Once Daily Therapy With Isosorbide-5-Mononitrate Causes Endothelial Dysfunction in Humans

Thomas, George; DiFabio, Jonathan M.; Gori, Tommaso; Parker, John D.

doi:10.1016/j.jacc.2006.10.074

Cited by 114 publications

(83 citation statements)

References 32 publications

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“…18,19 Recent studies have demonstrated that chronic administration of nitrates induces endothelial dysfunction. 20, 21 The present study showed that long-term nitrate treatment is significantly independently associated with cardiac events in VSA patients. Long-term nitrate treatment might cause nitrate tolerance, thus leading to subsequent endothelial dysfunction.…”

Section: -18supporting

confidence: 53%

“…Long-term ISMN treatment, even on a once-daily use, might therefore not be beneficial for preventing nitrate tolerance or preventing endothelial dysfunction. 21 CCBs are widely used medications in the management of VSA, and a recent guideline for the diagnosis and treatment of VSA recommended CCBs as first-line agents for VSA patients. 1 Short-acting nitrates are recommended only for sublingual administration, spraying in the oral cavity, or intravenous administration during an anginal attack.…”

Section: Effects Of Medications On Cardiac Events In Vsa Patientsmentioning

confidence: 99%

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Effect of Long-Term Nitrate Treatment on Cardiac Events in Patients With Vasospastic Angina

Kosugi

Nakagomi

Shibui

et al. 2011

Circ J

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Background:Nitrates have been widely used as anti-ischemic drugs in patients with vasospastic angina (VSA). However, the effect of long-term nitrate treatment on cardiac events in VSA patients remains unclear. Methods and Results:Two-hundred and thirty-one patients with VSA who had not been receiving any antiischemic drugs, including calcium channel blockers (CCBs), nitrates, nicorandil, or any combination of these medications were prospectively enrolled in the present study. All patients had a positive acetylcholine provocation test with normal coronary angiograms, and they received CCBs after enrollment. They were divided into 2 groups based on whether nitrates were included in the treatment: a nitrate group (n=86) and a without nitrate group (n=145). The baseline clinical characteristics and frequency of anginal attacks within 48 h before enrollment were similar between the 2 groups. With a median follow-up period of 70.5 months, 29 patients developed cardiac events, including 7 sudden cardiac deaths and 22 re-admissions for acute coronary syndrome. Cardiac events occurred in 19.8% of the nitrate group and in only 8.3% of the patients who were not taking nitrates (P=0.015). In a multivariate analysis, long-term nitrate treatment (hazard ratio 5.18, 95% confidence interval: 1.69-15.89, P=0.004) was an independent predictor of cardiac events. Conclusions:These data indicate that long-term nitrate treatment in addition to CCBs might not reduce cardiac events in VSA patients. (Circ J 2011; 75: 2196 - 2205

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Section: -18supporting

confidence: 53%

Section: Effects Of Medications On Cardiac Events In Vsa Patientsmentioning

confidence: 99%

Effect of Long-Term Nitrate Treatment on Cardiac Events in Patients With Vasospastic Angina

Kosugi

Nakagomi

Shibui

et al. 2011

Circ J

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“…26, 28 Isosorbide mononitrate with 1 −ONO2 was found to induce the development of moderate nitrate tolerance, despite suppression of vascular superoxide production. 27 Coadministration of angiotensin-converting enzyme inhibitors has been reported to improve endothelial dysfunction, but not to improve nitrate tolerance. 15, 29 Intermittent administration of organic nitrates with nitrate-free intervals has been demonstrated to avoid tolerance, but with several disadvantages, including lack of protection against angina and rebound ischemia during or after the nitrate-free periods.…”

Section: Discussionmentioning

confidence: 99%

Coadministration of Carvedilol Attenuates Nitrate Tolerance by Preventing Cytochrome P450 Depletion

