Effects of oral propylthiouracil treatment on nitric oxide production in rat aorta

Grieve, David; Fletcher, Sara; Pitsillides, Andrew A.; Botham, Kathleen M.; Elliott, Jonathan

doi:10.1038/sj.bjp.0702501

Cited by 30 publications

(22 citation statements)

References 31 publications

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“…These data are consistent with the increased and decreased responsiveness to acetylcholine, the endothelium-dependent vasodilator, in perfused kidneys and isolated aortas from hyperthyroid and hypothyroid rats respectively (5). Our data in the hypothyroid group contrast with the increased staining of endothelial NOS using immunohistochemical techniques in the aortic endothelium of hypothyroid rats (30). However, it is well known that immunohistochemistry is a suitable technique to detect the presence of proteins in a given tissue but it is not a very accurate method to detect differences between groups.…”

Section: Discussioncontrasting

confidence: 52%

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Nitric oxide synthase activity in hyperthyroid and hypothyroid rats

Quesada

Sainz

Wangensteen

et al. 2002

European Journal of Endocrinology

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Objective: Thyroid disorders are accompanied by important changes in haemodynamic and cardiac functions and renal sodium handling. Since nitric oxide (NO) plays a crucial role in regulating vascular tone and renal sodium excretion, the present paper was designed to determine whether changes in the activity of NO synthase (NOS) participate in the cardiovascular and renal manifestations of thyroid disorders. Methods: We measured NOS activity in the heart (left and right ventricles), vessels (aorta and cava) and kidney (cortex and medulla) of euthyroid, hyperthyroid and hypothyroid rats after 6 weeks of treatment. NOS activity was determined by measuring the conversion of L-Results: NOS activity was higher in all tissues from hyperthyroid rats when compared with controls, except in the right ventricle. In the hypothyroid group, NOS activity showed a more heterogeneous pattern, with significant increases in both ventricles but significant reduction in the aorta, while in the vena cava, renal cortex and medulla the enzyme activity also tended to be higher, but significance was not reached. Conclusions: These data indicated that NOS activity was upregulated in tissues primarily related to blood pressure control in hyperthyroid rats, suggesting that an increased NO production may contribute to the hyperdynamic circulation in hyperthyroidism and may have a protective homeostatic effect in the target organs of the hypertension that accompanies this endocrine disease. The aortic and renal findings in hypothyroid rats suggested a possible role for NOS in the increased peripheral resistance and the normal pressure -diuresis -natriuresis response of these hypotensive animals, although hypothyroidism produced a heterogeneous tissue response in NOS activity.

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Section: Discussioncontrasting

confidence: 52%

“…However, it is well known that immunohistochemistry is a suitable technique to detect the presence of proteins in a given tissue but it is not a very accurate method to detect differences between groups. In fact, these observations were not accompanied by a quantitative analysis (30).…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide synthase activity in hyperthyroid and hypothyroid rats

Quesada

Sainz

Wangensteen

et al. 2002

European Journal of Endocrinology

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“…22 PTU was found to enhance the production of nitric oxide in rat aorta, although this effect was attributed to its hypothyroid activity. 23 Oxidation of LDL is a key step in the development of atherosclerosis. 2 The effect of PTU on lipid peroxidation has been investigated previously.…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of Propylthiouracil Independent of Its Hypothyroid Effect on Atherogenesis in Cholesterol-Fed Rabbits

et al. 2004

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Background-Propylthiouracil (PTU) is used to treat hyperthyroid patients by its hypothyroid effect. PTU also is found to have potent antioxidant and immunosuppressive effects. These findings suggest that PTU may play a role in the prevention of atherosclerosis. Methods and Results-This study evaluates the effect of PTU on atherosclerotic change in rabbits fed a high-cholesterol diet. The pronounced atherosclerotic lesions in the aortas of rabbits fed a 2% cholesterol diet for 12 weeks were significantly attenuated by the concurrent addition of 0.1% PTU to the drinking water. However, exogenous supplementation of thyroid hormone in hypothyroid PTU-treated rabbits did not abrogate the protective effect of PTU on atherogenesis. Immunohistochemical analysis showed that PTU administration apparently reduced the intimal smooth muscle cell/macrophage ratio in the atherosclerotic plaques of rabbits fed a 2% cholesterol diet. In vitro, the addition of PTU to the medium of cultured rat vascular smooth muscle cells led to a dose-dependent inhibition of cell proliferation and migration. Furthermore, this study confirmed that PTU dose-dependently increased expression of PTEN, a tumor suppressor gene known to be involved in the coordinate inhibition of VSMC proliferation and migration. Conclusions-This study demonstrated that PTU inhibited the development of atherosclerosis through a thyroidindependent mechanism that may be explained, at least in part, by the ability of PTU to inhibit vascular smooth muscle cell proliferation and migration. Furthermore, PTEN induction, via disruption of the phosphatidylinsitol 3-kinasemediated pathway, plays a crucial role in mediating the inhibitory action on vascular smooth muscle cell proliferation and migration.

