To determine whether chronic angiotensin II (Ang II) type I receptor (ATR) antagonism improves recovery of left ventricular (LV) function after ischemia-reperfusion (IR) and increases AT,R and Ang II type 2 receptor (AT2R) protein expression in isolated working rat hearts, rats were randomized to pretreatment with either losartan (30 mg/kg/day) or UP269-6 (3 mg/kg/day), or no drug (control), for 1 week or 3 weeks before IR (50 min perfusion, 25 min ischemia, 40 min reperfusion). In vitro LV work and power and ex vivo AT,R and AT2R proteins (immunoblots) were measured. Compared to baseline perfusion, LV work and power showed variable recovery in control, losartan, and UP269-6 groups. Compared to control, losartan preserved recovery of LV work and power while UP269-6 showed less recovery after IR at both 1 week and 3 weeks. Both antagonists increased AT2R but not AT,R protein. The duration of pretreatment did not affect the expression of ATR or AT2R proteins. The results indicate that chronic AT,R blockade over 1 or 3 weeks increases AT2R (not ATIR) protein expression and may preserve but not improve postischemic functional recovery compared to controls in isolated working rat hearts.
1. Jugdutt BI. Angiotensin II receptor blockers. In Crawford MH (ed). 1998 Cardiology Clinics Annual of Drug Therapy, vol 2. WB Saunders, Philadelphia, pp. 1-17, 1998
2.
2. Yoshiyama M, Kim S, Yamagishi H, et al. Cardio-protective effect of the angiotensin II type 1 receptor antagonist TCV-116 on ischemia-reperfusion injury. Am Heart J128:1-6, 1994
3.
3. 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 3P nuclear magnetic resonance. J Cardiovasc Pharmacol24:573-586, 1994
4.
4. Yang BC, Phillips MI, Ambeuhl PEJ, et al. Increase in angiotensin II type 1 receptor expression immediately after ischemia-reperfusion in isolated rat hearts. Circulation96:922-926, 1997
5.
5. Yang BC, Phillips MI, Zhang YC, et al. Critical role of AT, receptor expression after ischemia/reperfusion in isolated rat hearts: Beneficial effect of antisense ligodeoxynu-cleotides directed at AT, receptor mRNA. Circ Res83:552-559, 1998
6.
6. 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. Circulation94:3087-3089, 1996
7.
7. Ford WR, Clanachan AS, Lopaschuk GD, et al. Intrinsic Ang II type 1 receptor stimulation contributes to recovery of postischemic mechanical function. Am J Physiol274:1524-1531, 1998
8.
8. Xu Y, Menon V, Jugdutt BI. Cardioprotection after angiotensin II type 1 blockade involves angiotensin II type 2 receptor expression and activation of protein kinase C in acutely reperfused myocardial infarction in the dog. Effect of UP269-6 and losartan on AT,- and AT2-receptor expression and IP3 receptor and PKCe proteins. J Renin Angiotensin Aldosterone Syst1: 184-195, 2000
9.
9. Jugdutt BI, Xu Y, Balghith M, et al. Cardioprotection induced by ATIR blockade after reperfused myocardial infarction: Association with regional increase in AT2R, IP3R and PKCe proteins and cGMP. J Cardiovasc Pharmacol Ther5:301-311, 2000
10.
10. Cazes M, Provost D, Versigny A, et al. In vivo pharmacological characterization of UP269-6, a novel nonpeptide angiotensin II receptor antagonist. Eur J Pharmacol284:157-170, 1995
11.
11. De Leiris J, Harrding DP, Pestre S. The isolated perfused rat heart: A model for studying myocardial hypoxia or ischemia. Basic Res Cardiol79:313-321, 1984
12.
12. Galinanes M, Hearse DJ. Assessment of ischemic injury and protective interventions: The Langendorff versus the working rat heart preparation. Can J Cardiol6:83-91, 1990
13.
13. Lopaschuk GD. Alterations in fatty acid oxidation during reperfusion of the heart after myocardial ischemia. Am J Cardiol80:11a-16a, 1997
14.
14. Lopaschuk GD, Stanley WC. Glucose metabolism in the ischemic heart (editorial). Circulation95:313-315, 1997
15.
15. Wong PC, Price WA, Chiu AT, et al. Nonpeptide angiotensin II receptor antagonists. VIII. Characterization of functional antagonism displayed by DuP 753, an orally active antihypertensive agent. J Pharmacol Exp Ther252(2):719-725, 1990
16.
16. Neely JR, Liebermeister H, Battersby EJ, et al. Effect of pressure development on oxygen consumption by isolated rat heart. Am J Physiol212:804-814, 1967
17.
17. 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 Res84:587-604, 1999
18.
18. Werrmann JG, Cohen SM. Use of losartan to examine the role of the cardiac renin-angiotensin system in myocardial dysfunction during ischemia and reperfusion. J Cardiovasc Pharmacol27:177-182, 1996
19.
19. Finegan BA, Lopaschuk GD, Gandhi M, Clanachan AS. Inhibition of glycolysis and enhanced mechanical function of working rat hearts as a result of adenosine A, receptor stimulation during reperfusion following ischemia. Br J Pharmacol118:355-363, 1996
20.
20. Csajka C, Buclin T, Brunner HR, et al. Pharmacokinetic-pharmacodynamic profile of angiotensin II receptor antagonist. Clin Pharmacokinetics32:1-29, 1997
21.
21. Blackband SJ, Chatham JC, O'Dell W, et al. Echo planar imaging of isolated perfused rat hearts at 4.7T: A comparison of Langendorff and working heart preparations. Magn Reson Med15:240-245, 1990
22.
22. Hearse BJ, Zucchi R, Buschmans E, et al. Forskolin and myocardial function in the normal, ischemia and reperfused rat heart. Can J Cardiol2(5):303-312, 1986
23.
23. Mochizuki S, Murase T, Yamaoka M, et al. LPL activity in ischemia and anoxic myocardium. Basic Res Cardiol82(Suppl 1):45-52, 1987
24.
24. 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 type 2 receptors. J Clin Invest99:1926-1935, 1997
25.
25. Jalowy A, Schulz R, Dorge 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 Cardiol32:1787-1796, 1998
