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(Circulation. 2002;106:e147.)
© 2002 American Heart Association, Inc.

Correspondence

Angiotensin-(1–7) Attenuates the Development of Heart Failure After Myocardial Infarction in Rats

John McMurray, BSc(Hons), MBChB(Hons), MD, FRCP, FESC; Andrew P. Davie, BSc(Hons), MBChB, MD, MRCP

University of Glasgow, Glasgow, Scotland

To the Editor:

We read with interest the report by Loot et al¹ and the accompanying editorial² on the possible role of angiotensin-(1–7) in heart failure and cardiovascular regulation in general. It is also commonly stated (and repeated by Ferrario²) that angiotensin converting-enzyme (ACE) inhibitors increase angiotensin-(1–7) and that angiotensin-(1–7) may contribute to the actions of ACE inhibitors. We believe that neither of these views may be valid.

Although it is true that angiotensin-(1–7) may have pharmacological and even physiological effects in experimental animals, the same cannot be said for humans. We have shown that even high concentrations of angiotensin-(1–7) given by brachial arterial infusion do not cause forearm vasodilatation in patients with chronic heart failure.³ Neither were we able to show any potentiation of the vasodilator action of bradykinin, as reported in animal studies and discussed by Ferrario.² The only other study in humans that we know of showed that high doses of angiotensin-(1–7) actually had a pressor effect, rather than the vasodepressor effect predicted on the basis of experiments in animals.⁴

The view that ACE inhibitors increase plasma angiotensin-(1–7) concentrations is based on 1 study in humans.⁵ Although that study showed that angiotensin-(1–7) levels were increased by a last dose of captopril at the end of 6 months of treatment with captopril, even that increased level was not as high as the pretreatment level, which was itself unaffected by the first dose of captopril. This was in marked contrast to the effects of captopril on angiotensin I levels.

Consequently, we would caution readers that the role of angiotensin-(1–7) both in cardiovascular regulation and in the action of ACE inhibitors is far from clear in humans. What evidence there is suggests that angiotensin-(1–7) may be physiologically and pathophysiologically irrelevant.

References

1. Loot A, Roks AJM, Henning RH, et al. Angiotensin-(1–7) attenuates the development of heart failure after myocardial infarction in rats. Circulation. 2002; 105: 1548–1550.[Abstract/Free Full Text]
   
2. Ferrario CM. Does angiotensin-(1–7) contribute to cardiac adaptation and preservation of endothelial function in heart failure? Circulation. 2002; 105: 1523–1525.[Free Full Text]
   
3. Davie AP, McMurray JJV. Effect of angiotensin-(1–7) and bradykinin in patients with heart failure treated with an ACE inhibitor. Hypertension. 1999; 34: 457–460.[Abstract/Free Full Text]
   
4. Kono T, Taniguchi A, Imura H, et al. Biological activities of angiotensin II-(1-6)-hexapeptide and angiotensin II-(1–7)-heptapeptide in man. Life Sci. 1986; 38: 1515–1519.[CrossRef][Medline] [Order article via Infotrieve]
   
5. Luque M, Martin P, Martell N, et al. Effects of captopril related to increased levels of prostacyclin and angiotensin-(1–7) in essential hypertension. J Hypertens. 1996; 14: 799–805.[CrossRef][Medline] [Order article via Infotrieve]
   

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Response

Annemarieke E. Loot, MSc; Anton J.M. Roks, PhD; Robert H. Henning, MD, PhD; Wiek H. van Gilst, PhD

Department of Clinical Pharmacology, University of Groningen, Groningen, the Netherlands

René A. Tio, MD, PhD

Department of Cardiology, University Hospital Groningen, Groningen, the Netherlands

Albert J.H. Suurmeyer, MD, PhD

Department of Pathology, University Hospital Groningen, Groningen, the Netherlands

Frans Boomsma, PhD

Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands

We fully agree with McMurray and Davie that the effects of angiotensin (Ang)-(1–7) in humans are poorly documented. Nevertheless, it seems premature to conclude only from their study that Ang-(1–7) is devoid of effects in humans. In this particular study in heart failure patients on chronic angiotensin-converting enzyme (ACE) inhibitor therapy, they observed that Ang-(1–7) does not affect the vasodilator actions of bradykinin in human forearm.¹ These results may be explained by the fact that the potentiating effect of Ang-(1–7) on bradykinin is mediated solely through ACE inhibition.² In contrast, in similar experiments in healthy, untreated volunteers, Ueda et al³ did show a clear potentiation of bradykinin-induced forearm vasodilatation by Ang-(1–7). In addition, we have previously shown that Ang-(1–7) inhibits Ang II-induced vasoconstriction in isolated human vessels.⁴

Moreover, the above mentioned studies all focus on acute hemodynamic effects of Ang-(1–7). Our present study,⁵ however, shows that chronic infusion of the peptide is effective in preventing heart failure and preserves endothelial function. Correspondingly, no one will dispute the long-term benefits ACE inhibitors in heart failure, but their short-term hemodynamic effects are limited.

In conclusion, the current (sparse) literature rather supports a role for Ang-(1–7) in regulation of cardiovascular function in humans. Further studies, in particular those using long-term administration of Ang-(1–7) in patients, will be needed to provide conclusive answers.

References

1. Davie AP, McMurray JJV. Effect of angiotensin-(1–7) and bradykinin in patients with heart failure treated with an ACE inhibitor. Hypertension. 1999; 34: 457–460.[Abstract/Free Full Text]
   
2. Tom B, de Vries R, Saxena PR, et al. Bradykinin potentiation by angiotensin-(1–7) and ACE inhibitors correlates with ACE C- and N-domain blockade. Hypertension. 2001; 38: 95–99.[Abstract/Free Full Text]
   
3. Ueda S, Masumori-Maemoto S, Wada A, et al. Angiotensin(1–7) potentiates bradykinin-induced vasodilatation in man. J Hypertens. 2001; 19: 2001–2009.[CrossRef][Medline] [Order article via Infotrieve]
   
4. Roks AJM, van Geel PP, Pinto YM, et al. Angiotensin-(1–7) is a modulator of the human renin-angiotensin system. Hypertension. 1999; 34: 296–301.[Abstract/Free Full Text]
   
5. Loot AE, Roks AJ, Henning RH, et al. Angiotensin-(1–7) attenuates the development of heart failure after myocardial infarction in rats. Circulation. 2002; 105: 1548–1550.[Abstract/Free Full Text]
   

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