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Differential Effects of Pentaerythritol Tetranitrate and Nitroglycerin on The View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector Journal of the American College of Cardiology Vol. 38, No. 3, 2001 © 2001 by the American College of Cardiology ISSN 0735-1097/01/$20.00 Published by Elsevier Science Inc. PII S0735-1097(01)01414-0 Pharmacology Differential Effects of Pentaerythritol Tetranitrate and Nitroglycerin on the Development of Tolerance and Evidence of Lipid Peroxidation: A Human In Vivo Study Ursula Jurt, MD,*† Tommaso Gori, MD,*‡ Amir Ravandi, PHD,§ Saeid Babaei, MSC,§ Peter Zeman,* John D. Parker, MD, FACC*† Toronto, Canada OBJECTIVES We investigated the development of nitrate tolerance after continuous exposure to nitroglyc- erin (GTN) as compared with pentaerythritol tetranitrate (PETN) in humans. BACKGROUND Sustained therapy with GTN causes tolerance and has been associated with increased production of free oxygen radicals by the endothelium. Pentaerythritol tetranitrate is an organic nitrate that has been used in the therapy of angina. There have been no investigations concerning the development of tolerance to PETN in humans. Animal investigations suggested that continuous therapy with PETN does not cause increased free radical production or hemodynamic tolerance. METHODS We randomized 30 healthy volunteers to continuous GTN (0.6 mg/h/24 h), long-acting PETN (60 mg orally three times a day) or no treatment (control group) for seven days. We studied systemic blood pressure responses and venous volume responses to GTN with strain-gauge plethysmography. The levels of cytotoxic aldehydes and isoprostanes were measured as markers of free radical-mediated lipid peroxidation. RESULTS Tolerance, as demonstrated by blood pressure and forearm plethysmography, developed in the GTN group and was absent in the PETN group (p Ͻ 0.05). Therapy with GTN was associated with a significant increase in plasma markers of lipid peroxidation. This response was not observed in those treated with PETN (isoprostanes: control: 38 Ϯ 5; GTN: 59 Ϯ 6; PETN: 38 Ϯ 3 ␮g/ml; p Ͻ 0.005). CONCLUSIONS Treatment with PETN does not cause tolerance and is not associated with evidence of increased free radical production. (J Am Coll Cardiol 2001;38:854–9) © 2001 by the American College of Cardiology Organic nitrates have been used for more than 100 years in limited. Investigations concerning the clinical efficacy of this the treatment of myocardial ischemia and congestive heart nitrate drug have been limited, and there have been no failure, but the development of tolerance still represents a human studies addressing the issue of tolerance during limitation to their use. Tolerance can be defined as loss of therapy with this compound. Interestingly, recent animal nitrate effects on symptomatic benefit or hemodynamic data suggest that PETN might have antiatherosclerotic parameters after continuous exposure. There is clear evi- effects (1–3) and that continuous exposure to this compound dence that tolerance develops to the effects of nitroglycerin does not cause tolerance (4). Furthermore, animal experi- (GTN) as well as with isosorbide mononitrate and dinitrate ments have suggested that PETN therapy is not associated when they are administered in a fashion that leads to with increased free radical production by the endothelium sustained therapeutic plasma concentrations. (3,5,6), a phenomenon that has now been repeatedly dem- Pentaerythritol tetranitrate (PETN) is an organic nitrate onstrated with GTN (7–9). This study was designed to that has been used extensively in Europe for many years. investigate the hemodynamic and biochemical effects of Although this compound has been available in North continuous therapy with PETN as compared with transder- America, its clinical application in that market has been mal GTN or no treatment. From the *Division of Cardiology, Department of Medicine, Mount Sinai METHODS Hospital, Toronto, Canada; †University Health Network, Toronto, Canada; ‡Car- diovascular Collaborative Program, Toronto, Canada; and the §Department of Study population. Thirty healthy male nonsmoking vol- Laboratory Medicine and Pathobiology, Banting and Best Department of Medical Research, University of Toronto, Toronto, Canada. Supported by a grant-in-aid from unteers (age range 19 to 39 years) were included in the the Heart and Stroke Foundation of Ontario (B3160). Dr. Gori is supported by a study. Subjects were asked to abstain from medications or granting arrangement between the University of Siena, Siena, Italy, and the University supplemental vitamins during the study period and from of Toronto, Toronto, Canada. Manuscript received October 17, 2000; revised manuscript received April 23, 2001, alcohol or caffeine-containing beverages for at least 12 h accepted May 15, 2001. before each study visit. A 3-h fasting period preceded visits. JACC Vol. 38, No. 3, 2001 Jurt et al. 855 September 2001:854–9 PETN versus GTN tained. Blood pressure and heart rate were taken again with Abbreviations