Troglitazone Reduces Contraction by Inhibition of Vascular Smooth Muscle Cell Ca2+ Currents and Not Endothelial Nitric Oxide Production

Song, Jianben; Walsh, Mary F.; Igwe, Robert C.; Ram, Jeffrey L.; Barazi, M; Domínguez, Ligia J.; Sowers, James R.

doi:10.2337/diab.46.4.659

Cited by 75 publications

(53 citation statements)

References 40 publications

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“…Thus, the explanation for the observed increase in muscle blood flow among lean Ala12 carriers is unclear. PPARγ activation is known to modify vascular responsiveness in vivo [31][32][33] and in vitro [34][35][36], but the effect of PPARγ2 Pro12Ala polymorphism has never been assessed previously. Thus, Ala12 carriers appear to have a constitutively higher blood flow compared with Pro12 homozygotes.…”

Section: Discussionmentioning

confidence: 99%

The in vivo effects of the Pro12Ala PPARγ2 polymorphism on adipose tissue NEFA metabolism: the first use of the Oxford Biobank

et al. 2005

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Aims/hypothesis: To investigate the phenotypic effects of common polymorphisms on adipose tissue metabolism and cardiovascular risk factors, we set out to establish a biobank with the unique feature of allowing a prospective recruit-by-genotype approach. The first use of this biobank investigates the effects of the peroxisome proliferatoractivated receptor-γ (PPARγ) Pro12Ala polymorphism on integrative tissue-specific physiology. We hypothesised that Ala12 allele carriers demonstrate greater adipose tissue metabolic flexibility and insulin sensitivity. Materials and methods: From a comprehensive population register, subjects were recruited into a biobank, which was genotyped for the Pro12Ala polymorphism. Twelve healthy male Ala12 carriers and 12 matched Pro12 homozygotes underwent detailed physiological phenotyping using stable isotope techniques, and measurements of blood flow and arteriovenous differences in adipose tissue and muscle in response to a mixed meal containing [1,1,[1][2][3][4][5][6][7][8][9][10][11][12][13]

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Section: Discussionmentioning

confidence: 99%

The in vivo effects of the Pro12Ala PPARγ2 polymorphism on adipose tissue NEFA metabolism: the first use of the Oxford Biobank

et al. 2005

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“…Research in animal models has shown that troglitazone and pioglitazone caused peripheral vasodilation, which was mediated by prostaglandin production associated with increased calcium fluxes in smooth muscle (85,86). There also may be differential effects between rosiglitazone and troglitazone on human small arteries (87).…”

Section: Effects Of Reducingmentioning

confidence: 99%

Dermal Neurovascular Dysfunction in Type 2 Diabetes

et al. 2001

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OBJECTIVE -To review evidence for a relationship between dermal neurovascular dysfunction and other components of the metabolic syndrome of type 2 diabetes.RESEARCH DESIGN AND METHODS -We review and present data supporting concepts relating dermal neurovascular function to prediabetes and the metabolic syndrome. Skin blood flow can be easily measured by laser Doppler techniques.RESULTS -Heat and gravity have been shown to have specific neural, nitrergic, and independent mediators to regulate skin blood flow. We describe data showing that this new tool identifies dermal neurovascular dysfunction in the majority of type 2 diabetic patients. The defect in skin vasodilation is detectable before the development of diabetes and is partially correctable with insulin sensitizers. This defect is associated with C-fiber dysfunction (i.e., the dermal neurovascular unit) and coexists with variables of the insulin resistance syndrome. The defect most likely results from an imbalance among the endogenous vasodilator compound nitric oxide, the vasodilator neuropeptides substance P and calcitonin gene-related peptide, and the vasoconstrictors angiotensin II and endothelin. Hypertension per se increases skin vasodilation and does not impair the responses to gravity, which is opposite to that of diabetes, suggesting that the effects of diabetes override and counteract those of hypertension.CONCLUSIONS -These observations suggest that dermal neurovascular function is largely regulated by peripheral C-fiber neurons and that dysregulation may be a component of the metabolic syndrome associated with type 2 diabetes. Diabetes Care 24:1468 -1475, 2001A number of functional disturbances are found in the dermal microvasculature of diabetic subjects. These include decreased microvascular blood flow (1), increased vascular resistance (2), decreased tissue PO 2 (3), and altered vascular permeability characteristics, such as loss of the anionic charge barrier and decreased charge selectivity. Decreased microvascular blood flow and increased vascular resistance in diabetes could result from alterations in dermal neurovascular function, such as impaired dilator responses to substance P, calcitonin gene-related peptide (CGRP), and reactivity to nociceptive stimulation. Diabetes also disrupts vasomotion-the rhythmic contraction exhibited by arterioles and small arteries (4,5). Unmyelinated C-fibers, which constitute the central reflex pathway, are assumed to be damaged in diabetic neuropathy, contributing to abnormalities in cutaneous blood flow (6). Warm thermal sensation is a functional measure of C-fibers in the periphery, and the impairment of this function was paralleled by a reduction of vasomotion. These findings support an interaction between small unmyelinated C-fiber function and vasomotion, although it is not clear whether the neurological deficit precedes or follows the loss of baseline vascular response. A clear relationship between skin microvascular insufficiency and neuropathy has not yet been established. It is possible that ski...

