(Circulation. 1999;100:2305.)
© 1999 American Heart Association, Inc.
Editorials |
Bradykinin in the Heart
Friend Or Foe?
From the University of Alabama, Department of Medicine, Vascular Biology and Hypertension Program, Division of Cardiovascular Disease and the Birmingham Veterans Affairs Medical Center, University Station, Birmingham, Ala.
Key Words: Editorials • bradykinin • angiotensin • myocardium • heart failure • hypertension
Hypertension and heart failure are marked by activation of both the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system. These forms of neurohumoral activation, in turn, have deleterious effects on the heart, kidney, and other target organs, worsening the prognosis in these disease states. Pharmacological agents that interrupt the RAAS are useful in both improving hemodynamics and preventing morbidity and mortality in such patients. In particular, treatment with ACE inhibitors has been shown to improve survival in patients with advanced heart failure and after myocardial infarction. It is hypothesized that ACE inhibitors exert beneficial effects by inhibiting both circulating and cardiac tissue ACE, thus attenuating unfavorable remodeling of the left ventricle (LV), reducing afterload, and improving the balance between thrombotic and thrombolytic factors. It remains unclear whether the dominant mechanism of action of ACE inhibitors in the setting of LV dysfunction relates to their global hemodynamic effects (which result in improved loading conditions), to reduced production of angiotensin (Ang) II with subsequent diminished Ang II type 1 (AT1) receptor activation, or to alteration of other neurohormonal systems, such as the kallikrein-kinin system.
Importantly, in addition to generating Ang II from Ang I, ACE catalyzes the degradation of bradykinin (BK) to inactive metabolites.1 Studies of recombinant full-length ACE have shown that the apparent Km of ACE for BK is substantially lower than for Ang I, which indicates more favorable kinetics for hydrolysis of BK than for conversion of Ang I to Ang II.2 Furthermore, site-directed mutagenesis demonstrated that the Km for BK was lower than that for Ang I at both N and C active sites of ACE, which suggests that at physiological concentrations, BK could be a preferential substrate over Ang I at both active sites of ACE.2
The biological effects of BK and other kinins are mediated by stimulation of specific receptors, classified as BK1 and BK2, both of which have been cloned and extensively characterized.3 BK1 receptors are expressed mainly in pathological conditions such as tissue injury and are thought to mediate the inflammatory and pain-producing effects of kinins; BK2 receptors mediate most of the known cardiovascular effects of kinins. In the vasculature, BK-mediated activation of endothelial BK2 receptors stimulates endogenous nitric oxide synthase (NOS), thus increasing NO and counteracting the effects of Ang II by inhibiting contraction and growth of smooth muscle cells.4 Both BK2 receptors5 and NOS activity have been detected in cardiac myocytes,6 and an intact kallikrein/kinin system has been found in the heart.7 Kinins are detectable in the effluent of isolated perfused hearts and are increased by ACE inhibitors, as well as by ischemia,8 9 which demonstrates that the cardiac kallikrein/kinin system can be regulated.
Studies in a mouse strain with targeted disruption of the BK2 receptor gene have given important new insights into the role of the kallikrein/kinin system in the pathogenesis of hypertension and heart failure.10 11 Mice lacking a functional BK2 gene (BK2r-/-) have higher blood pressures and heavier hearts than wild-type mice, as well as exaggerated pressor responses to exogenous Ang II and to chronic dietary salt supplementation.10 Chronic administration of an AT1 receptor antagonist reduced blood pressures of BK2r-/- mice to levels seen in wild-type mice, whereas either blockade of the BK2 receptor with icatibant or inhibition of NOS with nitro-L-arginine-methyl ester (L-NAME) increased blood pressures of wild-type mice to levels seen in BK2r-/- animals. These data suggest that a normally functioning BK2 receptor is needed for the maintenance of normal blood pressure homeostasis and that inactivation of this receptor could contribute to the development of hypertension by leaving the activity of endogenous vasoconstrictor agents, particularly Ang II, unopposed.
