doi: 10.1161/01.CIR.0000163541.73938.3B
(Circulation. 2005;111:e278-e279.)
© 2005 American Heart Association, Inc.
Correspondence |
Letter Regarding Article by Kaufmann et al, "Systemic Inhibition of Nitric Oxide Synthase Unmasks Neural Constraint of Maximal Myocardial Blood Flow in Humans"
Massachusetts General Hospital, Harvard Medical School, Boston, Mass
Kaufmann et al1 suggest that augmented adenosine flow with NG-monomethyl-L-arginine (L-NMMA) requires inhibition of CNS neuronal nitric oxide synthase (nNOS), increased cardiac sympathetic nerve stimulation, and ß2-agonism of coronary arterioles because (1) heart transplant patients (n=6), assumed to be denervated, did not show similar increase and (2) patients given phenylephrine to raise arterial pressure to levels equivalent to those given L-NMMA plus adenosine also did not show increased myocardial blood flow (MBF).
Sympathetic reinnervation is not only a function of time after transplantation, however. Depending on definitions of "early" versus "late," evidence of sympathetic innervation may be present by 12 months2 and possibly sooner because it occurs in <1 year in animals. Accordingly, the principal conclusion of the study rests on a small sample and an assumption that may not be warranted. Moreover, cardiac sympathetic reinnervation occurs first over the anterobasal region of the left ventricle. Thus, MBF data analysis might have been better focused on that region rather than on the whole heart.
In addition, data from the phenylephrine group are difficult to interpret because the authors suggest that 
-adrenergic constriction limits the MBF response to adenosine. Thus, the use of an -agonist to raise arterial pressure may not be helpful in proving that augmentation of mean arterial pressure, observed with L-NMMA, cannot account for the study results. Furthermore, Buus et al3 demonstrated decreased, not increased, MBF response to adenosine in the presence of systemic NG-nitro-L-arginine methyl ester (L-NAME). Kaufmann et al1 suggest L-NAME does not cross the blood-brain barrier and thus conclude that the experiments are not comparable. Another study, however, suggests that L-NAME may cross the blood-brain barrier.4
Moreover, in a previous study, rest MBF demonstrated no change in the same patients after placebo and L-NMMA.5 In addition, maximal myocardial conductance with adenosine was reduced by L-NMMA and absolute adenosine MBF was unchanged.5 Because Kaufman et al had given a dose of only 7.5 mg/kg L-NMMA when they started adenosine MBF measurements and the other group5 had given a dose of 12.7 mg/kg, one might speculate that differences in the dose resulted in differences in the extent of inhibition not only of CNS nNOS but also cardiac eNOS and nNOS, which in a system as complex as NOS/NO in humans could have caused opposite results in the 2 studies—an outcome resembling that of intravenous norepinephrine infusion in dogs, in which an initial decrease in coronary resistance is followed by a more sustained increase. With the norepinephrine experiment, timing is essential to conclusions drawn, as is the presence or absence of anesthesia. With L-NMMA, dose surely matters because the authors observed no effect on adenosine MBF with 3 mg/kg L-NMMA.
In light of the above considerations, there may be reason to question the authors’ interpretation of their data and the principal conclusion of their study.
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1. Kaufmann PA, Rimoldi O, Gnecchi-Ruscone T, Bonser RS, Lüscher TF, Camici PG. Systemic inhibition of nitric oxide synthase unmasks neural constraint of maximal myocardial blood flow in humans. Circulation. 2004; 110: 1431–1436.
2. Wilson RF, Christensen BV, Olivari MT, Simon A, White CW, Laxson DD. Evidence for structural sympathetic reinnervation after orthotopic cardiac transplantation in humans. Circulation. 1991; 83: 1210–1220.
3. Buus NH, Bottcher M, Hermansen F, Sander M, Nielsen TT, Mulvany MJ. Influence of nitric oxide synthase and adrenergic inhibition on adenosine-induced myocardial hyperemia. Circulation. 2001; 104: 2305–2310.
4. Wagner BP, Stingele R, Williams MA, Wilson DA, Traystman RJ, Hanley DF. NO contributes to neurohypophysial but not other regional cerebral fluorocarbon-induced hyperemia in cats. Am J Physiol. 1997; 273: H1994–H2000.[Medline] [Order article via Infotrieve]
5. Tawakol A, Forgione MA, Stuehlinger M, Alpert NM, Cooke JP, Loscalzo J, Fischman AJ, Creager MA, Gewirtz H. Homocysteine impairs coronary microvascular dilator function in humans. J Am Coll Cardiol. 2002; 40: 1051–1058.
Response
MRC Clinical Sciences Centre, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London, UK
Department of Cardiopulmonary Transplantation, Queen Elizabeth Medical Centre, Birmingham, UK
Cardiovascular Center, Division of Cardiology and Nuclear Cardiology Section, University Hospital, Zürich, Switzerland
We appreciate Dr Gewirtz’s interest in our article1 and are pleased to have the opportunity to respond to the issues he has raised.
