Cardioprotection Induced by AT1R Blockade After Reperfused Myocardial Infarction: Association With Regional Increase in AT2R,IP3R and PKCε Proteins and cGMP

Abstract

Background: We hypothesized that the cardioprotective effect of angiotensin II (AngII) type 1 receptor (AT,R) blockade during in vivo ischemia-reperfusion (IR) might be associated with an increase in AngII type 2 receptor (AT₂R) protein, as well as 1,4,5-inositol trisphosphate type 2 receptor (IP₃R) and protein kinase C _ε , (PKC_ε) proteins and cyclic guanosine 3',5' monophosphate (cGMP).

Methods and Results: We studied the effects of the AT₁R blocker, candesartan, on in vivo left ventricular (LV) systolic and diastolic function and remodeling (echocardiogram/Doppler) and hemodynamics during canine reperfused anterior infarction (90-minute ischemia, 120-minute reperfusion), and ex vivo infarct size and AT₁R/AT₂R, IP₃R, and PKC_ε proteins (immunoblots), and cGMP (enzyme immunoassay). Compared with controls, candesartan (1 mg/kg intravenously over 30-minute preischemia) inhibited the AngII pressor response, decreased preload and afterload, improved LV systolic and diastolic function, limited LV remodeling, decreased infarct size (55% vs 27% risk; P < .000003), markedly increased AT₂R, IP₃R, and PKC_ε proteins in the infarct zone, but not the AT,R protein, and increased infarct more than noninfarct cGMP.

Conclusions: The overall results suggest that cardioprotective effects of AT₁R blockade on acute IR injury might involve AT₂R activation and downstream signaling via IP₃R, PKC_ε, and cGMP.

Keywords

candesartan ventricular function remodeling ischemia-reperfusion.

References

Jugdutt BI Angiotensin II receptor blockers. In Crawford MH (ed): 1998 Cardiology Clinics Annual of Drug Therapy (vol 2). Saunders, Philadelphia, PA, pp. 1-17, 1998

Pitt B. , Segal R. , Martinez FA ,et al, on behalf of the ELITE Study Investigators. Randomized trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in Elderly Study, ELITE). Lancet 349:747, 1997

Ford WR , Khan MI , Jugdutt BI Effect of the novel angiotensin II type 1 receptor antagonist L-158,809 on acute infarct expansion and acute anterior myocardial infarction in the dog . Can J Cardiol 14:73, 1998

Jalowy A. , Schulz R. , Dörge H. , et al. Infarct size reduction by AT,-receptor blockade through a signal cascade of AT2-receptor activation, bradykinin and prostaglandins in pigs. J Am Coll Cardiol 32:1787, 1998

Pitt B. , Poole-Wilson PA , Segal R. , et al. Losartan Heart Failure Survival Study - Elite II. Circulation 100:I-782, 1999 (abstr)

McKelvie RS , Yusuf S. , Pericak D. , et al. Comparison of candesartan, enalapril, and their combination in congestive heart failure. Randomized evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study. Circulation 100:1056, 1999

Kitakaze M. , Minamino T. , Node K. , et al. Beneficial effects of inhibition of angiotensin-converting enzyme on ischemic myocardium during coronary hypoperfusion in dogs. Circulation 92:950, 1995

Dörge H. , Behrends M. , Schulz R. , et al. Attenuation of myocardial stunning by the AT1 receptor antagonist candesartan. Basic Res Cardiol 94:208, 1999

Werrmann JG , Cohen SM Comparison of the effects of angiotensin converting enzyme inhibition with those of angiotensin II receptor antagonism on functional and metabolic recovery in the post-ischemic working rat heart as studied by 31Pnuclear magnetic resonance . J Cardiovasc Pharmacol 24:573, 1994

10.

Yoshiyama M. , Kim S. , Yamagishi H. , et al. Cardioprotective effect of the angiotensin II type 1 receptor antagonist TCV-116 on ischemia-reperfusion injury. Am Heart J 128:1, 1994

11.