In the current issue of Circulation, Emanueli and coworkers11 follow up this important work by demonstrating the gradual development of a dilated cardiomyopathy associated with perivascular and reparative fibrosis in BK2r-/- mice. Importantly, mice heterozygous for the BK2 receptor (BK2r+/-) had a delayed increase in blood pressure, attenuated LV dilation and fibrosis, and preserved LV function compared with BK2r-/- mice, which demonstrates a gene dosage effect on the cardiovascular phenotype. BK2r+/- mice, in which the cardiovascular effects of the kallikrein/kinin system are attenuated but not extinguished, are likely more reflective of the human state, in which increases in blood pressure and LV enlargement and dysfunction generally develop slowly over a lifetime.
The concept that BK may play an important role in cardiovascular function and in the pathogenesis of cardiovascular disease in humans gained further credence from the observation that chronic ACE inhibitor treatment increases circulating and/or tissue kinin levels2 but does not produce sustained inhibition of Ang II.12 The beneficial effects of ACE inhibitor therapy are maintained in the face of normal plasma and tissue Ang II levels. Continued Ang II production during ACE inhibitor therapy occurs in the human heart and blood vessels because of alternative Ang II–forming pathways, particularly serine protease chymase, that bypass ACE.
Evidence obtained from both animal models and humans suggests that the benefits of ACE inhibitor therapy may be mediated by kinins. In patients with hypertension, the coadministration of the selective BK2 receptor antagonist icatibant significantly attenuated the acute hypotensive effect of captopril.13 This effect was observed in both black and white hypertensive subjects, as well as in normotensive volunteers. Work in isolated ejecting guinea pig hearts also demonstrated BK-induced enhancement of LV relaxation that was attributable to the paracrine release of NO.14 Similarly, captopril caused a progressive acceleration of LV relaxation without affecting systolic parameters or coronary artery flow in the isolated ejecting guinea pig heart15 and in the hypertrophied rat heart.16 These findings are in keeping with recent studies demonstrating that infusion of enalaprilat into the left anterior descending coronary artery of patients with LV hypertrophy improved regional diastolic function of the anterior wall in the absence of systemic hemodynamic and neurohormonal effects.17 These in vivo studies must be taken in context with the finding that BK significantly reduced the amplitude of shortening of isolated guinea pig ventricular myocytes in culture only when myocytes were cocultured with endothelial cells.18
In addition to the aforementioned interactions between the RAAS and the kallikrein/kinin system at the level of ACE, there is mounting evidence for a direct relationship between Ang peptides and BK levels in-vivo. Siragy et al19 reported that during low sodium intake, BK levels were increased in the interstitial fluid space of the dog kidney and that this effect was mediated by activation of the RAAS via a non-AT1 receptor pathway. Subsequent studies20 in the rat in vivo demonstrated that during low sodium intake, Ang II infused into the renal artery stimulated renal interstitial cGMP and that this effect was blocked by the AT2 receptor antagonist PD 123319 and the NOS inhibitor L-NAME. These data suggest that activation of the RAAS during sodium depletion increases BK and NO production through stimulation of the AT2 receptor by Ang II. The authors postulated that the increase in renal BK levels during sodium depletion offsets or modulates the vasoconstriction induced by stimulation of the RAAS.
Another interaction between the RAAS and the kallikrein/kinin system has been reported at the level of the Ang II peptide fragments, including Ang-(1–7), with BK. Ang-(1–7) is formed from Ang I and Ang II by peptidases other than ACE, and ACE inhibition is associated with elevations of Ang-(1–7), because blockade of ACE activity diverts the pathway of Ang II formation from Ang II to Ang-(1–7). Furthermore, studies in isolated canine coronary arteries21 have shown that Ang-(1–7) acts as a local mediator of kinin-induced vasodilation by releasing NO and inhibiting ACE. Recent data have demonstrated that the hypotensive effect of ACE inhibitor treatment in the spontaneously hypertensive rat was mediated by Ang-(1–7) via stimulation of a non-AT1/AT2 angiotensin subtype receptor.22 Thus, it has been hypothesized that Ang-(1–7) is synergistic with BK either because it has an agonist effect on a novel non-AT1/AT2 angiotensin subtype receptor, because it is an alternative ligand for the BK2 receptor, or because it inhibits the enzymatic inactivation of BK.
