LETTERS TO THE EDITOR
Is the lower mortality in patients treated with aspirin and angiotensin-converting enzyme inhibitors due to decreased norepinephrine release?
Roberto Levi, MD, DSca,
Ryushi Maruyama, MDa,
Neil C. E. Smith, BSca and
Nahid Seyedi, PhDa
a Department of Pharmacology, Cornell University Weill Medical College, 1300 York Avenue, Room LC419, New York, New York 10021, USA
We read with great interest the article by Leor et al. (1) supporting the use of aspirin in patients with coronary artery disease treated with angiotensin-converting enzyme (ACE) inhibitors. Their study challenges the old tenet that aspirin may prevent the cardioprotective effects of ACE inhibitors. Because ACE inhibitors prolong bradykinin’s half-life, their cardioprotective effects have been traditionally attributed to the antithrombotic and vasodilating actions of prostacyclin released from the endothelium by bradykinin (2). Evidence from our laboratory, however, supports the new findings of Leor et al. (1). We have recently demonstrated that bradykinin is generated not only by the endothelium, but also by cardiac sympathetic nerve endings (3). This promotes norepinephrine release in myocardial ischemia, thus contributing to reperfusion arrhythmias (4). Bradykinin-induced norepinephrine release in the heart is potentiated by cyclooxygenase products (5). Because aspirin inhibits cyclooxygenase, one would expect aspirin to diminish the bradykinin-induced, norepinephrine release from cardiac adrenergic terminals. Indeed, we have found this to be the case with indomethacin, another cyclooxygenase inhibitor (5). Endothelial dysfunction is known to occur in atherosclerotic coronary artery disease, myocardial ischemia and heart failure (6,7). Therefore, in these disease states, the prostacyclin- and nitric-oxide–mediated endothelium-dependent cardioprotective effects of bradykinin are likely to be attenuated, and the deleterious effects of bradykinin-induced norepinephrine release predominate. In fact, coronary arteries with dysfunctional endothelium are hypersensitive to the vasoconstricting effects of catecholamines (8). Thus, the improved survival demonstrated by Leor et al. (1) may be due to an aspirin-induced reduction of norepinephrine release within the heart. Indeed, in the Evaluation of Losartan in the Elderly (ELITE) study (9), plasma norepinephrine was found to be increased in patients treated with the ACE inhibitor captopril, but decreased in those treated with the angiotensin receptor antagonist losartan. Increased plasma norepinephrine is associated with a greater risk of cardiovascular morbidity and mortality (10). In the ELITE study, patients taking captopril had a higher mortality rate than those taking losartan (9). Accordingly, decreased norepinephrine release could well be an important mechanism associated with the lower mortality found by Leor et al. (1) in patients treated with ACE inhibitors and aspirin in combination.
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1. Leor J, Reicher-Reiss H, Goldbourt U, et al. Aspirin and mortality in patients treated with angiotensin-converting enzyme inhibitors—a cohort study of 11,575 patients with coronary artery disease. J Am Coll Cardiol. 1999;33:1920–1925[Abstract/Free Full Text]
2. Scicli AG. Increases in cardiac kinins as a new mechanism to protect the heart. Hypertension. 1994;23:419–421[Free Full Text]
3. Seyedi N, Win T, Lander HM, Levi R. Bradykinin B2-receptor activation augments norepinephrine exocytosis from cardiac sympathetic nerve endings: mediation by autocrine/paracrine mechanisms. Circ Res. 1997;81:774–784[Abstract/Free Full Text]
4. Hatta E, Maruyama R, Marshall SJ, Imamura M, Levi R. Bradykinin promotes ischemic norepinephrine release in guinea pig and human hearts. J Pharmacol Exp Ther. 1999;288:919–927[Abstract/Free Full Text]
5. Seyedi N, Maruyama R, Levi R. Bradykinin activates a cross-signaling pathway between sensory and adrenergic nerve endings in the heart: a novel mechanism of ischemic norepinephrine release? J Pharmacol Exp Ther. 1999;290:656–663[Abstract/Free Full Text]
6. Kubo SH, Rector TS, Bank AJ, Williams RE, Heifetz SM. Endothelium-dependent vasodilation is attenuated in patients with heart failure. Circulation. 1991;84:1589–1596[Abstract/Free Full Text]
7. Busse R, Fleming I. Endothelial dysfunction in atherosclerosis. J Vasc Res. 1996;33:181–194[Medline]
8. Vita JA, Treasure CB, Yeung AC, et al. Patients with evidence of coronary endothelial dysfunction as assessed by acetylcholine infusion demonstrate marked increase in sensitivity to constrictor effects of catecholamines. Circulation. 1992;85:1390–1397[Abstract/Free Full Text]
9. Pitt B, Segal R, Martinez FA, et al. Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly [ELITE] Study). Lancet. 1997;349:747–752[CrossRef][Medline]
10. Benedict CR, Shelton B, Johnstone DE, et al. Prognostic significance of plasma norepinephrine in patients with asymptomatic left ventricular dysfunction. Circulation. 1996;94:690–697[Abstract/Free Full Text]
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