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The Kallikrein-Kinin System in Post-Myocardial Infarction Cardiac Remodeling
The Kallikrein–Kinin System in Post–Myocardial Infarction Cardiac Remodeling Kai C. Wollert,
MD,
and Helmut Drexler,
MD
Angiotensin converting-enzyme (ACE) inhibitors attenuate cardiac hypertrophy and prolong survival in animal models and patients after myocardial infarction (MI). Considering the dual function of the ACE, the therapeutic efficacy of ACE inhibitors after MI implicates the renin– angiotensin system and/or the kallikrein–kinin system in the pathophysiology of postinfarction cardiac remodeling. We evaluated the role of kinins, and their potential contribution to the antiremodeling effects of ACE inhibition in this setting. Rats underwent coronary artery ligation followed by chronic B2 kinin receptor blockade with icatibant (HOE 140). Additional groups of MI rats were treated with the ACE inhibitor lisinopril, alone or in combination with icatibant. B2 kinin receptor blockade enhanced the deposition of collagen (morphometric analysis) in the left ventricular interstitial space after MI, whereas markers of cardiomyocyte hypertrophy (left
ventricular weights and prepro-atrial natriuretic factor [ANF] expression) were not affected. Chronic ACE inhibition reduced collagen deposition and cardiomyocyte hypertrophy after MI. The inhibitory action of ACE inhibition on interstitial collagen was partially reversed by B2 kinin receptor blockade. However, B2 kinin receptor blockade did not attenuate the effects of ACE inhibition on cardiomyocyte hypertrophy. In conclusion, kinins inhibit the interstitial accumulation of collagen, but do not modulate cardiomyocyte hypertrophy after MI. Kinins contribute to the reduction of myocardial collagen accumulation by ACE inhibition; however, the effects of ACE inhibition on cardiomyocyte hypertrophy are related to reduced generation of angiotensin II. Q1997 by Excerpta Medica, Inc. Am J Cardiol 1997;80(3A):158A–161A
to a myocardial infarction (MI), the undergoes a remodeling process, characterIizednheartresponse by an early expansion of the infarcted area, pro-
ation of angiotensin II, but also from an inhibition of kinin breakdown. Indeed, the antihypertrophic effects of ACE inhibitors in rats with aortic banding can be abolished by the coadministration of a B2 kinin receptor antagonist.15 We assessed the significance of endogenous kinins, not augmented by ACE inhibition, in the regulation of post-MI ventricular remodeling, and delineated the contribution of kinins to the therapeutic actions of ACE inhibitors in this setting.
gressive dilatation of the left ventricle, and hypertrophic growth of the viable myocardium.1 – 3 Treatment with angiotensin-converting enzyme (ACE) inhibitors attenuates the remodeling process and prolongs survival in animal models and patients after MI.4 Animal studies indicate that angiotensin II type 1 (AT1) receptor antagonists attenuate ventricular remodeling and increase survival post-MI as well.5,6 The therapeutic efficacy of ACE inhibitors and AT1 receptor antagonists suggests a critical role for the renin–angiotensin system in post-MI ventricular remodeling. In further support of this notion, several components of the renin–angiotensin system—including angiotensinogen, the angiotensin-converting enzyme, and the AT1a and AT2 receptor subtypes— are up-regulated in the viable myocardium after MI.7 – 10 ACE (kininase II) not only catalyses the generation of angiotensin II from angiotensin I, but also functions as a potent kinin-degrading enzyme in plasma and tissues.11 – 13 Accordingly, plasma and tissue kinin levels are increased during treatment with ACE inhibitors.14 Considering the dual function of ACE, the therapeutic actions of ACE inhibitors after MI may result not only from a reduced generFrom the Abteilung Kardiologie, Medizinische Hochschule Hannover, Hannover, Germany. Supported in part by the German Research Foundation (Dr 148/ 6-3 and 148/7-2). Address for reprints: Helmut Drexler, MD, Abteilung Kardiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
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RESULTS AND DISCUSSION Bradykinin and related kinins are potent vasoactive peptides that are released from kininogen precursors by plasma and tissue kallikreins.16 Kallikrein and kininogen are synthesized in a number of tissues, including the heart,17,18 the vascular wall,19 – 21 and the kidneys.22,23 Tissue bradykinin levels are severalfold higher than circulating levels, indicating that kinins act predominantly in an autocrine and/or paracrine manner.13 ACE represents the major kinin-degrading enzyme in plasma and tissues.11 – 13 Considering the therapeutic efficacy of ACE inhibitors after MI, one might speculate that the kallikrein–kinin system is involved in the pathophysiology of post-MI ventricular remodeling. Accordingly, we evaluated the role of the endogenous kallikrein–kinin system in the chronic phase of post-MI ventricular remodeling, and assessed the contribution of kinin potentiation to the therapeutic effects of ACE inhibition in this setting.24 Experimental myocardial infarction was induced in Sprague–Dawley rats by left coronary artery ligation, as described previously.9 A sham operation was performed in control animals.9 The