It has been proposed that both the RAAS and the kallikrein/kinin system are activated in pathophysiological states and that BK protects against the adverse effects of Ang II in these situations. For example, in a canine model of pacing tachycardia-induced heart failure, Cheng and coworkers23 demonstrated that circulating BK levels were significantly increased and that BK, acting through BK2 receptors, produced coronary vasodilation and improved LV relaxation and ventricular performance. Furthermore, concomitant treatment with BK2 receptor antagonists has been shown to reverse ACE inhibitor–induced attenuation of LV hypertrophy in dog24 and rat25 models of myocardial infarction and pressure overload hypertrophy. However, Weber and coworkers have questioned the proposed protective effects of BK at the myocardial structural level. In rat models of chronic exogenous Ang II infusion26 and myocardial infarction,27 administration of icatibant prevented perivascular fibrosis, which suggests that pharmacological interference with BK receptor binding or prostaglandin synthesis is associated with reduced fibrillar collagen formation. These findings suggest that in the setting of chronic Ang II excess, BK may have a deleterious effect on myocardial structure that is mediated by the BK2 receptor.
BK is also upregulated in acutely ischemic myocardium, and its effects may offset the increases in myocardial oxygen demand imposed by enhanced local production of catecholamines and Ang II. It has been hypothesized that further enhancement in BK production in the setting of ACE inhibitor therapy may protect the ischemic myocardium by these mechanisms. In support of this hypothesis, Yang and coworkers28 demonstrated that the cardioprotective effect of preconditioning was abolished in BK2 knockout mice, as well as in mice deficient in high-molecular-weight kininogen.
However, there is controversy regarding the protective effect of BK in myocardial ischemia. Seyedi and coworkers29 demonstrated an active kallikrein/kinin system in a preparation of sympathetic nerve endings from the guinea pig heart that produced norepinephrine exocytosis when BK synthesis was increased or when its breakdown was retarded by ACE inhibitor treatment. This observation is consistent with the finding of diminished norepinephrine release from isolated atria of BK2r-/- mice.30 Taken together, these findings raise the possibility of a differential effect of BK accumulation in the cardiac interstitium, where it interacts directly with nerve terminals and fibroblasts and may have a deleterious effect by promoting norepinephrine release and perivascular/myocardial fibrosis, versus at the luminal surface of the vasculature, where it interacts with endothelial cells and may have a beneficial effect by promoting NO synthesis. Further study is needed to test this intriguing hypothesis.
Footnotes
Reprint requests to Louis J. Dell’Italia, MD, McCallum Basic Health Sciences Building, 1918 University Blvd, Room 834, Birmingham, AL 35294-0005.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
1. Margolius HS. Kallikreins and kinins: molecular characteristics and cellular and tissue responses. Diabetes. 1996;45(suppl I):S14–S19.
2.
Zisman LS. Inhibiting tissue
angiotensin-converting enzyme: a pound of flesh without the
blood. Circulation. 1998;98:2788–2790.
3. Tscope CP, Gohlke YZ, Zhu W, Linz B, Scholkens B, Unger T. Antihypertensive and cardioprotective effects after angiotensin-converting enzyme inhibition: role of kinins. J Card Fail. 1997;3:133–148.[Medline] [Order article via Infotrieve]
4. Garg VC, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest. 1989;83:1774–1777.
5.
Minshall RD, Nakamure F, Becker RP, Rabito SF.
Characterization of bradykinin B2 receptors in
adult myocardium and neonatal rat
cardiomyocytes. Circ Res. 1995;76:773–780.
6.
Balligand JL, Kobzik L, Han X, Kaye DM, Belhassen L,
Ohara DS, Kelly RA, Smith TW, Michel T. Nitric oxide-dependent
parasympathetic signaling is due to activation of constitutive
endothelial (type III) nitric oxide synthase in cardiac
myocytes. J Biol Chem. 1995;270:14582–14586.
7.
Nolly H, Carbina LA, Scicli G, Carretero OA, Scicli
AG. A local kallikrein-kinin system is present in rat hearts.
Hypertension. 1994;23:919–923.
