Endothelin Antagonism Uncovers Insulin-Mediated Vasorelaxation In Vitro and In Vivo

Verma, Subodh; Yao, Linfu; Stewart, Duncan J.; Dumont, Aaron S.; Anderson, Todd J.; McNeill, John H.

doi:10.1161/01.hyp.37.2.328

Cited by 46 publications

(43 citation statements)

References 24 publications

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“…45 During hyperinsulinemia, insulin-mediated production of endothelin may increase and induce the vasoconstriction associated with endothelial dysfunction. [46][47][48] Further study is needed to clarify the relationship between insulin resistance and endothelial dysfunction. This is the first report to use the catheter-type NO sensor to directly show a decrease in NO bioavailability in high-fatdiet-induced obese dogs.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of Coronary Endothelial Function by Catheter-Type NO Sensor in High-Fat-Diet-Induced Obese Dogs

Kume

Kawamoto

Okura

et al. 2009

Circ J

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Circ J 2009; 73: 562 -567 n the coronary circulation, endothelium-derived nitric oxide (NO) plays a fundamental role in the regulation of blood flow, exerting a tonic vasodilator influence at rest and with increasing myocardial metabolism. 1 The bioavailability of NO is thought to be diminished in subjects with various coronary risk factors and/or pathologic conditions, such as aging, gender, obesity, hypertension, hypercholesterolemia, diabetes mellitus, and metabolic syndrome. [2][3][4][5][6][7][8][9][10][11][12] Thus, endothelial dysfunction, characterized by decreased bioavailability of NO, has been recognized as a predictor of cardiovascular risk and outcome. [13][14][15][16][17] Editorial p 434Coronary endothelial function is most commonly assessed by intracoronary injection of acetylcholine (ACh), which stimulates release of NO and dilates the coronary arteries, but in patients with coronary endothelial dysfunction, infusion of ACh results in paradoxical vasoconstriction. [18][19][20][21][22] This method is widely used in diagnosing coronary vasospastic angina. 17,23 However, there are still many uncertainties about the bioavailability of NO and the precise dynamics of NO have not been investigated. In order to evaluate both endothelial function and the bioavailability of NO in the coronary circulation, direct measurement of the NO concentration in the coronary circulation would be of great value. Recently, we developed a catheter-type NO sensor and demonstrated its validity for in-vivo measurement of NO in the coronary circulation. [24][25][26][27] The purpose of this study was to evaluate the influence of a high-fat diet on the bioavailability of NO by using the catheter-type NO sensor in vivo. MethodsThis study conformed to the Guideline for Care and Use of Laboratory Animals published by the National Institutes of Health (NIH publication No. 85-23, revised 1985) and was conducted under protocols approved by the Kawasaki Medical School Animal Care and Use Committee. High-Fat DietMongrel dogs (n=8) were assigned to either a control group (n=3) that received a regular diet (60 kcal · kg -1 · day -1 ) for 8 months or a high-fat-diet group (n=5; MANINE i/d dryTM, Hill's Nutrition Diet Inc, USA: 60 kcal · kg -1 · day -1 + lard 60 kcal · kg -1 · day -1 ) for 8 months. 28 Catheter-Type NO SensorThe NO sensor (amiNO-700 XL, Innovative Instruments, Tampa, FL, USA; 700 μm in diameter at the tip) was mounted in a 4Fr catheter (1,200 mm long; Hirakawa Hewtech, Tokyo, Japan) and fixed with silicon adhesive. The oxidative current of NO was monitored continuously. (Received August 24, 2008; revised manuscript received October 20, 2008; accepted November 5, 2008; released online February 3, 2009 (n=5) were fed a high-fat diet (120 kcal · kg -1 · day -1 ) for 8 months, then endothelial function was assessed by the change in NO concentration induced by acetylcholine (ACh) (∆NO). Simultaneously, average peak velocity (APV) was obtained by Doppler guide wire. Although fasting plasma glucose levels did not change a...