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protocol was approved by the local ethical committee on animal research. Treatment was initiated 7 days after coronary ligation, i.e., during the chronic phase after MI, when the scarring process of the infarcted area is well under way.25 Post-MI rats were randomized into 4 groups and treated with (1) vehicle (tap water); (2) the B2 kinin receptor antagonist icatibant (HOE 140, Hoechst)26; (3) ACE inhibitor lisinopril; and (4) a combination of lisinopril and icatibant. Sham-operated animals were treated with vehicle. The ACE inhibitor lisinopril was dissolved in the drinking water at 38.5 mg/L, a dosage that was previously shown to result in a 25-fold rightward shift of the angiotensin I pressure–response curve during long-term treatment of rats.9 Icatibant was administered intraperitoneally by osmotic minipumps at 400 mg/kg per day, a dosage that resulted in a 35fold rightward shift of the bradykinin pressure–response curve (not shown). After treatment for 25 days, mean arterial blood pressure and heart rate were measured invasively. Subsequently, body weights and left ventricular weights were determined. To confirm an equal distribution of MI sizes among the infarcted groups, the scar length to circumference ratio (%) was determined by planimetry using a transverse slice cut from the equatorial plane of the left ventricle.9 The MI scar including the border zone was then removed from the remaining viable left ventricular myocardium; in sham-operated animals, corresponding parts of the left ventricle were discarded. Noninfarcted left ventricular tissue from the interventricular septum and the left ventricular free wall was used for morphometric and molecular analyses: Interstitial collagen volume fraction was quantified by computer-assisted tissue morphometry,5 prepro-atrial natriuretic factor (ANF) expression was determined by northern blot analysis.9 Despite the replacement of the infarcted area with a thin wall of scar tissue, left ventricular weights in vehicle-treated MI rats were unchanged as compared with sham-operated controls (Table I), strongly suggesting reactive hypertrophy of the surviving left ventricular myocardium.27 In agreement with previous studies, the remodeling process involved both the myocyte and the nonmyocyte compartments of the viable left ventricular myocardium: Left ventricular hypertrophy was associated with an up-regulation of prepro-ANF expression, a molecular marker of cardiomyocyte hypertrophy,28 and an increased deposition of fibrillar collagen in the left ventricular interstitial space (Table I).29,30 The role of the kallikrein–kinin system in postinfarction ventricular remodeling: B2 kinin receptor blockade
significantly increased left ventricular interstitial collagen, but did not alter cardiac weights or left ventricular prepro-ANF expression (Table I), suggesting that (1) endogenous kinins exert an inhibitory effect on the interstitial deposition of collagen in the myocardium, and (2) endogenous kinins are not involved in the regulation of cardiomyocyte hypertrophy after MI. Arterial blood pressure in post-MI rats was lower as compared with sham-operated controls, and
was not affected by B2 kinin receptor blockade (Table I). The increase in left ventricular collagen after B2 kinin receptor blockade was therefore not related to blood pressure changes, suggesting that blood pressure is not the prime determinant of collagen deposition in the noninfarcted myocardium after MI. In this regard, a recent study31 in rats made hypertensive by aortic banding demonstrated that myocardial fibrosis can be prevented by ACE inhibition even in a nonhypotensive dosage. In this study, the effect of ACE inhibition on interstitial collagen was attributed to a reduction of angiotensin II formation and/or an inhibition of kinin breakdown within the myocardium.31 Rat cardiac fibroblasts express B2 kinin receptors,32 and preliminary data suggest that bradykinin decreases collagen synthesis in rat cardiac fibroblasts.33 Based on these in vitro studies, it has been proposed that locally generated kinins may inhibit fibrous tissue formation in the heart.34 Our findings, demonstrating an increase in left ventricular collagen during B2 kinin receptor blockade in the absence of changes in arterial blood pressure, support this hypothesis and provide the first in vivo evidence that endogenous kinins, not augmented by ACE inhibition, attenuate the interstitial deposition of collagen in the myocardium. The contribution of kinin potentiation to the effects of ACE inhibition after myocardial infarction: As shown
previously by our group, high-dose ACE inhibition with lisinopril—characterized by a sustained reduction of arterial blood pressure and a pronounced inhibition of tissue ACE—is required to attenuate cardiac remodeling and to prolong survival after MI in the rat.9 By contrast, low-dose lisinopril, although exerting significant inhibition of plasma and pulmonary ACE, does not affect the remodeling process and does not reduce long-term mortality.9 To delineate the contribution of kinins to the therapeutic effects of high-dose ACE inhibition post-MI, we employed the B2 kinin receptor antagonist icatibant. In agreement with our previous results, high-dose lisinopril reduced left ventricular weights and left ventricular prepro-ANF expression after MI; moreover, lisinopril attenuated the deposition of collagen in the left ventricular interstitial space (Table I). B2 kinin receptor blockade did not attenuate the effects of lisinopril on left ventricular weights and left ventricular prepro-ANF expression, i.e., markers of cardiomyocyte hypertrophy (Table I). By contrast, the effects of lisinopril on left ventricular collagen were partially reversed by chronic B2 kinin receptor blockade. The reduction of arterial blood pressure by high-dose lisinopril was not affected by B2 kinin receptor blockade and therefore appeared to be kinin independent (Table I). The contribution of kinins to the cardiovascular effects of ACE inhibitors has previously been investigated in animal models of hypertension: B2 kinin receptor blockade abolishes the effects of ACE inhibition on arterial blood pressure and cardiac weights in rats with aortic coarctation,15 suggesting that kinins may contribute to the antihypertrophic
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TABLE I Results of Myocardial Infarction Induced by Left Coronary Artery Ligation Sham, Vehicle n MI size (%) HR (min01) MAP (mm Hg) BW (g) LVW (g) LVW/BW (g/kg) preproANF/28S (ratio) CVF (%)
