Troglitazone and vascular reactivity: Role of glucose and calcium

Ali, Syed Sohail; Igwe, Robert C.; Walsh, Mary F.; Sowers, James R.

doi:10.1016/s0026-0495(99)90021-5

Cited by 8 publications

(5 citation statements)

References 38 publications

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“…Rather, as repeatedly reviewed (Sarafidis and Nilsson, 2006;Giles and Sander, 2007;Kelly and Bank, 2007;Sarafidis, 2008;Takahashi and Kushiro, 2008;Kalaitzidis et al, 2009), many thiazolidinedione studies show decreases in blood pressure for which the abovementioned thiazolidinedione vasorelaxant action is considered a primary mechanism (Kalaitzidis et al, 2009). Thus, like the previous demonstrations of thiazolidinedione-induced vasorelaxation (Peuler et al, 1997;Ali et al, 1999;Peuler, 2002;, our present identification of fibrate-induced vasorelaxation adds an important new dimension to the current concern surrounding stimulatory effects of PPAR agonists in general on renin-angiotensin-aldosteronerelated hypertension in humans. Clearly, further in-depth examination of direct vascular effects of gemfibrozil (and other fibrates) is now warranted in this context.…”

Section: Effects Of Gemfibrozil On K Ne and Avp Induced Contractionssupporting

confidence: 64%

“…troglitazone, pioglitazone and rosiglitazone (Peuler et al, 1997;Ali et al, 1999;Peuler, 2002;. For example, in a previous study, we examined multiple concentrations of the thiazolidinedione troglitazone (2,4,8,16, and 32 μM) for vasorelaxant effects on K-, NE-and AVP-induced contractions in tail arterial tissue rings prepared from the adult male rat .…”

Section: Effects Of Gemfibrozil On K Ne and Avp Induced Contractionsmentioning

confidence: 99%

“…But receptor agonists like NE and AVP are commonly known to activate more smooth muscle contractile mechanisms than that activated by a high concentration of extracellular K (Chen and Rembold, 1995;Kostrzewska et al, 2000;Fallet et al, 2005) and there is convincing evidence that the thiazolidinediones oppose these additional mechanisms. For example, there is evidence that thiazolidinediones open membrane-bound voltage-operated K channels and inhibit receptor-mediated release of calcium from intracellular sarcoplasmic reticulum (SR) storage sites (Ali et al, 1999;Peuler, 2002). The same may be true for gemfibrozil and remains to be determined in future efforts beyond the scope of the present study.…”

Section: Effects Of Gemfibrozil On K Ne and Avp Induced Contractionsmentioning

confidence: 99%

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Evidence of direct smooth muscle relaxant effects of the fibrate gemfibrozil

Phelps

Peuler

2010

J. Smooth Muscle Res.

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Fibrates are commonly employed to treat abnormal lipid metabolism via their unique ability to stimulate peroxisome proliferator-activated receptor alpha (PPARα). Interestingly, they also decrease systemic arterial pressure, despite recent evidence that PPARα may contribute to expression of renin and related hypertension. Yet, mechanisms responsible for their potential antihypertensive activity remain unresolved. Rapid decreases in arterial pressure following bolus intravenous injections of bezafibrate strongly suggest they may relax arterial smooth muscle directly. But since bezafibrate is highly susceptible to photodegradation in aqueous media, it has never been critically tested for this possibility in vitro with isolated arterial smooth muscle preparations. Accordingly, we tested gemfibrozil which is resistant to photodegradation. We examined it over a therapeutically-relevant range (50-400 μM) for both acute and delayed relaxant effects on contractions of the isolated rat tail artery; contractions induced by either depolarizing its smooth muscle cell membranes with high potassium or stimulating its membrane-bound receptors with norepinephrine and arginine-vasopressin. We also examined these same gemfibrozil levels for effects on spontaneously-occurring phasic rhythmic contractile activity, typically not seen in arteries under in vitro conditions but commonly exhibited by smooth muscle of uterus, duodenum and bladder. We found that gemfibrozil significantly relaxed all induced forms of contraction in the rat tail artery, acutely at the higher test levels and after a delay of a few hours at the lower test levels. The highest test level of gemfibrozil (400 μM) also completely abolished spontaneously-occurring contractile activity of the isolated uterus and duodenum and markedly suppressed it in the bladder. This is the first evidence that a fibrate drug can directly relax smooth muscle contractions, either induced by various contractile agents or spontaneously-occurring. These findings are particularly relevant to both the recently renewed concern over the impact of fibrates on hypertension and a new understanding of their gastrointestinal side effects.