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Section: Discussionmentioning

confidence: 99%

Evaluation of Coronary Endothelial Function by Catheter-Type NO Sensor in High-Fat-Diet-Induced Obese Dogs

Kume

Kawamoto

Okura

et al. 2009

Circ J

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“…8,9 We and others have shown previously that in resistance arteries of skeletal muscle, NO-dependent vasodilator effects of insulin are antagonized by endothelin-mediated vasoconstrictor effects. Selective impairment of the vasodilator effects of insulin in these arteries results in insulin-mediated vasoconstriction.…”

Section: Conclusion-tnf-␣mentioning

confidence: 97%

Physiological Concentrations of Insulin Induce Endothelin-Dependent Vasoconstriction of Skeletal Muscle Resistance Arteries in the Presence of Tumor Necrosis Factor-α Dependence on c-Jun N-Terminal Kinase

Eringa

Stehouwer

Walburg

et al. 2006

ATVB

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Objective-Tumor necrosis factor-␣ (TNF-␣) has been linked to obesity-related insulin resistance and impaired endothelium-dependent vasodilatation, but the mechanisms have not been elucidated. To investigate whether TNF-␣ directly impairs insulin-mediated vasoreactivity in skeletal muscle resistance arteries and the role of c-Jun N-terminal kinase (JNK) in this interference. Methods and Results-Insulin-mediated vasoreactivity of isolated resistance arteries of the rat cremaster muscle to insulin (4 to 3400 U/mL) was studied in the absence and presence of TNF-␣ (10 ng/mL). Although insulin or TNF-␣ alone did not affect arterial diameter, insulin induced dose-dependent vasoconstriction of cremaster resistance arteries in the presence of TNF-␣, (Ϫ12Ϯ1% at 272 U/mL). Blocking endothelin receptors in the absence of TNF-␣ uncovered insulin-mediated vasodilatation (18Ϯ6% at 272 U/mL) but not in the presence of TNF-␣ (2Ϯ2% at 272 U/mL), showing that TNF-␣ inhibits vasodilator effects of insulin. Using digital imaging microscopy, we discovered that TNF-␣ activates JNK in arterial endothelium, visible as an increase in phosphorylated JNK. Moreover, inhibition of JNK with the cell-permeable peptide inhibitor L-JNKI abolished insulin-mediated vasoconstriction in the presence of TNF-␣, showing that JNK is required for interaction between TNF-␣ and insulin. Key Words: cytokines Ⅲ endothelin Ⅲ endothelium Ⅲ insulin resistance Ⅲ microcirculation Ⅲ vascular biology I mpairment of insulin-mediated glucose disposal (ie, insulin resistance) is associated with obesity 1 and hypertension. 2 Increased production of the proinflammatory cytokine tumor necrosis factor-␣ (TNF-␣) is associated with obesity-related insulin resistance 3,4 as well as obesity-related hypertension. 5 The mechanisms behind these relationships have not been elucidated. Conclusions-TNF-␣We and others hypothesized that impaired endotheliumdependent vasodilatation plays an important role in insulin resistance and hypertension. 6 Impaired endotheliumdependent vasodilatation increases vascular resistance, which, in muscle, may contribute to decreased insulinmediated glucose disposal. 7 A specific type of endotheliumdependent vasodilatation that may be relevant in this regard is insulin-mediated vasodilatation.Vasodilator and vasoconstrictor effects of insulin have been described, and the normal response to insulin is thought to be vasodilator or neutral. 8,9 We and others have shown previously that in resistance arteries of skeletal muscle, NO-dependent vasodilator effects of insulin are antagonized by endothelin-mediated vasoconstrictor effects. Selective impairment of the vasodilator effects of insulin in these arteries results in insulin-mediated vasoconstriction. 8,10 Physiological factors that cause such a selective impairment of insulinmediated vasoreactivity have not been identified.TNF-␣ has been proposed to impair vasodilator effects of insulin in the skeletal muscle microcirculation. 8,21 Furthermore, in macrovascular endothelial cells, TNF-␣ has been shown t...