6 0 382 { 17 124 { 2* 458 { 22 1.01 { 0.03 2.21 { 0.05 0.1 { 0.0† 1.2 { 0.2‡
MI, Vehicle
MI, Icatibant
MI, Lisinopril
7
8 40 { 4 354 { 14 93 { 4 431 { 8 0.94 { 0.01 2.18 { 0.03 1.5 { 0.3 11.0 { 0.2‡
7 41 { 4 354 { 20 74 { 4† 428 { 11 0.82 { 0.03* 1.93 { 0.07† 0.3 { 0.1† 3.2 { 0.2‡
41 379 100 428 0.98 2.29 2.3 6.1
{5 { 10 {5 { 16 { 0.04 { 0.05 { 0.4 { 0.2
MI, Lisinopril / Icatibant 7 40 351 76 423 0.79 1.87 0.8 4.9
{6 { 46 { 5† { 13 { 0.03† { 0.04‡ { 0.4* { 0.3*,§
n, number of animals per group; HR, heart rate; MAP, mean arterial blood pressure; BW, body weight; LVW, left ventricular weight; CVF, left ventricular collagen volume fraction. Data are presented as mean { SE. Differences between groups were first evaluated by analysis of variance (ANOVA). Subsequently, 5 prespecified post hoc comparisons were performed by Bonferroni’s t test: sham(V) vs MI(V), MI(I) vs MI(V), MI(L) vs MI(V), MI(L/I) vs MI(V), and MI(L/I) vs MI(L). A 2-tailed p-value õ0.05 was considered to indicate statistical significance. *p õ0.05; †p õ0.01; ‡p õ0.001 vs MI(V); §p õ0.001 MI(L/I) vs MI(L); otherwise p Å nonsignificant for MI(L/I) vs MI(L).
effects of ACE inhibitors in certain pathophysiologic situations. By contrast, the antihypertensive and antihypertrophic effects of ACE inhibition in strokeprone spontaneously hypertensive rats are kinin independent.35 The reason(s) for this discrepancy is (are) not known at the present time.36 We propose that the contribution of kinins to the cardiovascular effects of ACE inhibitors post-MI may depend on the degree of activation of the endogenous kiningenerating system: Acute myocardial ischemia/infarction induces an increased release of kinins from the heart, and is associated with elevated circulating kinin levels.12,37,38 In this situation, B2 kinin receptor blockade increases arterial blood pressure and reverses the hypotensive effect of ACE inhibition.39 By contrast, B2 kinin receptor blockade does not alter arterial blood pressure and does not counteract the hypotensive effects of ACE inhibition in normotensive rats without myocardial ischemia, suggesting that kinins are present in subthreshold concentrations.40 Likewise, B2 kinin receptor blockade did not affect arterial blood pressure and did not attenuate the hypotensive effects of ACE inhibition in our study. Differences in the activation status of the kallikrein–kinin system might therefore account for the different role of kinins during the acute versus the chronic phase after myocardial ischemia/infarction. McDonald et al41,42 recently assessed the role of kinins for the antihypertrophic effects of ramipril in a dog model of localized myocardial necrosis. In agreement with our previous study employing lisinopril in post-MI rats,9 a hypotensive dose of ramipril was required to prevent the increase in left ventricular mass after myocardial damage.42 However, in contrast to the results in the rat model, the antihypertrophic effects of ramipril in dogs with myocardial necrosis were abolished by B2 kinin receptor blockade.41 The timing of ACE inhibition differed between the studies of McDonald et al and our investigation: In the dog model, therapy was initiated 1 day after the DC shock procedure; by contrast, in our study treatment was started in the chronic phase, i.e., 7 days after coronary ligation. Early-onset ACE inhibition in dogs after coronary ligation has been 160A
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shown to prevent expansion of the infarcted area, marked increase in chamber volume, and increase in left ventricular mass, which develop during the first week after MI.43 Conceivably, the significance of kinin potentiation for the antigrowth effects of ACE inhibitors may be more pronouced in the early phase after myocardial injury, i.e., for the effects of ACE inhibitors on infarct size,39 infarct expansion, early chamber dilatation, and early increase in ventricular mass.43 In our study, B2 kinin receptor blockade partially reversed the effects of lisinopril on left ventricular interstitial fibrosis, suggesting that kinins contribute to the ability of ACE inhibition to reduce left ventricular collagen accumulation. Notably, rats treated with the B2 kinin receptor antagonist alone displayed increased left ventricular collagen. Therefore, it cannot be ruled out that the inhibitory action of the B2 kinin receptor antagonist on the antifibrotic effects of lisinopril reflects an inhibition of unaugmented basal kinin levels, rather than an inhibition of kinin levels augmented by lisinopril. Left ventricular collagen accumulation in rats receiving combined treatment with icatibant and lisinopril was significantly reduced as compared with vehicle-treated animals, thereby also implicating angiotensin II– mediated mechanism(s) in the reduction of myocardial collagen accumulation during ACE inhibition. In this regard, increased expression of ACE and the AT1 receptor has been shown to be anatomically coincident with sites of collagen formation within the viable myocardium after MI, supporting the notion that fibrous tissue formation may be regulated by locally generated angiotensin II.44,45
CONCLUSIONS As demonstrated in the present study, endogenous kinins attenuate the deposition of collagen in the left ventricular interstitial space during the chronic phase of post-MI cardiac remodeling. By contrast, endogenous kinins do not modulate cardiomyocyte hypertrophy in this setting. Kinin potentiation appears to contribute to the effects of long-term ACE inhibition on left ventricular collagen after MI. The beneficial effects of ACE inhibition on cardio-
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myocyte hypertrophy, however, are mediated by a kinin-independent mechanism, i.e., reduced generation of angiotensin II. Acknowledgment: We are grateful to Bernward A. Scho¨lkens, MD, and to Anita Lo¨w, MD, for providing us with icatibant and lisinopril, respectively.