8. Lamontagne D, Nadeau R, Adam A. Effect of enalaprilat on bradykinin and des-Arg9-bradykinin release following reperfusion of the ischemic rat heart. Br J Pharmacol. 1995;115:476–478.[Medline] [Order article via Infotrieve]
9.
Campbell DJ, Kladis A, Duncan AM. Effect of converting
enzyme inhibitors on angiotensin and bradykinin
peptides. Hypertension. 1994;23:439–449.
10.
Madeddu P, Varoni MV, Palomba D, Emanueli C, Demontis
MP, Glorioso N, Dessi-Fulgheri P, Sarzani R, Anania V.
Cardiovascular phenotype of a mouse strain with
disruption of the bradykinin B2-receptor gene. Circulation. 1997;96:3570–3578.
11.
Emanueli C, Maestri R, Corradi D, Marchione R, Minasi
A, Tozzi MG, Salis MB, Straino S, Capogrossi M, Olivetti G, Madeddu P.
Dilated and failing cardiomyopathy in bradykinin
B2 receptor knockout mice.
Circulation. 1999;100:2359–2365.
12.
Baruch L, Anand I, Cohen IS, Ziesche S, Judd D, Cohn
JN, for the Vasodilator Heart Failure Trial (V-HeFT) Study Group.
Augmented short- and long-term hemodynamic and hormonal
effects of an angiotensin receptor blocker added to
angiotensin converting enzyme inhibitor therapy
in patients with heart failure. Circulation. 1999;99:2658–2664.
13.
Gainer JV, Morrow JD, Loveland A, King DJ, Brown NJ.
Effect of bradykinin-receptor blockade on the response to
angiotensin-converting-enzyme inhibitor in
normotensive and hypertensive subjects. N Engl J
Med. 1998;339:1285–1292.
14.
Grocott-Mason R, Anning P, Evans H, Lewis MJ, Shah AM.
Modulation of left ventricular relaxation in the isolated
ejecting heart by endogenous nitric oxide. Am J
Physiol. 1994;267:H1804–H1813.
15.
Anning P, Grocott-Mason RM, Lewis MJ, Shah AM.
Enhancement of left ventricular relaxation in the isolated
heart by an angiotensin-converting enzyme
inhibitor. Circulation. 1995;92:2660–2665.
16.
Schunkert H, Jackson B, Tang SS, Schoen FJ, Smits JFM,
Apstein CS, Lorell BH. Distribution and functional significance of
cardiac ACE in hypertrophied rat hearts. Circulation. 1993;87:1328–1339.
17.
Friedrich SP, Lorell BH, Rousseau MF, Hayashida W, Hess
OM, Douglas PS, Gordon S, Keighley CS, Benedict C, Krayenbuehl HP,
Grossman W, Pouleur H. Intracardiac angiotensin-converting
enzyme inhibition improves diastolic function in patients
with left ventricular hypertrophy due to aortic
stenosis. Circulation. 1994;90:2761–2771.
18.
Brady AJB, Warren JB, Poole-Wilson PA, Williams TJ,
Harding SE. Nitric oxide attenuates cardiac myocyte contraction.
Am J Physiol. 1993;265:H176–H182.
19. Siragy HM, Jaffa AA, Margolius HS, Carey RM. Renin-angiotensin system modulates renal bradykinin production. Am J Physiol. 1996;271(Regul Integr Comp Physiol 40):R1090–R1095.
20. Siragy HM, Carey RM. The subtype 2 (AT2) angiotensin receptor mediates renal production of nitric oxide in conscious rats. J Clin Invest. 1997;97:264–269.
21.
Brosnihan KB, Li P, Ferrario CM.
Angiotensin-(1–7) dilates canine coronary arteries
through kinins and nitric oxide. Hypertension. 1996;27:523–528.
22. Asad A, Gorelik G, Cabrini LA, Scicli AG. Angiotensin-(1–7) induces bradykinin-mediated hypotensive responses in anesthetized rats. Hypertension. 1997;30(pt 1):217–221.
23.
Cheng CP, Onishi K, Ohte N, Suzuki M, Little WC.