Nakahira

Minamiyama

Takemura

et al. 2010

Circ J

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Background: Long-term administration of nitroglycerin (NTG) causes tolerance secondary to increased vascular formation of reactive oxygen species. Carvedilol, which has potent antioxidant activity in addition to functioning as an adrenergic blocker, prevents nitrate tolerance by a still to be elucidated mechanism. The present study investigated how carvedilol attenuates nitrate tolerance, particularly with reference to cytochrome P450 (CYP), an enzyme involved in the development of tolerance. Methods and Results:Male Wistar rats were subjected to 48-h continuous infusion of NTG alone (0.5 mg/h) or NTG with concomitant carvedilol (20 or 100 μg/h), and then compared with vehicle-treated rats (4 groups; n=6 in each group). Following the continuous administration, nitrate tolerance, assessed by bolus NTG injections, was hemodynamically prevented by coadministration of carvedilol. Levels of CYP1A1/1A2, superoxide production, and phosphorylated vasodilator-stimulated phosphoprotein at serine 239 (P-VASP) were examined in the aortic wall and heart tissue. When NTG alone was continuously administered, vascular superoxide was produced, there was a decrease in the cardiac CYP1A1/1A2 level, and depletion of P-VASP. However, each of these changes induced by continuous NTG administration was significantly attenuated by coadministration of carvedilol and the extent of attenuation was more pronounced at the higher dose (100 μg/h). Conclusions:Coadministration of carvedilol attenuates nitrate tolerance through maintenance of NO/cGMP pathway activity by preventing free radical generation and CYP depletion. (Circ J 2010; 74: 1711 - 1717

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“…Long-term use of nitrates has been implicated to cause endothelial dysfunction both by oxygen free radical mediated abnormalities in endothelium-dependent vasomotor responses and by inhibition and down regulation of vascular aldehyde dehydrogenase (ALDH-2). 21,22 Nicardipine has been used prophylactically as an intragraft infusion to prevent no-reflow in patients undergoing elective SVG-saphenous venous graft. 23 Unlike studies with other vasodilators such as intravenous potassium channel activator, nicorandil, 24 intracoronary verapamil, 25 and adenosine, 26 pretreatment with intracoronary nicardipine in patients undergoing elective PCI showed no statistically significant benefit in our study.…”

Section: Discussionmentioning

confidence: 99%

Effect of Intracoronary Nicardipine on Cardiac Enzymes After Elective Percutaneous Coronary Intervention

Arora

Alfayoumi

Khawaja

et al. 2009

Clinical Cardiology

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Background: Elevation in cardiac enzymes after percutaneous coronary intervention (PCI) is common and is associated with adverse clinical outcomes. Hypothesis: Administration of intracoronary nicardipine-a calcium channel blocker will reduce cardiac enzyme levels in patients undergoing elective PCI. Methods: In a single center, prospective, double-blind placebo-controlled trial, 193 patients undergoing elective PCI (with or without stenting) for chronic stable angina and/or an abnormal stress test were randomized to receive 200 mcg of intracoronary nicardipine (n = 93) or saline solution (n = 100) prior to intervention. Cardiac enzyme levels were measured immediately and at 8 and 16 hours after the procedure. Major adverse clinical events (MACE) were assessed at 30 days and at 6 months. Results: Incidence of periprocedural myonecrosis defined as elevation of troponin I levels >1× the upper limit of normal was similar in both groups (placebo 15.4% vs drug 10.6%; P = 0.47). There was no significant difference in peak troponin I levels after PCI between the 2 groups (placebo 0.58 ng/mL ± 1.08 ng/mL vs drug 0.97 ng/mL ± 3.6 ng/mL; P = 0.35). Major adverse clinical events at 6 months were infrequent and not statistically different in the 2 groups (placebo 3.4% vs drug 1.2%; P = 0.52). Multivariate analysis revealed that pretreatment with nicardipine was not associated with reduction in the incidence of troponin I elevation (odds ratio [OR]: 0.54; 95% confidence interval [CI]: 0.18-1.6; P = 0.28). Conclusions: In low-risk patients undergoing elective PCI, intracoronary nicardipine administration did not produce a significant cardioprotective effect in reducing postprocedural cardiac enzymes leakage.

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Once Daily Therapy With Isosorbide-5-Mononitrate Causes Endothelial Dysfunction in Humans

Abstract: We document for the first time that IS-5-MN impairs endothelial function in humans in vivo. Suggesting a role of oxygen free radicals, nitrate-induced abnormalities in endothelium-dependent vasomotor responses were reversed by the antioxidant vitamin C.

Cited by 114 publications

References 32 publications

Effect of Long-Term Nitrate Treatment on Cardiac Events in Patients With Vasospastic Angina

Effect of Long-Term Nitrate Treatment on Cardiac Events in Patients With Vasospastic Angina

Coadministration of Carvedilol Attenuates Nitrate Tolerance by Preventing Cytochrome P450 Depletion

Effect of Intracoronary Nicardipine on Cardiac Enzymes After Elective Percutaneous Coronary Intervention

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