1. Weisman HF, Bush DE, Mannisi JA, Weisfeldt ML, Healy B. Cellular mechanisms of myocardial infarct expansion. Circulation 1988;78:186–201. 2. Pfeffer JM. Progressive ventricular dilation in experimental myocardial infarction and its attenuation by angiotensin-converting enzyme inhibition. Am J Cardiol 1991;68:17D–25D. 3. Olivetti G, Capasso JM, Meggs LG, Sonnenblick EH, Anversa P. Cellular basis of chronic ventricular remodeling after myocardial infarction in rats. Circ Res 1991;68:856–869. 4. Pfeffer JM, Fischer TA, Pfeffer MA. Angiotensin-converting enzyme inhibition and ventricular remodeling after myocardial infarction. Annu Rev Physiol 1995;57:805–826. 5. Schieffer B, Wirger A, Meybrunn M, Seitz S, Holtz J, Riede UN, Drexler H. Comparative effects of chronic angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor blockade on cardiac remodeling after myocardial infarction in the rat. Circulation 1994;89:2273–2282. 6. Milavetz JJ, Raya TE, Johnson CS, Morkin E, Goldman S. Survival after myocardial infarction in rats: captopril versus losartan. J Am Coll Cardiol 1996;27:714–719. 7. Lindpaintner K, Lu W, Niedermajer N, Schieffer B, Just H, Ganten D, Drexler H. Selective activation of cardiac angiotensinogen gene expression in post-infarction ventricular remodeling in the rat. J Mol Cell Cardiol 1993;25:133–143. 8. Studer R, Reinecke H, Mu¨ller B, Holtz J, Just H, Drexler H. Increased angiotensin-1 converting enzyme gene expression in the failing human heart. Quantification by competitive RNA polymerase chain reaction. J Clin Invest 1994;94:301–310. 9. Wollert KC, Studer R, von Bu¨low B, Drexler H. Survival after myocardial infarction in the rat. Role of tissue angiotensin-converting enzyme inhibition. Circulation 1994;90:2457–2467. 10. Nio Y, Matsubara H, Murasawa S, Kanasaki M, Inada M. Regulation of gene transcription of angiotensin II receptor subtypes in myocardial infarction. J Clin Invest 1995;95:46–54. 11. Ishida H, Scicli AG, Carretero OA. Contribution of various rat plasma peptidases to kinin hydrolysis. J Pharmacol Exp Ther 1989;251:817–820. 12. Baumgarten CR, Linz W, Kunkel G, Scho¨lkens BA, Wiemer G. Ramiprilat increases bradykinin outflow from isolated hearts of rat. Br J Pharmacol 1993;108:293–295. 13. Campbell DJ, Kladis A, Duncan AM. Bradykinin peptides in kidney, blood, and other tissues of the rat. Hypertension 1993;21:155–165. 14. Campbell DJ, Kladis A, Duncan AM. Effects of converting enzyme inhibitors on angiotensin and bradykinin peptides. Hypertension 1994;23:439–449. 15. Linz W, Scho¨lkens BA. A specific B2-bradykinin receptor antagonist Hoe140 abolishes the antihypertrophic effect of ramipril. Br J Pharmacol 1992;105:771–772. 16. Bhoola KD, Figueroa CD, Worthy K. Bioregulation of kinins: kallikreins, kininogens, and kininases. Pharmacol Rev 1992;44:1–80. 17. Xiong W, Chen L, Woodley-Miller C, Simson JV, Chao J. Identification, purification and localization of tissue kallikrein in rat heart. Biochem J 1990;267:639–646. 18. Nolly H, Carbini LA, Scicli G, Carretero OA, Scicli AG. A local kallikrein– kinin system is present in rat hearts. Hypertension 1994;23:919–923. 19. Schmaier AH, Kuo A, Lundberg D, Murray S, Cines DB. The expression of high molecular weight kininogen on human umbilical vein endothelial cells. J Biol Chem 1988;263:16327–16333. 20. Saed GM, Carretero OA, MacDonald RJ, Scicli AG. Kallikrein messenger RNA in rat arteries and veins. Circ Res 1990;67:510–516. 21. Nolly H, Carretero OA, Scicli AG. Kallikrein release by vascular tissue. Am J Physiol 1993;265:H1209–H1214. 22. Figueroa CD, Maciver AG, Mackenzie JC, Bhoola KD. Localization of immunoreactive kininogen and tissue kallikrein in the human nephron. Histochemistry 1988;89:437–442.
