Restricted accessOtherFirst published online 2000-06
Cardioprotection after angiotensin II type 1 blockade involves angiotensin II type 2 receptor expression and activation of protein kinase C-ε in acutely reperfused myocardial infarction in the dog
To determine whether cardioprotection after chronic angiotensin II (Ang II) type 1 (AT1) receptor blockade involves Ang II type 2 (AT2) receptor expression and protein kinase C-ε (PKCε) activation, we measured in vivo haemodynamics and left ventricular (LV) remodelling and dysfunction (echocardiogram/ Doppler) and ex vivo AT1/AT2-receptor expression, IP 3R (1, 4, 5-inositol trisphosphate type 2 receptor) and PKCε proteins in dogs with acutely reperfused (90 minutes ischaemia, 90 minutes reperfusion) myocardial infarction (MI) following seven days of AT1-receptor blockade with oral losartan or UP269-6. The animals were randomised to sham; sham + losartan or UP269-6; MI alone; MI + losartan; MI + UP269-6. More marked AT1-receptor blockade with UP269-6 (greater inhibition of Ang II pressor responses) was associated with a smaller increase in preload, less systolic and diastolic dysfunction, less infarct expansion, and smaller LV diastolic and systolic volumes. However, both AT1-receptor antagonists decreased infarct size. Importantly, MI decreased AT1-receptor and AT2-receptor expression while MI after AT1-receptor antagonism increased AT1-receptor (mRNA, not protein) and AT 2-receptor (mRNA and protein) expression as well as IP3R and PKCε proteins and cyclic guanosine 3', 5' monophosphate (cGMP). These results suggest that cardioprotection induced by chronic AT1-receptor antagonism involves enhanced AT2-receptor expression and possibly downstream signalling through IP3R, PKCε and cGMP.
Dzau VJCell biology and genetics of angiotensin in cardiovascular disease . J Hypertens1994;12 (Suppl):S3-S10.
2.
Timmermans Pbmwm , Wong PC, Chiu AT et al. Angiotensin II receptors and angiotensin II receptor antagonists. Pharmacol Rev1993 ;45:205-51.
3.
Jugdutt BIRole of angiotensin II receptor blockade during remodeling after myocardial infarction. In: N.S. Dhalla, P. Zahadra, I.M.C. Dixon and R.E. Beamish (Eds). `Angiotensin II Receptor Blockade: Physiological and Clinical Implications'Kluwer Academic Publishers:Boston , 1998: 437-49.
4.
Urata H., Healy B., Stewart RW et al. Angiotensin II forming pathways in normal and failing human hearts. Circ Res1990; 66:883-90.
5.
Balcells E., Meng QC, Hageman et al. Angiotensin II formation in dog heart is mediated by different pathways in vivo and in vitro. Am J Physiol1996;271:H417-H421.
6.
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. Circulation1991;83:1333-42.
7.
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 Hypertens1997;11(Suppl 2):S19-S25.
8.
Wiemer G., Schölkens BA,Wagner A. et al. The possible role of angiotensin II subtype AT2 receptors in endothelial cells and isolated ischaemic rat hearts. J Hypertens1993;11:S234-S235.
9.
Liu YH, Yang XP, Sharov VG et al. Effects of angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor antagonists in rats with heart failure. Role of kinins and angiotensin II type 2 receptors. J Clin Invest1997;99:1926-35.
10.
JalowyA,Schulz R., Dörge H. et al. Infarct size reduction by AT1-receptor blockade through a signal cascade of AT2-receptor activation, bradykinin and prostaglandins in pigs . J Am Coll Cardiol1998;32:1787-96.
11.
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 ischaemia-induced preconditiong. Circ Res1999;84:587-604.
12.
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 . Circulation1999;99:22-5.
13.
Rabkin SWCardiac angiotensin II subtype 2 receptor signal transduction pathways: embryonic cardiomyocytes and human heart. In: Angiotensin II Receptor Blockade: Physiological and Clinical Implications. Dhalla NS, Zahradka P , Dixon I and Beamish R (eds). Boston: Kluwer Academic, 1998: 367-84.
14.
Tasker PN, Michelangeli F., Nixon GFExpression and distribution of the type 1 and type 3 inositol 1,4,5-triphosphate receptor in developing vascular smooth muscle. Circ Res1999;84:536-42.
15.
Perez PJ, Ramos-Franco J., Fill M. et al. Identification and functional reconstitution of the type 2 inositol 1,4,5-triphosphate receptor from ventricular cardiac myocytes. J Biol Chem1997;272:23961-9.
16.
Csajka C., Buclin T., Brunner HR et al. Pharmacokineticpharmacodynamic profile of angiotensin II receptor antagonist. Clin Pharmacokinetics1997;32:1-29.
17.
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 AT1 receptors. Br JPharmacol1999;126:1057-65.
