Insulin-induced vasodilation is dependent on tetrahydrobiopterin synthesis

Verma, Subodh; Arikawa, Emi; Yao, Linfu; Laher, Ismail; McNeill, John H.

doi:10.1016/s0026-0495(98)90273-6

Cited by 28 publications

(16 citation statements)

References 16 publications

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“…According to the contemporary conceptual framework, insulin stimulates BH 4 synthesis via activation of GTP cyclohydrolase-1, whereas in insulin-resistant states these effects are impaired (33,35). The oxidative stress associated with insulin resistance may influence endothelial cell function through a depletion of BH 4 because the biosynthesis of BH 4 depends on a normal cellular redox state (16,25).…”

Section: Discussionmentioning

confidence: 99%

Tetrahydrobiopterin increases insulin sensitivity in patients with type 2 diabetes and coronary heart disease

Nyström¹,

Nygren²,

Sjöholm³

2004

American Journal of Physiology-Endocrinology and Metabolism

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Section: Discussionmentioning

confidence: 99%

Tetrahydrobiopterin increases insulin sensitivity in patients with type 2 diabetes and coronary heart disease

Nyström¹,

Nygren²,

Sjöholm³

2004

American Journal of Physiology-Endocrinology and Metabolism

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“…vasodilation. Fourth, the component of insulin-mediated vasodilation observed after ET blockade was BH 4 -dependent because these responses were prevented by inhibition of BH 4 synthesis by DAHP (during concurrent ET receptor blockade). Taken together, these data support the notion that at low/subthreshold concentrations, insulin-induced stimulation of ET-1 production may serve to inhibit vasorelaxation by antagonizing the effects of insulin on endothelium-dependent NO production in a BH 4 dependent fashion.…”

Section: Discussionmentioning

confidence: 99%

“…Our reasons to use DAHP to inhibit endothelium-dependent relaxation were based on studies in rat arteries that indicated that insulin-mediated vasodilation is dependent on BH 4 synthesis. 4 …”

Section: Study 5: Effects Of Dahp On the Vascular Responses To Insulimentioning

confidence: 99%

“…2 In this regard, insulin can stimulate the production of tetrahydrobiopterin (BH 4 )-dependent nitric oxide (NO) formation while concurrently augmenting the production of the potent endotheliumderived vasoconstrictor endothelin-1 (ET-1) (Figure 1). 3,4 Although insulin-induced vasorelaxation occurs at physiological concentrations in humans, this effect appears to be mainly a pharmacological one in rat aortas. The mechanism underlying the lack of insulin-mediated dilation at low/ subthreshold concentrations (in vitro) remains unknown but could relate to the simultaneous production of ET-1 by insulin.…”

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confidence: 99%

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

et al. 2001

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Abstract-The endothelial actions of insulin remain an area of intense research because they relate to both insulin sensitivity and vascular tone. Physiological doses of insulin evoke endothelium-dependent vasorelaxation in humans; however, this remains a pharmacological phenomenon in rat aortas. Because insulin may stimulate the divergent production of both nitric oxide and endothelin-1, we hypothesized that the lack of insulin-induced vasorelaxation at low/subthreshold concentrations may be due to the concurrent production of endothelin-1, which in turn serves to inhibit nitric oxide-dependent, insulin-mediated dilation. To investigate this, we studied the effects of subthreshold concentrations of insulin (100 mU/L) on norepinephrine-induced contraction in rat aortas following short-term and long-term endothelin blockade. In addition, the effects of tetrahydrobiopterin inhibition (with diaminohydroxyprimidine) on norepinephrine-induced contraction in the presence of insulin and endothelin receptor blockade were investigated. Subthreshold concentrations of insulin failed to evoke vasorelaxation in rat aortas. Strikingly, short-term endothelin A/B receptor blockade with bosentan (10 Ϫ2 mmol/L) uncovered insulin-mediated dilation; the percent maximum contraction and sensitivity of aortas to norepinephrine were attenuated (% maximum relaxation: bosentanϩinsulin 74Ϯ4%* versus bosentan 92Ϯ3%, insulin 107Ϯ5% PϽ0.002; pD 2 values: bosentanϩinsulin 6.87Ϯ0.14* versus bosentan 7.40Ϯ0.15, insulin 7.63Ϯ0.11, *PϽ0.002). This effect was mediated through endothelin A receptors because bosentan and BQ-123 (10 Ϫ2 mmol/L) attenuated norepinephrine-induced contraction to a similar degree. In addition, insulin evoked vasorelaxation in aortas isolated from rats after long-term bosentan treatment (100 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 , 3 weeks). The component of insulin-mediated vasorelaxation uncovered by endothelin receptor blockade was tetrahydrobiopterindependent because it was reversed by diaminohydroxyprimidine. These data demonstrate, for the first time, the functional interaction between insulin, endothelin-1, and tetrahydrobiopterin in modulating vascular tone in rat aortas in vitro and in vivo. Key Words: insulin Ⅲ endothelin Ⅲ vasodilation Ⅲ insulin resistance Ⅲ hypertension Ⅲ rat aorta Ⅲ tetrahydrobiopterin Ⅲ bosentan T he vascular actions of insulin represent an area of much current interest as they relate to both whole-body glucose metabolism/insulin sensitivity and vascular tone/hypertension. 1,2 The balance of published information suggests that the vascular actions of insulin are mediated chiefly through the regulation of endothelium-derived factors. 2 In this regard, insulin can stimulate the production of tetrahydrobiopterin (BH 4 )-dependent nitric oxide (NO) formation while concurrently augmenting the production of the potent endotheliumderived vasoconstrictor endothelin-1 (ET-1) (Figure 1). 3,4 Although insulin-induced vasorelaxation occurs at physiological concentrations in humans, this effect appears to be mainly a pharmacol...