23. Inoue H, Fukui K, Miyake Y. Identification and structure of the rat true
tissue kallikrein gene expressed in the kidney. J Biochem 1989;105:834–840. 24. Wollert KC, Studer R, Doerfer K, Schieffer E, Holubarsch C, Just H, Drexler
H. Differential effects of kinins on cardiomyocyte hypertrophy and interstitial collagen matrix in the surviving myocardium after myocardial infarction in the rat. Circulation 1997;95:1910–1917. 25. Fishbein MC, MacLean D, Maroko PR. Experimental myocardial infarction in the rat: qualitative and quantitative changes during pathologic evolution. Am J Pathol 1978;90:57–70. 26. Wirth K, Hock FJ, Albus U, Linz W, Alpermann HG, Anagnostopoulos H, Henke S, Breipohl G, Ko¨nig W, Knolle J, Scho¨lkens BA. Hoe140 a new potent and long acting bradykinin-antagonist: in vivo studies. Br J Pharmacol 1991;102:774–777. 27. Anversa P, Beghi C, Kikkawa Y, Olivetti G. Myocardial infarction in rats: infarct size, myocyte hypertrophy and capillary growth. Circ Res 1986;58:26– 37. 28. Drexler H, Ha¨nze J, Finckh M, Lu W, Just H, Lang RE. Atrial natriuretic peptide in a rat model of cardiac failure. Atrial and ventricular mRNA, atrial content, plasma levels, and effect of volume loading. Circulation 1989;79:620– 633. 29. Michel JB, Lattion AL, Salzmann JL, de Lourdes Cerol M, Philippe M, Camilleri JP, Corvol P. Hormonal and cardiac effects of converting enzyme inhibition in rat myocardial infarction. Circ Res 1988;62:641–650. 30. McCormick RJ, Musch TI, Bergman BC, Thomas DP. Regional differences in LV collagen accumulation and mature cross-linking after myocardial infarction in rats. Am J Physiol 1994;266:H354–H359. 31. Linz W, Schaper J, Wiemer G, Albus U, Scho¨lkens BA. Ramipril prevents left ventricular hypertrophy with myocardial fibrosis without blood pressure reduction: a one year study in rats. Br J Pharmacol 1992;107:970–975. 32. Katwa LC, Ratajska A, Cleutjens JPM, Sun Y, Zhou G, Lee SJ, Weber KT. Angiotensin-converting enzyme and kininase-II-like activities in cultured valvular interstitial cells of the rat heart. Cardiovasc Res 1995;29:57–64. 33. Villarreal FJ, Kim NN. Bradykinin and nitric oxide downregulate cardiac extracellular matrix production. Presented at the American Heart Association Scientific Conference on the Molecular Biology of the Normal, Hypertrophied, and Failing Heart. Salt Lake City, Utah, 1996. 34. Weber KT, Sun Y, Guarda E. Structural remodeling in hypertensive heart disease and the role of hormones. Hypertension 1994;23:869–877. 35. Gohlke P, Linz W, Scho¨lkens BA, Kuwer I, Bartenbach S, Schnell A, Unger T. Angiotensin-converting enzyme inhibition improves cardiac function. Role of bradykinin. Hypertension 1994;23:411–418. 36. Scicli AG. Increases in cardiac kinins as a new mechanism to protect the heart. Hypertension 1994;23:419–421. 37. Hashimoto K, Hamamoto H, Honda Y, Hirose M, Furukawa S, Kimura E. Changes in components of kinin system and hemodynamics in acute myocardial infarction. Am Heart J 1978;95:619–626. 38. Matsuki T, Shoji T, Yoshida S, Kudoh Y, Motoe M, Inoue M, Nakata T, Hosada S, Shimamoto K, Yellon D, Iimura O. Sympathetically induced myocardial ischemia causes the heart to release plasma kinin. Cardiovasc Res 1987;21:428–432. 39. Hartman JC, Wall TM, Hullinger TG, Shebuski RJ. Reduction of myocardial infarct size in rabbits by ramiprilat: reversal by the bradykinin antagonist Hoe140. J Cardiovasc Pharmacol 1993;21:996–1003. 40. Farhy RD, Carretero OA, Ho KL, Scicli AG. Role of kinins and nitric oxide in the effects of angiotensin-converting enzyme inhibitors on neointima formation. Circ Res 1993;72:1202–1210. 41. 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;2043–2048. 42. McDonald KM, Garr M, Carlyle PF, Francis GS, Hauer K, Hunter DW, Parish T, Stillamn A, Cohn JN. Relative effects of a1-adrenoreceptor blockade, converting enzyme inhibitor therapy, and angiotensin II subtype 1 receptor blockade on ventricular remodeling in the dog. Circulation 1994;90:3034– 3046. 43. Jugdutt BI, Khan MI, Jugdutt SJ, Blinston GE. Effect of enalapril on ventricular remodeling and function during healing after anterior myocardial infarction in the dog. Circulation 1995;91:802–812. 44. Sun Y, Weber KT. Angiotensin II receptor binding following myocardial infarction in the rat. Cardiovasc Res 1994;28:1623–1628. 45. Sun Y, Cleutjens JPM, Diaz-Arias AA, Weber KT. Cardiac angiotensin converting enzyme and myocardial fibrosis in the rat. Cardiovasc Res 1994;28:1423–1432.