Yang BC , Phillips MI , Ambeuhl Pej , et al. Increase in angiotensin II type 1 receptor expression immediately after ischemia-reperfusion in isolated rat hearts. Circulation 96:922, 1997

12.

Yang BC , Phillips MI , Zhang YC , et al. Critical role of AT1 receptor expression after ischemia/reperfusion in isolated rat hearts: Beneficial effect of antisense ligodeoxynucleotides directed at AT1 receptor mRNA. Circ Res 83:552, 1998

13.

Ford WR , Clanachan AS , Jugdutt BI Opposite effects of angiotensin receptor antagonists on recovery of mechanical function after ischemia-reperfusion in isolated working rat hearts . Circulation 94:3087, 1996

14.

Ford WR , Clanachan AS , Lopaschuk GD , et al. Intrinsic AngII type 1 receptor stimulation contributes to recovery of postischemic mechanical function. Am J Physiol 274:H1524, 1998

15.

Kohya T. , Yokoshiki H. , Tohse N. , et al. Regression of left ventricular hypertrophy prevents ischemia-induced lethal arrhythmias: Beneficial effect of angiotensin II blockade. Circ Res 76:892, 1995

16.

Wiemer G. , Schölkens BA , Wagner A. , Heitsch H. , Linz W. The possible role of angiotensin II subtype AT2 receptors in endothelial cells and isolated ischemic rat hearts. J Hypertens 11:S234, 1993

17.

Thomas GP , Ferrier GR , Howlett SE Losartan exerts antiarrhythmic activity independent of angiotensin II receptor blockade in simulated ventricular ischemia and reperfusion. J Pharmacol Exp Ther 278:1090, 1996

18.

Schwarz ER , Montino H. , Fleischhauer J. , et al. Angiotensin II receptor antagonist EXP3174 reduces infarct size comparable with enalaprilat and augments preconditioning in the pig heart . Cardiovasc Drugs Ther 11:687, 1997

19.

Liu Y-H. , Yang X-P. , Sharov VG , et al. Paracrine systems in the cardioprotective effect of angiotensin-converting enzyme inhibitors on myocardial ischemia/reperfusion injury in rats. Hypertension 27:7, 1996

20.

Sladek T. , Sladkova J. , Kolar F. , et al. The effect of AT1 receptor antagonist on chronic cardiac response to coronary artery ligation in rats. Cardiovasc Res 31:568, 1996

21.

Stauss HM , Zhu Y-C. , Redlich T. , et al. Angiotensin-converting enzyme inhibition in infarct-induced heart failure in rats: Bradykinin versus angiotensin II. J Cardiovasc Risk 1:255, 1994

22.

Liu Y. , Tsuchida A. , Cohen MV , et al. Pretreatment with angiotensin II activates protein kinase C and limits myocardial infarction in isolated rabbit hearts. J Mol Cell Cardiol 27:883, 1995

23.

Diaz RJ , Wilson GJ Selective blockade of AT, angiotensin II receptors abolishes ischemic preconditioning in isolated rabbit hearts. J Moll Cell Cardiol 29:129, 1997

24.

Richard V. , Ghaleh B. , Berdeaux A. , et al. Comparison of the effects of EXP3174, an angiotensin II antagonist, and enalaprilat on myocardial infarct size in anesthetized dogs. Br J Pharmacol 110:969, 1993

25.

McDonald KM , Garr M. , Carlyle PF , et al. Relative effects of α 1-adrenoreceptor blockade, converting enzyme inhibitor therapy, and angiotensin II subtype 1 receptor blockade on ventricular remodeling in the dog. Circulation 90:3034, 1994

26.

Hartman JC , Hullinger TG , Wall TM , et al. Reduction of myocardial infarct size by ramiprilat is independent of angiotensin II synthesis inhibition. Eur J Pharmacol 234:229, 1993

27.