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“…Only insulin induced a significant pulmonary arterial muscle relaxation, suggesting that it is the factor responsible for the cell-independent culture media effect. Others have previously reported that insulin induces vascular smooth muscle relaxation via an endothelium-dependent and likely eNOS-mediated mechanism (24), and this is operative in rat pulmonary arteries (2). L-NIO significantly reduced the non-conditioned media (BEGM)-induced relaxation, suggesting that this response is eNOSmediated.…”

Section: Discussionmentioning

confidence: 99%

Airway epithelial-derived factor relaxes pulmonary vascular smooth muscle

Farah

Li²,

McIntyre³

et al. 2009

American Journal of Physiology-Lung Cellular and Molecular Phys

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Farah OR, Li D, McIntyre BA, Pan J, Belik J. Airway epithelialderived factor relaxes pulmonary vascular smooth muscle. Am J Physiol Lung Cell Mol Physiol 296: L115-L120, 2009. First published October 24, 2008 doi:10.1152/ajplung.90391.2008.-The factors controlling the pulmonary vascular resistance under physiological conditions are poorly understood. We have previously reported on an apparent cross talk between the airway and adjacent pulmonary arterial bed where a factor likely derived from the bronchial epithelial cells reduced the magnitude of agonist-stimulated force in the vascular smooth muscle. The main purpose of this investigation was to evaluate whether bronchial epithelial cells release a pulmonary arterial smooth muscle relaxant factor. Conditioned media from SPOC-1 or BEAS-2B, a rat-and a human-derived bronchial epithelial cell line, respectively, were utilized. This media significantly relaxed precontracted adult but not fetal pulmonary arterial muscle in an oxygen tension-dependent manner. This response was mediated via soluble guanylate cyclase, involving AKT/PI3-kinase and neuronal nitric oxide synthase. Airway epithelial cell-conditioned media increased AKT phosphorylation in pulmonary smooth muscle cells (SMC) and reduced intracellular calcium change following ATP stimulation to a significantly greater extent than observed for bronchial SMC. The present data strongly support the evidence for bronchial epithelial cells releasing a stable and soluble factor capable of inducing pulmonary arterial SMC relaxation. We speculate that under physiological conditions, the maintenance of a low pulmonary vascular resistance, postnatally, is in part modulated by the airway epithelium. pulmonary hypertension; pulmonary vascular resistance; fetal; hypoxic pulmonary vasoconstriction response WE HAVE SHOWN THAT THE PRESENCE of an attached bronchus significantly reduces the rat pulmonary arterial smooth muscle contraction via a mechanism that appeared to be airway epithelium dependent (3). We reasoned that the bronchial epithelium releases a factor capable of relaxing the adjacent pulmonary arterial smooth muscle and coined the term bronchial epithelium-derived relaxing factor (BrEpRF). The fact that BrEpRF activity/expression was absent in fetal pulmonary arteries and under low oxygen concentration (4) led us to suggest that this factor is released under physiological conditions and may have an important role in the regulation of the pulmonary vascular resistance.Our previous data demonstrated that the adjacent airway tissue modulated the pulmonary arterial smooth muscle, but the cells responsible for the release of this relaxing factor and its signaling pathway was not known. The purpose of the present study was to determine whether isolated bronchial epithelial cells are capable of releasing a pulmonary arterial muscle relaxing factor in vitro and to examine its downstream targets. Based on our previous studies (3, 4), we hypothesized that these cells secrete BrEpRF, which in turn relaxes pulmonary smooth mu...

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Insulin-induced vasodilation is dependent on tetrahydrobiopterin synthesis

Cited by 28 publications

References 16 publications

Tetrahydrobiopterin increases insulin sensitivity in patients with type 2 diabetes and coronary heart disease

Tetrahydrobiopterin increases insulin sensitivity in patients with type 2 diabetes and coronary heart disease

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

Airway epithelial-derived factor relaxes pulmonary vascular smooth muscle

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