Inhibition of Phosphodiesterase 5 Selectively Reverses Nitrate Tolerance in the Venous Circulation

MacPherson, Jeffery D.; Gillespie, Timothy D.; Dunkerley, Heather A.; Maurice, Donald H.; Bennett, Brian M.

doi:10.1124/jpet.105.094763

Cited by 30 publications

(23 citation statements)

References 37 publications

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“…40 Recently, altered phosphodiesterase 5 activity was also implicated in the development of GTN tolerance in veins. 41 In striking contrast to our findings with AS, pretreatment of vessels with DEA/NO caused marked cross-tolerance to GTN. To our knowledge, this is the first report of crosstolerance to GTN, either in vitro or in vivo, after NONO-ate pretreatment.…”

Section: Discussioncontrasting

confidence: 99%

Nitroxyl Anion Donor, Angeli’s Salt, Does Not Develop Tolerance in Rat Isolated Aortae

et al. 2007

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Abstract-The nitroxyl anion (HNO) is emerging as a novel regulator of cardiovascular function with therapeutic potential in the treatment of diseases such as heart failure. It remains unknown whether tolerance develops to HNO donors, a limitation of currently used nitrovasodilators. The susceptibility of the HNO donor, Angeli's salt (AS), to the development of vascular tolerance was compared with the NO donors, glyceryl trinitrate (GTN) and diethylamine/NONOate (DEA/NO) in rat isolated aortae. Vasorelaxation to AS was attenuated (PϽ0.01) by the HNO scavenger L-cysteine, whereas the sensitivity to GTN and DEA/NO was decreased (

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Section: Discussioncontrasting

confidence: 99%

Nitroxyl Anion Donor, Angeli’s Salt, Does Not Develop Tolerance in Rat Isolated Aortae

et al. 2007

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“…Induction of both PDE1a [29] and PDE5a [67] by exposure to angiotensin II is thought to contribute to reduced cGMP/ PKG signaling and be a mechanism for exacerbated hypertension and vascular proliferation. PDE5 activity is also enhanced by chronic nitrate exposure, and its inhibition reverses nitrate tolerance [68,69].…”

Section: Pde Up-regulation: Role In No Tolerance and Disease Pathophymentioning

confidence: 99%

Phosphodiesterase regulation of nitric oxide signaling

Kass

Takimoto

Nagayama

et al. 2007

Cardiovascular Research

144

114

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Nitric oxide regulation of the cardiovascular system involves both cGMP-dependent and independent mechanisms. The former directly interacts with the family of catabolic phosphodiesterases (PDEs) that control cGMP levels and thus distal effects such as protein kinase G stimulation. Growing evidence supports an important role of several PDEs, including PDE1, PDE2, and PDE5, in the regulation of cGMP in both vascular smooth muscle and cardiac myocytes. These PDEs have relatively little impact on resting function, but they can potently modulate acute contractile tone in cells stimulated by external agonists such as angiotensin or catecholamines. Regulation by PDEs is compartmentalized, with selective interactions occurring between a given source of cGMP and PDE hydrolysis. PDE1 and/or PDE5 are also reportedly up-regulated in chronic disease conditions such as atherosclerosis or cardiac pressure-load stress and heart failure as well as in response to long-term exposure to nitrates. Such up-regulation is thought to contribute to vascular and cardiac pathophysiology and to drug tolerance. Recent studies utilizing selective PDE5 inhibitors support significant cross-signaling with NO-cGMP synthetic pathways that may be particularly helpful in treating certain disease states.

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“…Also, exposure to Ang II induces PDE5A expression in vascular smooth muscle cells, which not only contributes to reduction in cGMP/protein kinase G signaling but also exacerbates hypertension and vascular proliferation [51]. More importantly, chronic upregulation of PDE5 has been associated with nitrate tolerance [52].…”

Section: Pde Inhibitorsmentioning

confidence: 99%

Advances in Pharmacologic Modulation of Nitric Oxide in Hypertension

Mizuno

Jacob²,

Mason

2010

Curr Cardiol Rep

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A number of structural and functional mechanisms have been identified in the pathogenesis of hypertensive vascular disease, each of which requires effective therapy to reduce global cardiovascular risk. Hypertension, together with other cardiovascular risk factors, promotes endothelial dysfunction as evidenced by decreased nitric oxide (NO) release and reduced vascular responsiveness to normal vasodilatory stimuli. In addition, the mechanical forces inherent in hypertension activate neurohormonal mechanisms, including the renin-angiotensin system, which modulate vessel wall structure and function. Antihypertensive drugs may have class-specific hemodynamic and physiologic effects that attenuate these vascular disease processes. Pharmacologic approaches that enhance endothelial NO bioavailability have been shown to restore vasodilation while reducing clinical events. These agents improve NO bioavailability by increasing endogenous production through enzymatic mechanisms or by promoting the direct release of NO by its redox congeners in a spontaneous fashion. In this article, we review the basic mechanisms of endothelial dysfunction along with the use and comparative therapeutic benefits of various pharmacologic interventions, with particular emphasis on antihypertensive agents.

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Inhibition of Phosphodiesterase 5 Selectively Reverses Nitrate Tolerance in the Venous Circulation

Cited by 30 publications

References 37 publications

Nitroxyl Anion Donor, Angeli’s Salt, Does Not Develop Tolerance in Rat Isolated Aortae

Nitroxyl Anion Donor, Angeli’s Salt, Does Not Develop Tolerance in Rat Isolated Aortae

Phosphodiesterase regulation of nitric oxide signaling

Advances in Pharmacologic Modulation of Nitric Oxide in Hypertension

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