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“…In addition, it is feasible that endothelin could have contributed to such an effect, since GI 262570, which increases insulin sensitivity, could thereby stimulate endothelin release (Misurski et al, 2001;Verma et al, 2001), although there is also evidence that PPAR-␥ activators inhibit endothelin release from endothelial cells (Delerive et al, 1999;Satoh et al, 1999;Fukunaga et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Regional Hemodynamic Effects of the N-(2-Benzoylphenyl)-l-tyrosine Peroxisome Proliferator-Activated Receptor-γ Ligand, GI 262570 [(S)-2-(2-Benzoylphenylamino)-3-[4-[2-(5-methyl-2-phenyl-2-oxazol-4-yl)ethoxy]phenyl]propionic Acid], in Conscious Rats

Gardiner¹,

Nunez²,

Baer³

et al. 2004

J Pharmacol Exp Ther

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This study provides novel data on the regional hemodynamic effects of the peroxisome proliferator-activated receptor-␥ activator, GI 262570 [(S)-2-(2-benzoylphenylamino)-3-[4-[2-(5-methyl-2-phenyl-2-oxazol-4-yl)ethoxy]phenyl]propionic acid], in conscious, male Sprague-Dawley rats. Administration of GI 262570 twice daily for 4 days caused a slowly developing, modest fall in mean arterial blood pressure, associated with a progressive, hyperemic hindquarters vasodilatation, but with no consistent changes in renal or mesenteric hemodynamics. The hindquarters vasodilator effect of GI 262570 was not inhibited by the ␤ 2 -adrenoceptor antagonist, ICI 118551 ((Ϯ)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl) amino]-2-butanol hydrochloride), and was still apparent in the presence of the ␣-adrenoceptor antagonist, phentolamine. Neither the latter, nor antagonism of angiotensin (AT 1 ) and endothelin (ET A and ET B ) receptors unmasked vasodilator responses to GI 262570 in the renal or mesenteric vascular beds. In the presence of GI 262570, vasodilator responses to acetylcholine and vasoconstrictor responses to methoxamine were normal. Furthermore, the cardiovascular responses to nonselective nitric-oxide synthase inhibition were not influenced by GI 262570. Collectively, these results indicate that the vasodilator action of GI 262570 is specific to the hindquarters vascular bed (of those studied), does not involve ␣-or ␤ 2 -adrenoceptors, and is not associated with a change in basal or stimulated nitric oxide release.The thiazolidinediones were shown to enhance insulin sensitivity before it was known that they were activators of PPAR-␥ (Spiegelman, 1998;Willson et al., 2000Willson et al., , 2001Rosen and Spiegelman, 2001). Although PPAR-␥ is highly expressed in fat, it occurs in muscle and liver as well, and, to a lesser extent, in tissues of the cardiovascular system (Spiegelman, 1998;Bishop-Bailey, 2000). In the latter context, it is now apparent that the thiazolidinediones may influence cardiovascular function, particularly in patients with diabetes mellitus (Mudaliar and Henry, 2001;Martens et al., 2002), but it is not clear to what extent this involves PPAR-␥-dependent or -independent effects, changes in insulin sensitivity, and/or modulation of inflammatory processes (Spiegelman, 1998;Rosen and Spiegelman, 2001;Klappacher and Glass, 2002;Rival et al., 2002;Shiojiri et al., 2002). Moreover, the acute hemodynamic effects of PPAR-␥ activation in the nondiabetic state have not been described in detail.A novel series of N-(2-benzoylphenyl)-L-tyrosine compounds has been identified as potent PPAR-␥ agonists (Cobb This study was undertaken with financial support from GlaxoSmithKline. Some of the results reported herein have been presented to the British Pharmacological Society (Gardiner et al., 2002a).Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

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Endothelin Antagonism Uncovers Insulin-Mediated Vasorelaxation In Vitro and In Vivo

Cited by 46 publications

References 24 publications

Evaluation of Coronary Endothelial Function by Catheter-Type NO Sensor in High-Fat-Diet-Induced Obese Dogs

Evaluation of Coronary Endothelial Function by Catheter-Type NO Sensor in High-Fat-Diet-Induced Obese Dogs

Physiological Concentrations of Insulin Induce Endothelin-Dependent Vasoconstriction of Skeletal Muscle Resistance Arteries in the Presence of Tumor Necrosis Factor-α Dependence on c-Jun N-Terminal Kinase

Regional Hemodynamic Effects of the N-(2-Benzoylphenyl)-l-tyrosine Peroxisome Proliferator-Activated Receptor-γ Ligand, GI 262570 [(S)-2-(2-Benzoylphenylamino)-3-[4-[2-(5-methyl-2-phenyl-2-oxazol-4-yl)ethoxy]phenyl]propionic Acid], in Conscious Rats

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