18.
Cazes M., Provost D., Versigny A. et al. In vivo pharmacological characterization of UP269-6, a novel nonpeptide angiotensin II receptor antagonist. Eur J Pharmacol1995; 284:157-70.
19.
Lynch JJ Jr, Stump GL, Wallace AA et al. EXP3174, the AII antagonist human metabolite of losartan, but not losartan nor the angiotensin-converting enzyme inhibitor captopril, prevents the development of lethal ischaemic ventricular arrhythmias in a canine model of recent myocardial infarction. J Am Coll Cardiol1999;34:876-84.
20.
Wong PC, Hart SD, Duncia JV et al. Nonpeptide receptor antagonists. Studies with DuP753 and EXP3174 in dogs. Eur J Pharmacol1991;202:323-30.
21.
Pitt B., Segal R., Martinez FA et al, on behalf of the ELITE Study Investigators.Randomised trial of losartan versus captopril in patients over 65 with heart failure (Evaluation of Losartan in the Elderly Study, ELITE) . Lancet1997;349:747-52.
22.
Pitt B., Poole-Wilson PA, Segal R. et al. Losartan Heart Failure Survival Study - ELITE II [abstr]. Circulation1999;100(Suppl I):I-782.
23.
Richard V., Ghaleh B., Berdeaux A., Giudicelli J-F.Comparison of the effects of EXP3174, an angiotensin II antagonist, and enalaprilat on myocardial infarct size in anaesthetised dogs . Br J Pharmacol1993;110:969-74.
24.
McDonald KM , Garr M., Carlyle PF et al. Relative effects of α1-adrenoreceptor blockade, converting enzyme inhibitor therapy, and angiotensin II subtype 1 receptor blockade on ventricular remodeling in the dog. Circulation. 1994;90:3034-46.
25.
Siegl PKS , Chang RSL , Mantlo NB et al. In vivo pharmacology of L-158,809, a new highly potent and selective nonpeptide angiotensin II receptor antagonist . J Pharmacol Exp Ther1992;262:139-44.
26.
Ford WR, Khan MI, Jugdutt BIEffect 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 Cardiol1998;14:73-80.
27.
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. Circulation1995 ;92:926-34.
28.
Jugdutt BIEffect of reperfusion on ventricular mass, topography and function during healing of anterior infarction. Am J Physiol1997;272:H1205-11.
29.
Douglas PS,Tallant B.Hypertrophy, fibrosis and diastolic dysfunction in early canine experimental hypertension. J Am Coll Cardiol1991;17:530-6.
30.
Jugdutt BI, Humen DPLimitation of left ventricular hypertrophy and dysfunction by ACE inhibition after Q-wave myocardial infarction. Cardiology1998;89:283-90.
31.
Hein L., Meinel L., Pratt RE et al. Intracellular trafficking of angiotensin II and its AT11 and AT2 receptors: evidence for selective sorting of receptor and ligand. Mol Endocrinol1997;11(9):1266-77.
32.
Wang Z.-Q, Moore AF, Ozono R. et al. Immunolocalization of subtype 2 angiotensin II (AT2) receptor protein in rat heart. Hypertension1998;32:78-83.
33.
Christ DD, Wong PC, Wong YN et al. The pharmacokinetics and pharmacodynamics of the angiotensin II receptor antagonist losartan potassium (DuP753/MK954) in the dog. J Pharmacol Exp Ther1994;268:99-1205.
34.
Jugdutt BI, Becker LC, Hutchins GMEarly changes in collateral blood flow during myocardial infarction in conscious dogs. Am J Physiol1979;237:H371-H380.
35.
Becker LC, Jeremy RW, Schaper J. et al. Ultrastructural assessment of myocardial necrosis occurring during ischaemia and 3-h reperfusion in the dog. Am J Physiol1999;277:H243-H252.
36.
Dörge H., Behrends M., Schulz R. et al. Attenuation of myocardial stunning by the AT1 receptor antagonist candesartan. Basic Res Cardiol1999;94:208-14.
37.
McAlpine HM , Morton JJ, Leckie B. et al. Neuroendocrine activation after acute myocardial infarction. Br Heart J1988;60:117-24.
38.
Gondo M., Maruta H., Arakawa K.Direct formation of angiotensin II without renin or converting enzyme in the ischaemic dog heart. Jpn Heart J1989 ;30:219-29.
39.
Noda K., Sasaguri M., Ideishi M. et al. Role of locally formed angiotensin II and bradykinin in the reduction of myocardial infarct size in dogs. Cardiovasc Res1993;27:334-40.
40.
Seyedi N., Xu XB, Nasjletti A. et al. Coronary kinin generation mediates nitric oxide release after angiotensin receptor stimulation. Hypertension1995;26:164-70.
41.