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“…Interestingly, Shargorodsky et al (35) did report that rosiglitazone lowers systemic vascular resistance. Apart from a potentiation of insulin effect, rosiglitazone may induce vasodilatation by inhibition of calcium currents (36,37), reduction of endothelin-1 secretion (38), or downregulation of the sympathetic nervous system (39).…”

Section: Characterization Of Subject With Tzd-induced Edemamentioning

confidence: 99%

Fluid Retention and Vascular Effects of Rosiglitazone in Obese, Insulin-Resistant, Nondiabetic Subjects

et al. 2006

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OBJECTIVE -The use of thiazolidinedione (TZD) derivatives is associated with fluid retention, especially when combined with insulin. Because TZDs improve the metabolic effect of insulin, they may also reverse the blunted vascular response to insulin. We hypothesize that improvement of the action of insulin on vascular tone or permeability is the key mechanism of TZD-related fluid retention.RESEARCH DESIGN AND METHODS -In a randomized, double-blind, placebocontrolled, cross-over study in 18 obese, nondiabetic subjects with features of the metabolic syndrome, we investigated the effects of a 12-week treatment with 4 mg rosiglitazone twice a day on glucose disposal, hemodynamics (including forearm vasoconstrictor response to nitric oxide [NO]), synthase inhibition by N-monomethyl-L-arginine-acetate (L-NMMA), vascular permeability (transcapillary escape rate of albumin), and plasma volume during a hyperinsulinemiceuglycemic clamp (120 min, 120 mU/m 2 per min).RESULTS -As expected, rosiglitazone increased the glucose infusion rate during clamping. However, neither vascular permeability nor forearm blood flow response to hyperinsulinemia or L-NMMA was affected by rosiglitazone. Compared with placebo, rosiglitazone decreased diastolic blood pressure by 5 mmHg (95% CI 2.35-6.87, P ϭ 0.0005) and increased plasma volume by 255 ml/1.73 m 2 (80 -430, P ϭ 0.007). Interestingly, the positive effect of rosiglitazone on glucose disposal correlated with change in foot volume (R 2 ϭ 0.53, P ϭ 0.001).CONCLUSIONS -Rosiglitazone improved insulin sensitivity but had no effect on NOdependent vasodilatation in the forearm or vascular permeability in obese, insulin-resistant, nondiabetic subjects. As such, TZD-related fluid retention was not caused by improvement of the vascular actions of insulin. Nonetheless, rosiglitazone-induced improvement in insulin sensitivity appears to be correlated to edema formation. Diabetes Care 29:581-587, 2006T hiazolidinedione (TZD) derivatives improve insulin sensitivity and hence are valuable in the treatment of type 2 diabetes (1). Important adverse effects are fluid retention and peripheral edema formation. The precise mechanism(s) of these adverse effects are unclear and probably are multifactorial (2).Although multiple factors are involved, the existence of an initial trigger or main mechanism could be of clinical importance. In theory, the initial trigger of fluid retention may originate either from kidney, heart, or peripheral circulation. As TZD treatment is associated with a reduction in blood pressure (3-6), a primary renal mechanism seems unlikely. A primary cardiac origin also seems improbable, because long-term studies with rosiglitazone have not revealed any negative effect on myocardial structure or function (7).The combination of blood pressure reduction, fluid retention, and edema formation is compatible with changes in the peripheral circulation resulting in capillary leakage. This may be induced by certain actions of TZDs, such as improved insulin-mediated vasodilatation, direct vasoa...

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Troglitazone Reduces Contraction by Inhibition of Vascular Smooth Muscle Cell Ca2+ Currents and Not Endothelial Nitric Oxide Production

Cited by 75 publications

References 40 publications

The in vivo effects of the Pro12Ala PPARγ2 polymorphism on adipose tissue NEFA metabolism: the first use of the Oxford Biobank

The in vivo effects of the Pro12Ala PPARγ2 polymorphism on adipose tissue NEFA metabolism: the first use of the Oxford Biobank

Dermal Neurovascular Dysfunction in Type 2 Diabetes

Fluid Retention and Vascular Effects of Rosiglitazone in Obese, Insulin-Resistant, Nondiabetic Subjects

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