Functional effects of endogenous bradykinin in congestive
heart failure. J Am Coll Cardiol. 1998;31:1679–1686.
24. Linz W, Schölkens B. A specific B2 bradykinin receptor antagonist HOE 140 abolishes the antitrophic effect of ramipril. Br J Pharmacol. 1992;105:771–772.[Medline] [Order article via Infotrieve]
25.
McDonald KM, Mock J, D’Aloia A, Parrish T, Hauer K,
Francis G, Stillman A, Cohn JN. Bradykinin antagonism inhibits the
antigrowth effect of converting enzyme inhibition in the dog
myocardium after discrete transmural myocardial necrosis.
Circulation. 1995;91:2043–2048.
26. Sigusch HH, Campbell SE, Weber KT. Angiotensin II-induced myocardial fibrosis in rats: role of nitric oxide, prostaglandins and bradykinin. Cardiovasc Res. 1996;31:546–554.[Medline] [Order article via Infotrieve]
27. de Carvalho C, Sun Y, Weber KT. Wound healing following myocardial infarction in the rat: role for bradykinin and prostaglandins. J Moll Cell Cardiol. 1996;28:1279–1285.[Medline] [Order article via Infotrieve]
28. Yang X-P, Liu Y-H, Scicli GM, Webb CR, Carretero O. Role of kinins in the cardioprotective effect of preconditioning: study of myocardial ischemia/reperfusion injury in B2 kinin receptor knockout mice and kininogen deficient mice. Hypertension. 1997;30(pt 2):735–740.
29.
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.
30. Chulak C, Couture R, Fourcart S. Modulatory effects of bradykinin on noradrenaline release in isolated atria from normal and B2 knockout transgenic mice. Eur J Pharmacol. 1998;346:167–174.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  H. S. Lim, R. J. MacFadyen, and G. Y. H. Lip Diabetes Mellitus, the Renin-Angiotensin-Aldosterone System, and the Heart Arch Intern Med, September 13, 2004; 164(16): 1737 - 1748. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Oishi, R. Ozono, Y. Yano, Y. Teranishi, M. Akishita, M. Horiuchi, T. Oshima, and M. Kambe Cardioprotective Role of AT2 Receptor in Postinfarction Left Ventricular Remodeling Hypertension, March 1, 2003; 41(3): 814 - 818. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Scholze, E. Moskvina, M. Mayer, H. Just, H. Kubista, and S. Boehm Sympathoexcitation by Bradykinin Involves Ca2+-Independent Protein Kinase C J. Neurosci., July 15, 2002; 22(14): 5823 - 5832. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-C. Wei, C. M. Ferrario, K. B. Brosnihan, D. M. Farrell, W. E. Bradley, A. A. Jaffa, and L. J. Dell'Italia Angiotensin Peptides Modulate Bradykinin Levels in the Interstitium of the Dog Heart in Vivo J. Pharmacol. Exp. Ther., January 1, 2002; 300(1): 324 - 329. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. M. Multani, R. S. Krombach, A. T. Goldberg, M. K. King, J. W. Hendrick, J. A. Sample, S. C. Baicu, C. Joffs, M. deGasparo, and F. G. Spinale Myocardial Bradykinin Following Acute Angiotensin-Converting Enzyme Inhibition, AT1 Receptor Blockade, or Combined Inhibition in Congestive Heart Failure Journal of Cardiovascular Pharmacology and Therapeutics, December 1, 2001; 6(4): 369 - 376. [Abstract] [PDF]
|
|
|
|
 |
|
 M. Schachter ACE inhibitors, angiotensin receptor antagonists and bradykinin Journal of Renin-Angiotensin-Aldosterone System, March 1, 2000; 1(1): 27 - 29. [PDF]
|
|
|
|
 |
|
 X.-P. Yang, Y.-H. Liu, D. Mehta, M. A. Cavasin, E. Shesely, J. Xu, F. Liu, and O. A. Carretero Diminished Cardioprotective Response to Inhibition of Angiotensin-Converting Enzyme and Angiotensin II Type 1 Receptor in B2 Kinin Receptor Gene Knockout Mice Circ. Res., May 25, 2001; 88(10): 1072 - 1079. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||