Liu YH , Yang XP , Sharov VG , et al. Effects of angiotensin-converting enzyme inhibitors and angiotensin II type I receptor antagonists in rats with heart failure: Role of kinins and angiotensin type 2 receptors. J Clin Invest 99:1926, 1997

28.

Milavetz JJ , Raya TE , Johnson CS , et al. Survival after myocardial infarction in rats: Captopril versus losartan. J Am Coll Cardiol 27:714, 1996

29.

Richer C. , Fornes P. , Cazaubon C. , et al. Effects of long-term angiotensin II AT1 receptor blockade on survival, hemodynamics and cardiac remodeling in chronic heart failure in rats. Cardiovasc Res 41:100, 1999

30.

Bastien NR , Juneau A-V., Ouellette J. , et al. Chronic AT1 receptor blockade and angiotensin-converting enzyme (ACE) inhibition in (CHF 146) cardiomyopathic hamsters: Effects on cardiac hypertrophy and survival. Cardiovasc Res 43:77, 1999

31.

Yusuf S. , Maggioni AP , Rouleau JL Effects of candesartan, enalapril or their combination on exercise capacity, ventricular function, clinical deterioration and quality of life in heart failure: Randomized evaluation of strategies for left ventricular dysfunction (RESOLVD). Circulation 96:1-452, 1997 (suppl) (abstr)

32.

Bartunek J. , Weinberg EO , Tajima M. , et al. Angiotensin II type 2 receptor blockade amplifies the early signals of cardiac growth response to angiotensin II in hypertrophied hearts. Circulation 99:22, 1999

33.

Tasker PN , Michelangeli F. , Nixon GF Expression and distribution of the type 1 and type 3 inositol 1,4,5-trisphosphate receptor in developing vascular smooth muscle. Circ Res 84:536, 1999

34.

Perez PJ , Ramos-Franco J. , Fill M. , et al. Identification and functional reconstitution of the type 2 inositol 1,4,5-trisphosphate receptor from ventricular cardiac myocytes. J Biol Chem 272:23961, 1997

35.

Vanderheyden Pml , Fierens Flp , De Backer JP , et al. Distinction between surmountable and insurmountable selective AT1 receptor antagonists by use of CHO-K1 cells expressing human angiotensin II AT 1 receptors. Br J Pharmacol 126:1057, 1999

36.

Jugdutt BI , Khan MI , Jugdutt SJ , et al. Impact of left ventricular unloading after late reperfusion of canine anterior myocardial infarction on remodeling and function using isosorbide-5-mononitrate. Circulation 92:926, 1995

37.

Jugdutt BI Effect of reperfusion on ventricular mass, topography and function during healing of anterior infarction. Am J Physiol 272:H1205, 1997

38.

Douglas PS , Tallant B. Hypertrophy, fibrosis and diastolic dysfunction in early canine experimental hypertension. J Am Coll Cardiol 17:530, 1991

39.

Klein HH , Puschmann S. , Schaper J. , et al. The mechanism of the tetrazolium reaction in identifying experimental myocardial infarction. Virchows Arch 393:287, 1981

40.

Gregg DE , Patterson RE Functional importance of the coronary collaterals. N Engl J Med 303:1404, 1981

41.

Jugdutt BI , Becker LC , Hutchins GM Early changes in collateral blood flow during myocardial infarction in conscious dogs. Am J Physiol 237:H371, 1979

42.

Becker LC , Jeremy RW , Schaper J. , et al. Ultrastructural assessment of myocardial necrosis occurring during ischemia and 3-h reperfusion in the dog. Am J Physiol 277:H243, 1999

43.

Seyedi N. , Xu XB , Nasjletti A. , Hintze TH Coronary kinin generation mediates nitric oxide release after angiotensin receptor stimulation. Hypertension 26:164, 1995

44.

Gohlke P. , Pees C. , Unger T. AT2 receptor stimulation increases aortic cyclic GMP in SHRSP by a kinin-dependent mechanism. Hypertension 31:349, 1998

45.

