The Puzzle of Nitrate Tolerance

Gori, Tommaso; Parker, John D.

doi:10.1161/01.cir.0000036742.52907.91

Cited by 86 publications

(25 citation statements)

References 80 publications

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“…Our investigation does not address the mechanism, but it is possible that a decrease in NO bioavailability associated with a net increase in free radical bioavailability, known to occur during sustained GTN therapy, may lead to these changes in glucose metabolism. 16,17 The current findings do not confirm the findings of Kovacs et al who found that the acute transdermal GTN caused a decrease in plasma insulin responses during an OGTT without a parallel change in plasma glucose. 11 This difference may be the result of the larger sample size and differences in both the dose of transdermal GTN and the timing of the OGTT after GTN administration.…”

Section: Discussioncontrasting

confidence: 99%

“…It has been demonstrated in both animal and human models that sustained GTN therapy is associated with an increase bioavailability of free radical species and a decrease in the bioavailability of NO. 16,17 These effects have important physiologic consequence, as they lead to the development of endothelial dysfunction, 14,26 heightened sensitivity of the vasculature to vasoconstrictors, 27 evidence of free radical-induced lipid injury 28 along will changes in autonomic nervous system regulation. 29 It is these ''nonhemodynamic'' effects of organic nitrates that led to the hypothesis that continuous GTN might modify glucose homeostasis.…”

Section: Discussionmentioning

confidence: 99%

“…13 Sustained therapy with GTN and other organic nitrates has been shown to be associated with increased vascular production of radicals. [14][15][16][17] Although studies on the redox response to nitrates have focused on their apparent negative impact on vascular function, it is plausible that chronic nitrate therapy may have an impact on insulin and glucose interactions that is different from that which has been observed following acute exposure. Indeed, in a rabbit model Bajza et al reported that sustained, 7-day exposure to GTN therapy (which induced hemodynamic tolerance) was associated with a decrease in insulin sensitivity.…”

Section: Introductionmentioning

confidence: 99%

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Acute and Chronic Effects of Glyceryl Trinitrate Therapy on Insulin and Glucose Regulation in Humans

Jedrzkiewicz

Parker

2012

J Cardiovasc Pharmacol Ther

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This study examined the effect of acute and sustained transdermal glyceryl trinitrate (GTN) therapy on insulin and glucose regulation. Totally, 12 males (18-30 years) underwent a glucose tolerance test at baseline (visit 1), 90 minutes after acute transdermal GTN 0.6 mg/h (visit 2), following 7 days of continuous GTN (visit 3), and 2 to 3 days after stopping GTN (visit 4). At each visit, plasma glucose and insulin concentrations were measured before and 30, 60, 90, and 120 minutes after a 75-g oral glucose load. Indices of glucose metabolism that were examined included the insulin sensitivity index, the homeostasis model assessment of insulin resistance (HOMA-IR), and the insulinogenic index. The acute administration of GTN had no effect on glucose and insulin responses (visit 2). However, after 7 days of GTN exposure (visit 3) there was an increase in the mean glucose concentration measured after the oral glucose load. On visit 1, the mean glucose concentration (+ standard deviation) following the 75 g oral glucose challenge was 5.7 + 0.5 mmol/L. On visit 3, after 7 days of transdermal GTN therapy, the mean glucose concentration after the oral glucose was significantly higher; 6.2 + 0.5 mmol/L (P < .015; 95% confidence intervals 0.25-0.77). There was also an increase in the HOMA-IR index; on visit 1, the median HOMA-IR (interquartile range) was 5.2 (3.9) versus 6.9 (6.8) on visit 3 (P < .015). Other indices of glucose metabolism did not change. These observations document that GTN therapy modifies glucose metabolism causing evidence of increased insulin resistance during sustained therapy in normal humans.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Acute and Chronic Effects of Glyceryl Trinitrate Therapy on Insulin and Glucose Regulation in Humans

Jedrzkiewicz

Parker

2012

J Cardiovasc Pharmacol Ther

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“…Long-term administration of nitrates causes nitrate tolerance or tachyphylaxis in many species including man [4,5,7,8,10,11]. Recently, there has been a strong focus on a proposed free radical hypothesis.…”

Section: Discussionmentioning

confidence: 99%

“…Nitrate tolerance or tachyphylaxis is characterized by a reduction in the nitrate-induced cyclic GMP-mediated pathway [4]. Proposed mechanisms of tolerance include: (1) depletion of critical sulfhydryl groups [5], (2) desensitization of guanylyl cyclase [6], (3) impaired bioconversion of nitrates leading to diminished NO-release [7], (4) reduced generation of NO from nitrates [8], (5) increased activity of the cyclic GMP phosphodiesterase, which decreases cyclic GMP levels [9] and (6) a free radical hypothesis proposing increased oxidant stress [10,11]. Nitroglycerininduced reactive oxygen species also inhibit the activation of nitroglycerin by thiol oxidation of mitochondrial aldehyde dehydrogenase which might explain why nitroglycerin elicits mitochondrial superoxide formation and nitrate tolerance [12].…”

Section: Introductionmentioning

confidence: 99%

Chronic nitrates blunt the effects of not only nitric oxide but also natriuretic peptides in cardiac myocytes

Tan¹,

Zhang²,

Anyadike³

et al. 2007

Pharmacological Research

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Abstractexposure to nitrates causes tachyphylaxis to nitric oxide (NO), which reduces the effects of the second messenger cyclic GMP. We tested the hypothesis that prolonged exposure to NO would also blunt the effects of natriuretic peptides. Cardiac myocytes were isolated from control (N=7) and chronic nitroglycerin (patched, N=7) rabbits. Patched animals received a transdermal nitroglycerin patch (0.3 mg/hr for 5 days). Myocyte function was determined at baseline, after CNP (C-type natriuretic peptide, 10 −8 and 10 −7 M) or BNP (Brain natriuretic peptide, 10 −8 and 10 −7 M) or SNAP (S-nitroso-N-acetyl-penicilliamine, a NO donor, 10 −6 and 10 −5 M) followed by KT5823 (a cyclic GMP protein kinase inhibitor, 10 −6 M). Soluble and particulate guanylyl cyclase activities were measured in vitro and phosphoprotein analysis was performed. In control animals, CNP 10 −8 M (5.14±0.5%) and 10 −7 M (4.4±0.7%) significantly reduced percentage shortening from baseline (6.1±1.6%). KT5823 restored percentage shortening to 4.9±0.8%. Similar data were obtained with BNP and SNAP. In patched animals, CNP, BNP, SNAP had no significant effects on percentage shortening. The data on maximal rate of shortening and relaxation were consistent with these results. Guanylyl cyclase activities were not different in the control and patched animals. The myocytes from control and patched animals had similar protein phosphorylation patterns. Our data suggested that in addition to NO, the responses to both natriuretic peptides were downregulated after chronic exposure to nitroglycerin, but these effects were not due to changes in either guanylyl cyclase or cyclic GMP protein kinase, suggesting an altered downstream pathway.

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Vasodilator and Nitrates

Al‐Hesayen¹,

Parker²

2006

Heart Failure: Pharmacologic Management

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The Puzzle of Nitrate Tolerance

Cited by 86 publications

References 80 publications

Acute and Chronic Effects of Glyceryl Trinitrate Therapy on Insulin and Glucose Regulation in Humans

Acute and Chronic Effects of Glyceryl Trinitrate Therapy on Insulin and Glucose Regulation in Humans

Chronic nitrates blunt the effects of not only nitric oxide but also natriuretic peptides in cardiac myocytes

Vasodilator and Nitrates

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