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MD,
and Helmut Drexler,
MD
Angiotensin converting-enzyme (ACE) inhibitors attenuate cardiac hypertrophy and prolong survival in animal models and patients after myocardial infarction (MI). Considering the dual function of the ACE, the therapeutic efficacy of ACE inhibitors after MI implicates the renin– angiotensin system and/or the kallikrein–kinin system in the pathophysiology of postinfarction cardiac remodeling. We evaluated the role of kinins, and their potential contribution to the antiremodeling effects of ACE inhibition in this setting. Rats underwent coronary artery ligation followed by chronic B2 kinin receptor blockade with icatibant (HOE 140). Additional groups of MI rats were treated with the ACE inhibitor lisinopril, alone or in combination with icatibant. B2 kinin receptor blockade enhanced the deposition of collagen (morphometric analysis) in the left ventricular interstitial space after MI, whereas markers of cardiomyocyte hypertrophy (left
ventricular weights and prepro-atrial natriuretic factor [ANF] expression) were not affected. Chronic ACE inhibition reduced collagen deposition and cardiomyocyte hypertrophy after MI. The inhibitory action of ACE inhibition on interstitial collagen was partially reversed by B2 kinin receptor blockade. However, B2 kinin receptor blockade did not attenuate the effects of ACE inhibition on cardiomyocyte hypertrophy. In conclusion, kinins inhibit the interstitial accumulation of collagen, but do not modulate cardiomyocyte hypertrophy after MI. Kinins contribute to the reduction of myocardial collagen accumulation by ACE inhibition; however, the effects of ACE inhibition on cardiomyocyte hypertrophy are related to reduced generation of angiotensin II. Q1997 by Excerpta Medica, Inc. Am J Cardiol 1997;80(3A):158A–161A
to a myocardial infarction (MI), the undergoes a remodeling process, characterIizednheartresponse by an early expansion of the infarcted area, pro-
ation of angiotensin II, but also from an inhibition of kinin breakdown. Indeed, the antihypertrophic effects of ACE inhibitors in rats with aortic banding can be abolished by the coadministration of a B2 kinin receptor antagonist.15 We assessed the significance of endogenous kinins, not augmented by ACE inhibition, in the regulation of post-MI ventricular remodeling, and delineated the contribution of kinins to the therapeutic actions of ACE inhibitors in this setting.
gressive dilatation of the left ventricle, and hypertrophic growth of the viable myocardium.1 – 3 Treatment with angiotensin-converting enzyme (ACE) inhibitors attenuates the remodeling process and prolongs survival in animal models and patients after MI.4 Animal studies indicate that angiotensin II type 1 (AT1) receptor antagonists attenuate ventricular remodeling and increase survival post-MI as well.5,6 The therapeutic efficacy of ACE inhibitors and AT1 receptor antagonists suggests a critical role for the renin–angiotensin system in post-MI ventricular remodeling. In further support of this notion, several components of the renin–angiotensin system—including angiotensinogen, the angiotensin-converting enzyme, and the AT1a and AT2 receptor subtypes— are up-regulated in the viable myocardium after MI.7 – 10 ACE (kininase II) not only catalyses the generation of angiotensin II from angiotensin I, but also functions as a potent kinin-degrading enzyme in plasma and tissues.11 – 13 Accordingly, plasma and tissue kinin levels are increased during treatment with ACE inhibitors.14 Considering the dual function of ACE, the therapeutic actions of ACE inhibitors after MI may result not only from a reduced generFrom the Abteilung Kardiologie, Medizinische Hochschule Hannover, Hannover, Germany. Supported in part by the German Research Foundation (Dr 148/ 6-3 and 148/7-2). Address for reprints: Helmut Drexler, MD, Abteilung Kardiologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
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RESULTS AND DISCUSSION Bradykinin and related kinins are potent vasoactive peptides that are released from kininogen precursors by plasma and tissue kallikreins.16 Kallikrein and kininogen are synthesized in a number of tissues, including the heart,17,18 the vascular wall,19 – 21 and the kidneys.22,23 Tissue bradykinin levels are severalfold higher than circulating levels, indicating that kinins act predominantly in an autocrine and/or paracrine manner.13 ACE represents the major kinin-degrading enzyme in plasma and tissues.11 – 13 Considering the therapeutic efficacy of ACE inhibitors after MI, one might speculate that the kallikrein–kinin system is involved in the pathophysiology of post-MI ventricular remodeling. Accordingly, we evaluated the role of the endogenous kallikrein–kinin system in the chronic phase of post-MI ventricular remodeling, and assessed the contribution of kinin potentiation to the therapeutic effects of ACE inhibition in this setting.24 Experimental myocardial infarction was induced in Sprague–Dawley rats by left coronary artery ligation, as described previously.9 A sham operation was performed in control animals.9 The
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protocol was approved by the local ethical committee on animal research. Treatment was initiated 7 days after coronary ligation, i.e., during the chronic phase after MI, when the scarring process of the infarcted area is well under way.25 Post-MI rats were randomized into 4 groups and treated with (1) vehicle (tap water); (2) the B2 kinin receptor antagonist icatibant (HOE 140, Hoechst)26; (3) ACE inhibitor lisinopril; and (4) a combination of lisinopril and icatibant. Sham-operated animals were treated with vehicle. The ACE inhibitor lisinopril was dissolved in the drinking water at 38.5 mg/L, a dosage that was previously shown to result in a 25-fold rightward shift of the angiotensin I pressure–response curve during long-term treatment of rats.9 Icatibant was administered intraperitoneally by osmotic minipumps at 400 mg/kg per day, a dosage that resulted in a 35fold rightward shift of the bradykinin pressure–response curve (not shown). After treatment for 25 days, mean arterial blood pressure and heart rate were measured invasively. Subsequently, body weights and left ventricular weights were determined. To confirm an equal distribution of MI sizes among the infarcted groups, the scar length to circumference