Gohlke P., Pees C., Unger T.AT2 receptor stimulation increases aortic cyclic GMP in SHRSP by a kinin-dependent mechanism. Hypertension1998 ;31:349-55.
42.
Kelly RA, Balligand J-L., Smith TWNitric oxide and cardiac function. Circ Res1996;79:363-80.
43.
Horiuchi M. , Akishita M., Dzau VJRecent progress in angiotensin II type 2 receptor research in the cardiovascular system. Hypertension1999;33:613-621.
44.
Bokkala S., Joseph SKAngiotensin II-induced down-regulation of inositol trisphosphate receptors in WB rat liver epithelial cells. Evidence for involvement of the proteasome pathway. J Biol Chem1997;272:12454-61.
45.
Fryer LGD , Holness MJ, Decock JBJ et al. Cardiac protein kinase C expression in two models of cardiac hypertrophy associated with activated cardiac renin-angiotensin system: effects of experimental hyperthyroidism and genetic hypertension (the mRen-2 rat) . J Endocrin1998;158:27-33.
46.
Laursen JB, Rajagopalan S. et al. Role of superoxide in angiotensin II-induced but not catecholamine-induced hypertension. Circulation1997;95:588-93.
47.
Yasmin W., Strynadka KD, Schulz R.Generation of peroxynitrite contributes to ischaemia-reperfusion injury in isolated rat hearts. Cardiovasc Res1997 ;33:422-32.
48.
Yoshiyama M. , Kim S.,Yamagishi H. et al. Cardioprotective effect of the angiotensin II type 1 receptor antagonist TCV-116 on ischaemia-reperfusion injury. Am Heart J1994;128:1-6.
49.
Nio Y., Matsubara H., Murasawa S. et al. Regulation and gene transcription of angiotensin II receptor subtypes in myocardial infarction. J Clin Invest1995;95:46-54.
50.
Yang BC, Phillips MI, Ambeuhl PEJ et al. Increase in angiotensin II type 1 receptor expression immediately after ischaemia-reperfusion in isolated rat hearts. Circulation1997;96:922-6.
51.
Yamada T., Horiuchi M., Dzau VJAngiotensin II type 2 receptor mediates programmed cell death. Proc Natl Acad Sci USA1996;93:156-60.
52.
Fliss H., Gattinger D.Apoptosis in ischaemic and reperfusion rat myocardium. Circ Res1996;79:949-56.
53.
Yaoita H., Ogawa K., Maehara K. et al. Attenuation of ischaemia/reperfusion injury in rats by a caspase inhibitor. Circulation1998;97:276-81.
54.
Musat-Marcu S., Gunther HE, Jugdutt BI et al. Ischaemiareperfusion induces apoptosis in rat myocardium through a cycloheximide-inhibitable pathway . J Mol Cell Cardiol1999;31:1073-82.
55.
Kajstura J. , Cigola E., Malhotra A. et al. Angiotensin II induces apoptosis of adult ventricular myocytes in vitro. J Moll Cell Cardiol1997;29:859-70.
56.
Goussev,A.SharovVG,Shomoyama H. et al. Effects of ACE inhibition on cardiomyocyte apoptosis in dogs with heart failure. Am J Physiol1998;275:H626-H631.
57.
Jugdutt BI, Xu Y., Balghith M et al. Enhanced regional AT2 receptor and protein kinase C expression during cardioprotection induced by AT1 receptor blockade after reperfused canine myocardial infarction . (Abstract) J Renin Angioten Aldo System2000;1:60.
58.
Masaki H., Kurihara T.,Yamaki A. et al. Cardiac-specific over-expression of angiotensin II AT2 receptor causes attenuated response to AT1 receptor-mediated pressor and chronotropic effects. J Clin Invest1998;101:527-35.
59.
Ichiki T., Usui M. et al. Downregulation of angiotensin II type 1 receptor gene transcription by nitric oxide. Hypertension1998;31:342-8.
60.
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 Physiol1994;267:H844-H852.
61.
Kijima K., Matsubara H., Murasawa S. et al. Mechanical stretch induces enhanced expression of angiotensin II receptor subtypes in neonatal rat cardiac myocytes. Circ Res1996;79:887-97.
62.
Haywood GA, Gullestad L., Katsuya T. et al. AT1 and AT2 angiotensin receptor gene expression in human heart failure. Circulation1997;95:1201-6.
63.
Wharton J., Morgan K., Rutherford RAD et al. Differential distribution of angiotensin AT2-receptors in the normal and failing human heart. J Pharmacol Exp Ther1998;284:323-36.
64.
McKelvie RS ,Yusuf S., Pericak D. et al. Comparison of candesartan, enalapril, and their combination in congestive heart failure. Randomised evaluation of strategies for left ventricular dysfunction (RESOLVD) pilot study. Circulation1999; 100: 1056-64.