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“…15,16 Accordingly, PTU has recently been demonstrated to exhibit an anti-atherosclerotic effect. 17,18 The aims of this study were, therefore, to determine whether PTU can also effectively attenuate MCT-induced PAH in the rat, in terms of alterations in pulmonary microvasculature and structure, as well as to investigate the underlying mechanisms of biological signaling.…”

mentioning

confidence: 99%

Propylthiouracil Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats

Sun

Yuen

Kao

et al. 2009

Circ J

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ulmonary arterial hypertension (PAH) is a devastating disease that can drastically limit physical capacity and seriously reduce life expectancy. 1-4 Pathologic changes of PAH, characterized by vascular smooth muscle cell (VSMC) proliferation and obliteration of small pulmonary arteries, 5 may ultimately lead to heart failure and death. 3,4 Despite widespread use of state-ofthe-art medical management against PAH during the past decade, 6,7 the prognosis remains poor. 3,4,8,9 Although the precise mechanistic basis of PAH is currently unclear, a process involving endothelial dysfunction and VSMC proliferation and migration is essential in the development of all stages of PAH, from initiation, progression, and finally to the evolution of complications. [8][9][10] Monocrotaline (MCT), which is known to induce selective pulmonary endothelial injury in rats, [8][9][10][11][12] causes pulmonary hypertension, interstitial pulmonary fibrosis, and proliferation of muscular intimal cells in pulmonary arterioles and fibroblasts in the alveolar walls at the capillary level. 9,[11][12][13] Although the pathologic changes in MCT-induced PAH and clinical PAH are not similar, because of differences in pathogenesis, the MCT-induced PAH model has been validated and widely accepted for PAH-related studies because of the consistent induction of selective pulmonary arteriolar endothelial damage.In addition to its routine use in patients with hyperthyroidism, because of its thyroid-suppressing function, propylthiouracil (PTU) has also been shown to possess an antioxidant property, 14 enhance nitric oxide (NO) production, inhibit VSMC proliferation and migration, as well as collagen production. 15,16 Accordingly, PTU has recently been demonstrated to exhibit an anti-atherosclerotic effect. 17,18 The aims of this study were, therefore, to determine whether PTU can also effectively attenuate MCT-induced PAH in the rat, in terms of alterations in pulmonary microvasculature and structure, as well as to investigate the underlying mechanisms of biological signaling. Background: Propylthiouracil (PTU) enhances nitric oxide production and inhibits smooth muscle cell proliferation, suggesting a possible role in the prevention of pulmonary arterial hypertension (PAH). Methods Ethics Methods and Results:The 30 male Sprague-Dawley rats were randomized to receive saline injection only (group 1), monocrotaline (MCT) (70 mg/kg) only (group 2) or MCT + 0.1% PTU in drinking water (group 3) given on day 5 after MCT administration. By day 35, western blot showed lower connexin43 (Cx43) and membranous protein kinase C-ε expressions in the right ventricle (RV) of group 2 animals than in the other groups (all P<0.05). Conversely, Cx43 expression in the lung was higher in group 2 than in other groups (all P<0.02). Additionally, mRNA expressions of matrix metalloproteinase-9, tissue necrotic factor-α, and caspase-3 were higher, whereas Bcl-2 and endothelial nitric oxide synthase were lower, in the lungs and RV of group 2 rats than in the other groups (all P<0....

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Effects of oral propylthiouracil treatment on nitric oxide production in rat aorta

Cited by 30 publications

References 31 publications

Nitric oxide synthase activity in hyperthyroid and hypothyroid rats

Nitric oxide synthase activity in hyperthyroid and hypothyroid rats

Protective Effect of Propylthiouracil Independent of Its Hypothyroid Effect on Atherogenesis in Cholesterol-Fed Rabbits

Propylthiouracil Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rats

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