ratio (%) was determined by planimetry using a transverse slice cut from the equatorial plane of the left ventricle.9 The MI scar including the border zone was then removed from the remaining viable left ventricular myocardium; in sham-operated animals, corresponding parts of the left ventricle were discarded. Noninfarcted left ventricular tissue from the interventricular septum and the left ventricular free wall was used for morphometric and molecular analyses: Interstitial collagen volume fraction was quantified by computer-assisted tissue morphometry,5 prepro-atrial natriuretic factor (ANF) expression was determined by northern blot analysis.9 Despite the replacement of the infarcted area with a thin wall of scar tissue, left ventricular weights in vehicle-treated MI rats were unchanged as compared with sham-operated controls (Table I), strongly suggesting reactive hypertrophy of the surviving left ventricular myocardium.27 In agreement with previous studies, the remodeling process involved both the myocyte and the nonmyocyte compartments of the viable left ventricular myocardium: Left ventricular hypertrophy was associated with an up-regulation of prepro-ANF expression, a molecular marker of cardiomyocyte hypertrophy,28 and an increased deposition of fibrillar collagen in the left ventricular interstitial space (Table I).29,30 The role of the kallikrein–kinin system in postinfarction ventricular remodeling: B2 kinin receptor blockade
significantly increased left ventricular interstitial collagen, but did not alter cardiac weights or left ventricular prepro-ANF expression (Table I), suggesting that (1) endogenous kinins exert an inhibitory effect on the interstitial deposition of collagen in the myocardium, and (2) endogenous kinins are not involved in the regulation of cardiomyocyte hypertrophy after MI. Arterial blood pressure in post-MI rats was lower as compared with sham-operated controls, and
was not affected by B2 kinin receptor blockade (Table I). The increase in left ventricular collagen after B2 kinin receptor blockade was therefore not related to blood pressure changes, suggesting that blood pressure is not the prime determinant of collagen deposition in the noninfarcted myocardium after MI. In this regard, a recent study31 in rats made hypertensive by aortic banding demonstrated that myocardial fibrosis can be prevented by ACE inhibition even in a nonhypotensive dosage. In this study, the effect of ACE inhibition on interstitial collagen was attributed to a reduction of angiotensin II formation and/or an inhibition of kinin breakdown within the myocardium.31 Rat cardiac fibroblasts express B2 kinin receptors,32 and preliminary data suggest that bradykinin decreases collagen synthesis in rat cardiac fibroblasts.33 Based on these in vitro studies, it has been proposed that locally generated kinins may inhibit fibrous tissue formation in the heart.34 Our findings, demonstrating an increase in left ventricular collagen during B2 kinin receptor blockade in the absence of changes in arterial blood pressure, support this hypothesis and provide the first in vivo evidence that endogenous kinins, not augmented by ACE inhibition, attenuate the interstitial deposition of collagen in the myocardium. The contribution of kinin potentiation to the effects of ACE inhibition after myocardial infarction: As shown
previously by our group, high-dose ACE inhibition with lisinopril—characterized by a sustained reduction of arterial blood pressure and a pronounced inhibition of tissue ACE—is required to attenuate cardiac remodeling and to prolong survival after MI in the rat.9 By contrast, low-dose lisinopril, although exerting significant inhibition of plasma and pulmonary ACE, does not affect the remodeling process and does not reduce long-term mortality.9 To delineate the contribution of kinins to the therapeutic effects of high-dose ACE inhibition post-MI, we employed the B2 kinin receptor antagonist icatibant. In agreement with our previous results, high-dose lisinopril reduced left ventricular weights and left ventricular prepro-ANF expression after MI; moreover, lisinopril attenuated the deposition of collagen in the left ventricular interstitial space (Table I). B2 kinin receptor blockade did not attenuate the effects of lisinopril on left ventricular weights and left ventricular prepro-ANF expression, i.e., markers of cardiomyocyte hypertrophy (Table I). By contrast, the effects of lisinopril on left ventricular collagen were partially reversed by chronic B2 kinin receptor blockade. The reduction of arterial blood pressure by high-dose lisinopril was not affected by B2 kinin receptor blockade and therefore appeared to be kinin independent (Table I). The contribution of kinins to the cardiovascular effects of ACE inhibitors has previously been investigated in animal models of hypertension: B2 kinin receptor blockade abolishes the effects of ACE inhibition on arterial blood pressure and cardiac weights in rats with aortic coarctation,15 suggesting that kinins may contribute to the antihypertrophic
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TABLE I Results of Myocardial Infarction Induced by Left Coronary Artery Ligation Sham, Vehicle n MI size (%) HR (min01) MAP (mm Hg) BW (g) LVW (g) LVW/BW (g/kg) preproANF/28S (ratio) CVF (%)
6 0 382 { 17 124 { 2* 458 { 22 1.01 { 0.03 2.21 { 0.05 0.1 { 0.0† 1.2 { 0.2‡
MI, Vehicle
MI, Icatibant
MI, Lisinopril
7
8 40 { 4 354 { 14 93 { 4 431 { 8 0.94 { 0.01 2.18 { 0.03 1.5 { 0.3 11.0 { 0.2‡
7 41 { 4 354 { 20 74 { 4† 428 { 11 0.82 { 0.03* 1.93 { 0.07† 0.3 { 0.1† 3.2 { 0.2‡
41 379 100 428 0.98 2.29 2.3 6.1
{5 { 10 {5 { 16 { 0.04 { 0.05 { 0.4 { 0.2
MI, Lisinopril / Icatibant 7 40 351 76 423 0.79 1.87 0.8 4.9
{6 { 46 { 5† { 13 { 0.03† { 0.04‡ { 0.4* { 0.3*,§
n, number of animals per group; HR, heart rate; MAP, mean arterial blood pressure; BW, body weight; LVW, left ventricular weight; CVF, left ventricular collagen volume fraction. Data are presented as mean { SE. Differences between groups were first evaluated by analysis of variance (ANOVA). Subsequently, 5 prespecified post hoc comparisons were performed by Bonferroni’s t test: sham(V) vs MI(V), MI(I) vs MI(V), MI(L) vs MI(V), MI(L/I) vs MI(V), and MI(L/I) vs MI(L). A 2-tailed p-value õ0.05 was considered to indicate statistical significance. *p õ0.05; †p õ0.01; ‡p õ0.001 vs MI(V); §p õ0.001 MI(L/I) vs MI(L); otherwise p Å nonsignificant for MI(L/I) vs MI(L).
