulin sensitivity and lipid profile. Endothelium-dependent (flow-mediated dilation, FMD) and -independent (nitroglycerin) responses of the brachial artery were studied by high-resolution ultrasound before and during hyperinsulinemia (euglycemic clamp) in 25 normoglycemic, normotensive subjects. Participants were divided in an insulin sensitive and an insulin resistant subgroup based on their sensitivity index (SI Clamp ) values, with a cutoff of 8, and in a normal cholesterol and a high cholesterol subgroup based on their total cholesterol levels, with a cutoff of 5.2 mmol/L (200 mg/dL). In the whole population, FMD was lower during hyperinsulinemia compared to baseline (2.3±0.6% vs 6±0.6%, respectively; P<0.001). Resting FMD was lower in the insulin resistant compared to the insulin sensitive subgroup (4.2±0.9% vs 7.4±0.8%, respectively; P=0.014), and in the high cholesterol compared to the normal cholesterol subjects (4.4±0.7% vs 8±0.7%, respectively; P=0.002). Hyperinsulinemia decreased FMD in both the insulin sensitive (from 7.4±0.8% to 3.6±0.4%; P<0.001) and the insulin resistant subgroup (from 4.2% to 1.22%; P=0.012), and in both the normal cholesterol (from 8±0.7% to 3.9±0.4%; P<0.001) and high cholesterol (from 4.4±0.7% to 1.1±0.8%; P=0.01) participants. Acute hyperinsulinemia impairs conduit vessel endothelial function independent of insulin sensitivity and lipid profile. Insulin may trigger endothelial dysfunction and promote atherosclerosis. Insulin causes endothelial dysfunction in humans. Sites and mechanisms. Circulation 105:576-582, 2002. 2. Caballero AE, Saouaf R, Lim SC, Hamdy O, Habou-Elenin K, O'Connor C, Lagerfo FW, Horton ES, Veves A. The effects of troglitazone, an insulin-sensitizing agent, on the endothelial function in early and late type 2 diabetes: a placebo-controlled randomized clinical trial. Metabolism 52:173-180, 2003. 3. Calles-Escandon J, Mirza SA, Sobel BE, Schneider DJ. Induction of hyperinsulinemia combined with hypertriglyceridemia increases plasminogen activator inhibitor 1 in blood in normal human subjects. Diabetes 47:290-293, 1998. 4. Cardillo C, Kilcoyne CM, Nambi SS, Cannon RO, Quon MJ, Panza JA. Vasodilator response to systemic but not to local hyperinsulinemia in the human forearm.
Life Sciences, 1989
Summarv The systemic and regional hemodynamic effects of endothelin (ET), a novel endothelial derived vasoconstrictor peptide were studied in Wistar Kyoto rats. A bolus of 1 nmol/Kg ET intravenously induced a transient 43% decrease in blood pressure associated with a 57% decrease in systemic resistance and a 30% increase in cardiac output (p<0.01 for all parameters). This was followed by an increase of 20% in arterial pressure and of 71% in systemic resistance and a decrease of 30% in cardiac output at 10 minutes. The initial fall in blood pressure was not abolished by pretreatment with verapamil, captopril, indomethacin, ketanserin, atropine, methylene blue or ethanol. Verapamil abolished the hypertensive phase by markedly decreasing cardiac output. ET had selective effects on the arterial tree; during the hypotensive phase it caused a transient increase in blood flow in the carotid and femoral arteries (+41% and +83% respectively, p<0.01) but a decrease in flow in the renal and mesenteric arteries (-53% and-44% respectively, p<0.05). Accordingly, there was a decrease in resistance in the carotid and femoral beds (-55% and-67% respectively, p<0.01) and an increase in resistance in the renal and mesenteric beds (+102 %; p<0.01 and +23%; p= N.S. respectively). Subsequently there was an increase in resistance in all vascular beds to variable degrees. The maximal increase in resistance was in the renal bed (+156 %). Thus, ET causes initially a potent systemic vasorelaxation and an increase in cardiac output later progressing Io systemic vasoconstriction and a decrease in cardiac output. The initial vasodilation is selective, appearing in musculocutaneous beds but not in visceral beds. The role of the endothelial cell layer in modulating vascular tone has been recognized since the observations of Furchgott and Zawadzki (1). In addition to the endothelium derived relaxing factor (EDRF) that they described, constricting factor(s) were also found to be released from endothelial cells (2). Endothelin (ET), a 21 amino-acid residue polypeptide isolated recently from endothelial cell culture media, is reported to be one of the most potent vasoconstrictors known (3). Its effects on a variety of arteries in vitro are gradual, prolonged, dose dependent, endothelium independent and difficult to wash out (4). It is thought that this effect is due to activation of ion channels with a rapid increase in intracellular calcium over a few seconds followed by a gradual decline to a level 50-100% higher than the baseline (5). Accordingly, it was proposed that ET may have a physiological role in long term regulation of blood pressure (3). However, in vivo effects are somewhat unexpected: a bolus injection of ET produces a
Role of Endothelin in Diabetic Vascular Complications
Endocrine, 2001
Endothelin-1 (ET-1), a 21 amino acid peptide originally purified from conditioned medium of cultures of porcine aortic endothelial cells, is recognized as a product of many other cells as well. It is now known that there are three endothelin genes in the human genome (ET-1, ET-2, and ET-3). ET-1 and ET-2 are both strong vasoconstrictors, whereas ET-3 is a potentially weaker vasoconstrictor than the other two isoforms. Besides being the most potent vasoconstrictor yet known, ET-1 also acts as a mitogen on the vascular smooth muscle, and, thus, it may play a role in the development of vascular diseases. It is well known that accelerated angiopathy is a major complication in diabetes mellitus. As generalized endothelial cell damage is thought to occur in diabetic patients, ET-1, being released from the damaged endothelial cells, is able to make contact with the underlying vascular smooth muscle cells and thus could be one important cause of diabetic angiopathy. This article summarizes the reported literature of the role of ET-1 in the development of diabetic complications, with particular focus on the possible role of ET-1 in mediating the effects of angiotensin-converting enzyme inhibitors.
In-vivo interaction of nitric oxide and endothelin
Objective and methods Endothelin-1 (ET-1) was initially characterized as a potent vasoconstrictor. However, the expected role of ET-1 as a major blood pressure controlling peptide could not be clearly established. Moreover, ET-1 transgenic mice are not hypertensive. We assume that counter-regulating mechanisms such as the nitric oxide (NO) system or an altered expression of endothelin receptors might cause this finding.