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Section: Effects Of Gemfibrozil On K Ne and Avp Induced Contractionssupporting

confidence: 64%

Section: Effects Of Gemfibrozil On K Ne and Avp Induced Contractionsmentioning

confidence: 99%

Section: Effects Of Gemfibrozil On K Ne and Avp Induced Contractionsmentioning

confidence: 99%

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Evidence of direct smooth muscle relaxant effects of the fibrate gemfibrozil

Phelps

Peuler

2010

J. Smooth Muscle Res.

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“…[67] Troglitazone and pioglitazone inhibit calcium ion influx and attenuate responses to vasoactive agonists which act synergistically with insulin, but are independent of insulin action and NO production. [68,69] The proliferation and migration of VSMCs are responses to arterial injury and are core to restenosis and atherosclerosis. PPARγ ligands are potent inhibitors of angiogenesis in vitro and in vivo.…”

Section: Atherosclerosis and The Vascular Wallmentioning

confidence: 99%

Effects of the Thiazolidinediones on Cardiovascular Risk Factors

Gilling

Suwattee

Desouza

et al. 2002

American Journal of Cardiovascular Drugs

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Rosiglitazone and pioglitazone are medications from the thiazolidinedione class of compounds currently available for the treatment of type 2 diabetes mellitus. Traditionally used to enhance insulin sensitivity and decrease plasma insulin levels, added applications have emerged beyond those involving glycemic control. Cardiovascular risk factors associated with insulin resistance such as elevated blood pressure, dyslipidemia, abnormal fibrinolysis, and endothelial and vascular dysfunction have been shown to improve after thiazolidinedione treatment. Therapy with rosiglitazone or pioglitazone has been found to modify vascular reactivity and other processes involved in atherosclerosis. There may be differences between the agents in their effects on plasma lipid characteristics and particle size. These agents serve as excellent adjuncts to oral and insulin therapy for patients with type 2 diabetes mellitus and hold promise for the prevention of cardiovascular disease associated with the insulin resistance syndrome. Clinical trials are in progress to determine whether such therapy will lead to a reduction in cardiovascular events.

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“…TZDs have been demonstrated to have vasoactive effects on vascular tissue in vitro. Pretreatment of normotensive, endothelium-denuded thoracic aortic rings with troglitazone (TRO) increased EC 50 values for phenylephrine and KCl (6) or norepinephrine and KCl (1). In vivo administration of rosiglitazone is effective in both lowering blood pressure (2) and decreasing agonist-stimulated contraction in isolated vessels (10).…”

mentioning

confidence: 99%

A rapid, PPAR-γ-dependent effect of pioglitazone on the phosphorylation of MYPT

Atkins

Irey

Nan

et al. 2009

American Journal of Physiology-Cell Physiology

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Peroxisome proliferator-activated receptor (PPAR)-gamma ligands, thiazolidinediones, have been demonstrated to regulate vascular reactivity. We examined the effect of pioglitazone (PIO; 20 muM) in rat primary cultured aortic smooth muscle cells on constitutive phosphorylation of the regulatory subunit of myosin phosphatase (MYPT). PIO decreased the phosphorylation of Thr(697) on MYPT within 15 min, and the inhibition was maintained up to 6 h. The PPAR-gamma antagonist GW-9662 (5 microM) abrogated the inhibition of Thr(697) phosphorylation mediated by PIO. Because longer-term PIO treatment inhibits RhoA/Rho kinase (ROCK) signaling and Thr(697) phosphorylation, we tested the effect of the ROCK inhibitor Y-27632 (10 muM) on the inhibition of Thr(697) phosphorylation by PIO. Y-27632 alone inhibited Thr(697) phosphorylation, and there was an additive effect with PIO. In addition, up to 1 h of PIO treatment did not affect RhoA localization or decrease ROCK-dependent phosphorylation of Thr(855). These results suggest that the effect of PIO is independent of inhibition of RhoA/ROCK. PIO increased the phosphorylation of Ser(696) in the same time course as its effect on Thr(697). Ser(696) has been shown to be phosphorylated by PKA and PKG. PKA inhibitor H-89 (10 microM) and PKG inhibitor KT-5823 (0.5 microM) abrogated the effect of PIO on both Thr(697) and Ser(696) phosphorylation. The constitutive turnover of phosphorylation of Thr(697) is rapid, suggesting that the decreased phosphorylation of Thr(697) by PIO is due to enhanced phosphorylation of Ser(696). This is supported by the finding that PIO blocks ANG II-stimulated phosphorylation of Thr(697) but not ANG II-stimulated RhoA translocation. Therefore, the effect of shorter-term PIO apparently is to increase myosin light chain phosphatase activity, thereby desensitizing the vascular smooth muscle to agonist signaling.

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Troglitazone and vascular reactivity: Role of glucose and calcium

Cited by 8 publications

References 38 publications

Evidence of direct smooth muscle relaxant effects of the fibrate gemfibrozil

Evidence of direct smooth muscle relaxant effects of the fibrate gemfibrozil

Effects of the Thiazolidinediones on Cardiovascular Risk Factors

A rapid, PPAR-γ-dependent effect of pioglitazone on the phosphorylation of MYPT

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