In a previous study,2 none of the patients studied within 18 months of transplantation demonstrated evidence of reinnervation, as opposed to most patients studied between 1.5 and 7 years. In the article by Wilson et al,3 none of the patients studied within 5 months of transplantation had evidence of reinnervation, whereas most of those studied at a much later stage (37±3 months after transplantation) did. Therefore, it is reasonable to assume that our patients’ hearts, studied 6.5±2 months after transplantation, were still denervated.
The hypothesis that -adrenergic constriction limits the flow response to adenosine is erroneously attributed to us. In fact, we hypothesize (see page 1435 of our article)1 that the extra fall in minimal coronary resistance observed during co-infusion of adenosine and L-NMMA is the result of the activation of ß2-adrenoreceptors on the coronary microcirculation, supporting the results of Sun et al.4 In another study,5 no change in coronary flow reserve during intracoronary phenylephrine infusion, despite an increase in blood pressure, was found even when a simultaneous infusion of phenylephrine and phentolamine was used. This rules out direct phenylephrine-induced -adrenoreceptor vasoconstriction and supports its use as an active control.
As far as the assertion that L-NAME crosses the blood-brain barrier (referring to a study in anesthetized cats6 in which endothelial nitric oxide synthase [NOS] of the cerebral vessels [rather than neuronal NOS] was antagonized) is concerned, in the methods section of their article, the authors state, "Nevertheless, the immediate systemic hypertensive effect of L-NAME in blood-perfused animals and very recent data suggest that mainly endothelial NOS is responsible for cerebral hemodynamics."6 This is not a demonstration that L-NAME crosses the blood-brain barrier.
Dr Gewirtz also is concerned that in a previous study7 there was no increase in adenosine-induced hyperemia after L-NMMA. In this study, the flow measurement was started 2 minutes after beginning adenosine infusion (140 µg/kg). It is worth noting that the model for flow quantification with 13NH3 depends on tracer inflow during the first minute after its administration. In our study,1 we started scanning after 2 minutes of adenosine infusion using H215O. The model used for flow quantification with H215O is mainly dependent on tracer washout from tissue, which occurs during the last part of the 5.5-minute scan. Thus, in our study, adenosine was infused for >5 minutes before flow measurement as compared with 2 to 3 minutes in the other study.7 These differences prevent direct comparison of the 2 studies. Furthermore, a careful recalculation of the total L-NMMA dose delivered to the heart in the 2 studies seems not to support the discrepancy alleged by Dr Gewirtz. He has, perhaps, failed to take into account 2 important factors: The elimination half-life of L-NMMA in humans is 
60 minutes,8 and the half-life of 13N is 20 minutes (as opposed to 2 minutes for 15O); therefore, consecutive PET scans with 13N must be separated by at least 40 minutes to allow for radioactivity decay. Taking all of this into account, the total effective dose of L-NMMA delivered in Tawakol and associates’ study was 8 mg/kg, which is similar to our 7.66 mg/kg.
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1. Kaufmann PA, Rimoldi O, Gnecchi-Ruscone T, Bonser RS, Lüscher TF, Camici PG. Systemic inhibition of nitric oxide synthase unmasks neural constraint of maximal myocardial blood flow in humans. Circulation. 2004; 110: 1431–1436.
2. Bengel FM, Ueberfuhr P, Ziegler SI, Nekolla S, Reichart B, Schwaiger M. Serial assessment of sympathetic reinnervation after orthotopic heart transplantation: a longitudinal study using PET and C-11 hydroxyephedrine. Circulation. 1999; 99: 1866–1871.
3. Wilson RF, Christensen BV, Olivari MT, Simon A, White CW, Laxson DD. Evidence for structural sympathetic reinnervation after orthotopic cardiac transplantation in humans. Circulation. 1991; 83: 1210–1220.
4. Sun D, Huang A, Mital S, Kichuk MR, Marboe CC, Addonizio LJ, Michler RE, Koller A, Hintze TH, Kaley G. Norepinephrine elicits beta2-receptor–mediated dilation of isolated human coronary arterioles. Circulation. 2002; 106: 550–555.
5. Rossen JD, Winniford MD. Effect of increase in heart rate and arterial pressure on coronary flow reserve. J Am Coll Cardiol. 1993; 21: 343–348.[Abstract]
6. Wagner BP, Stingele R, Williams MA, Wilson DA, Traystman RJ, Hanley DF. NO contributes to neurohypophysial but not other regional cerebral fluorocarbon-induced hyperemia in cats. Am J Physiol. 1997; 273: H1994–H2000.[Medline] [Order article via Infotrieve]
7. Tawakol A, Forgione MA, Stuehlinger M, Alpert NM, Cooke JP, Loscalzo J, Fischman AJ, Creager MA, Gewirtz H. Homocysteine impairs coronary microvascular dilator function in humans. J Am Coll Cardiol. 2002; 40: 1051–1058.
8. Mayer BX, Mensik C, Krishnaswami S, Derendorf H, Eichler HG, Schmetterer L, Wolzt M. Pharmacokinetic-pharmacodynamic profile of systemic nitric oxide-synthase inhibition with L-NMMA in humans. Br J Clin Pharmacol. 1999; 47: 539–544.[CrossRef][Medline] [Order article via Infotrieve]
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