and Acronyms the same procedure, and FBV was measured as in visit 1. ANOVA ϭ analysis of variance Visits were conducted at mid-day in order to ensure that ES/MS ϭ on-line electrospray mass spectrometry the subjects had received their morning dose of the study ϭ FBV forearm venous blood volume drug. GTN ϭ nitroglycerin HPLC ϭ high-pressure liquid chromatography Measurement of FBV. Forearm venous blood volume at NO ϭ nitric oxide baseline and in response to sublingual GTN was measured PETN ϭ pentaerythritol tetranitrate using strain-gauge venous occlusion plethysmography as ROS ϭ reactive oxygen species previously reported (11). Briefly, hand circulation was ex- cluded by inflating a wrist cuff to 200 mm Hg during measurement periods. The upper arm cuff was inflated to The study protocol was approved by the University of 30 mm Hg and was kept inflated until a plateau was Toronto Human Subjects Review Committee, and written reached, representing the baseline FBV. Once a baseline informed consent was obtained in all cases. measure had been taken, 0.6 mg sublingual GTN were Study protocol. VISIT 1. On visit 1, after subjects were administered, and FBV was recorded for at least 10 min screened for admission into the study, standing arterial until a new plateau had been reached. Forearm venous blood blood pressure and heart rate were measured using an volume was measured in ml/100 ml of forearm tissue, and automatic calibrated sphygmomanometer (Critikon Com- the change in FBV in response to acute administration of pany LLC, Tampa, Florida). All results represented the 0.6 mg sublingual GTN was expressed as percent from average of three different measurements taken at 1-min baseline value. Forearm plethysmographic measurements intervals. Forearm venous blood volume (FBV) and re- were made using a Hokanson EC4 Plethysmograph (D. E. sponses to sublingual GTN (0.6 mg) were then recorded Hokanson Inc., Bellevue, Washington) and recorded on a using forearm venous occlusion mercury-in-silastic strain- multichannel recorder (Gould 5900 Card Cage, Gould gauge plethysmography. The details of this technique are Instrument Systems, Inc., Valley View, Ohio). All measure- described in the following text. ments and visits were performed in a quiet, temperature and humidity-controlled laboratory. VISIT 2. One week later, subjects arrived at our laboratory at Markers of oxidative stress. The levels of cytotoxic alde- the same time as for visit 1. Standing blood pressure and hydes and isoprostanes were determined as previously de- heat rate measurements were repeated. The subjects were scribed (12). Total lipid extract of plasma was prepared by then randomized in an investigator-blind, parallel design to the method of Folch et al. (13). The total lipid extract was receive transdermal GTN 0.6 mg/h (GTN group), PETN chromatographed on a normal phase 5-␮m Spherisorb 60 mg orally every 8 h (PETN group) or no treatment high-pressure liquid chromatography (HPLC) column (control group). Nitroglycerin patches were obtained from (250 ϫ 4.6 mm inner diameter, Alltech Associates, Deer- Novartis Pharmaceuticals (Dorval, Que´bec, Canada); field, Illinois). The column was installed into a Hewlett- PETN pills were obtained from Dexo S.A. (Nanterre, Packard (Andover, Massachusetts) model 1090 liquid chro- France). The first dose was administered in the laboratory, matograph and eluted with a linear gradient of 100% solvent and repeat blood pressure and heart rate measurements were A (chloroform/methanol/30% ammonium hydroxide, 80: taken 3 h after the initial dose in order to measure the 19.5:0.5, by volume) to 100% solvent B (chloroform/ response to acute administration. Subjects randomized to methanol/water/30% ammonium hydroxide, 60:34:5.5:0.5, nitrates were instructed by the randomizing nurse to wear by volume) in 14 min and then at 100% solvent B for 10 min the patch continuously, changing it every morning at the (14). The flow was set at 1 ml/min. The peaks were same time. Subjects were instructed not to reveal their monitored by on-line electrospray mass spectrometry (ES/ treatment allocation to the investigator. The randomizing MS). Normal phase HPLC with ES/MS was performed by ␮ nurse did not take part in any other aspect of study splitting the HPLC flow by 1/50, resulting in 20 l/ml being procedures or data analysis. Subjects randomized to PETN admitted to a Hewlett-Packard model 5988B quadrupole mass were asked to take 60 mg PETN orally every 8 h for the spectrometer equipped with a nebulizer-assisted electrospray following six days. This dosing regimen of PETN was interface (HP 59987A) (15). Arachidoyl phosphatidylcholine chosen in order to prevent a nitrate-free interval. The was added as internal standard. This method allowed us to half-life of PETN and its metabolites in humans is reported measure the levels of four cytotoxic aldehydes (16:0-C5 to be 8 h (10), and the formulation used was a long-acting aldehyde phosphatidylcholine, 18:0-C5 aldehyde phos- preparation designed to be given twice daily.
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