effects of ACE inhibitors in certain pathophysiologic situations. By contrast, the antihypertensive and antihypertrophic effects of ACE inhibition in strokeprone spontaneously hypertensive rats are kinin independent.35 The reason(s) for this discrepancy is (are) not known at the present time.36 We propose that the contribution of kinins to the cardiovascular effects of ACE inhibitors post-MI may depend on the degree of activation of the endogenous kiningenerating system: Acute myocardial ischemia/infarction induces an increased release of kinins from the heart, and is associated with elevated circulating kinin levels.12,37,38 In this situation, B2 kinin receptor blockade increases arterial blood pressure and reverses the hypotensive effect of ACE inhibition.39 By contrast, B2 kinin receptor blockade does not alter arterial blood pressure and does not counteract the hypotensive effects of ACE inhibition in normotensive rats without myocardial ischemia, suggesting that kinins are present in subthreshold concentrations.40 Likewise, B2 kinin receptor blockade did not affect arterial blood pressure and did not attenuate the hypotensive effects of ACE inhibition in our study. Differences in the activation status of the kallikrein–kinin system might therefore account for the different role of kinins during the acute versus the chronic phase after myocardial ischemia/infarction. McDonald et al41,42 recently assessed the role of kinins for the antihypertrophic effects of ramipril in a dog model of localized myocardial necrosis. In agreement with our previous study employing lisinopril in post-MI rats,9 a hypotensive dose of ramipril was required to prevent the increase in left ventricular mass after myocardial damage.42 However, in contrast to the results in the rat model, the antihypertrophic effects of ramipril in dogs with myocardial necrosis were abolished by B2 kinin receptor blockade.41 The timing of ACE inhibition differed between the studies of McDonald et al and our investigation: In the dog model, therapy was initiated 1 day after the DC shock procedure; by contrast, in our study treatment was started in the chronic phase, i.e., 7 days after coronary ligation. Early-onset ACE inhibition in dogs after coronary ligation has been 160A
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shown to prevent expansion of the infarcted area, marked increase in chamber volume, and increase in left ventricular mass, which develop during the first week after MI.43 Conceivably, the significance of kinin potentiation for the antigrowth effects of ACE inhibitors may be more pronouced in the early phase after myocardial injury, i.e., for the effects of ACE inhibitors on infarct size,39 infarct expansion, early chamber dilatation, and early increase in ventricular mass.43 In our study, B2 kinin receptor blockade partially reversed the effects of lisinopril on left ventricular interstitial fibrosis, suggesting that kinins contribute to the ability of ACE inhibition to reduce left ventricular collagen accumulation. Notably, rats treated with the B2 kinin receptor antagonist alone displayed increased left ventricular collagen. Therefore, it cannot be ruled out that the inhibitory action of the B2 kinin receptor antagonist on the antifibrotic effects of lisinopril reflects an inhibition of unaugmented basal kinin levels, rather than an inhibition of kinin levels augmented by lisinopril. Left ventricular collagen accumulation in rats receiving combined treatment with icatibant and lisinopril was significantly reduced as compared with vehicle-treated animals, thereby also implicating angiotensin II– mediated mechanism(s) in the reduction of myocardial collagen accumulation during ACE inhibition. In this regard, increased expression of ACE and the AT1 receptor has been shown to be anatomically coincident with sites of collagen formation within the viable myocardium after MI, supporting the notion that fibrous tissue formation may be regulated by locally generated angiotensin II.44,45
CONCLUSIONS As demonstrated in the present study, endogenous kinins attenuate the deposition of collagen in the left ventricular interstitial space during the chronic phase of post-MI cardiac remodeling. By contrast, endogenous kinins do not modulate cardiomyocyte hypertrophy in this setting. Kinin potentiation appears to contribute to the effects of long-term ACE inhibition on left ventricular collagen after MI. The beneficial effects of ACE inhibition on cardio-
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myocyte hypertrophy, however, are mediated by a kinin-independent mechanism, i.e., reduced generation of angiotensin II. Acknowledgment: We are grateful to Bernward A. Scho¨lkens, MD, and to Anita Lo¨w, MD, for providing us with icatibant and lisinopril, respectively.
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