Christen Y. , Waeber B. , Nussberger J. , et al. Oral administration of DuP753, a specific angiotensin II receptor antagonist, to normal male volunteers. Inhibition of pressor response to exogenous angiotensin I and II. Circulation 83:1333, 1991

46.

Hübner R. , Högemann AM , Sunzel M. , et al. Pharmacokinetics of candesartan after single and repeated doses of candesartan cilexetil in young and elderly human volunteers. J Hum Hypertens 11:S19, 1997 (suppl)

47.

Stoll M. , Steckelings UM , Paul M. , et al. The angiotensin AT2 receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Invest 95:651, 1995

48.

Yamada T. , Horiuchi M. , Dzau VJ Angiotensin II type 2 receptor mediates programmed cell death. Proc Natl Acad Sci U S A 93:156, 1996

49.

Tanaka M. , Tsuchida S. , Imai T. , et al. Vascular response to angiotensin II is exaggerated through an upregulation of AT1 Receptor in AT2 knockout mice. Biochem Biophys Res Commun 258:194, 1999

50.

Siragy HM , Inagami T. , Ichiki T. , et al. Sustained hypersensitivity to angiotensin II and its mechanism in mice lacking the subtype-2 (AT2) angiotensin receptor. Proc Natl Acad Sci U S A 96:6506, 1999

51.

Masaki H. , Kurihara T. , Yamaki A. , et al. Cardiac-specific overexpression of angiotensin II AT2 receptor causes attenuated response to AT1 receptor-mediated pressor and chronotropic effects. J Clin Invest 101:527, 1998

52.

Ichiki T. , Usui M. , Kato M. , et al. Downregulation of angiotensin II type 1 receptor gene transcription by nitric oxide. Hypertension 31:342, 1998

53.

Laursen JB , Rajagopalan S. , Galis Z. , et al Role of superoxide in angiotensin II-induced but not catecholamine-induced hypertension. Circulation 95:588, 1997

54.

Yasmin W. , Strynadka KD , Schulz R. Generation of peroxynitrite contributes to ischemia-reperfusion injury in isolated rat hearts. Cardiovasc Res 33:422, 1997

55.

Horiuchi M. , Akishita M. , Dzau VJ Recent progress in angiotensin II type 2 receptor research in the cardiovascular system. Hypertension 33:613, 1999

56.

Ping P. , Takano H. , Zhang J. , et al. Isoform-selective activation of protein kinase C by nitric oxide in the heart of conscious rabbits. A signaling mechanism for both nitric-oxide-induced and ischemia-induced preconditioning. Circ Res 84:587, 1999

57.

Rabkin SW Cardiac angiotensin II subtype 2 receptor signal transduction pathways: Embryonic cardiomyocytes and human heart, in Dhalla NS , Zahradka P , Dixon I , Beamish R (eds): Angiotensin II Receptor Blockade: Physiological and Clinical Implications . Kluwer Academic, Boston, pp. 367-384, 1998

58.

Nio Y. , Matsubara H. , Murasawa S. , et al. Regulation and gene transcription of angiotensin II receptor subtypes in myocardial infarction. J Clin Invest 95:46, 1995

59.

Lopez JJ , Lorell BH , Ingelfinger JR , et al. Distribution and function of cardiac angiotensin AT1-and AT2-receptor subtypes in hypertrophied rat hearts. Am J Physiol 267:H844, 1994

60.

Kijima K. , Matsubara H. , Murasawa S. , et al. Mechanical stretch induces enhanced expression of angiotensin II receptor subtypes in neonatal rat cardiac myocytes. Circ Res 79:887, 1996

61.

Haywood GA , Gullestad L. , Katsuya T. , et al. AT1 and AT2 angiotensin receptor gene expression in human heart failure. Circulation 95:1201, 1997

62.

Wharton J. , Morgan K. , Rutherford Rad , et al. Differential distribution of angiotensin AT2-receptors in the normal and failing human heart. J Pharmacol Exp Ther 284:323, 1998