EXPERIMENTAL STUDIES
Infarct size reduction by AT1-receptor blockade through a signal cascade of AT2-receptor activation, bradykinin and prostaglandins in pigs
Andreas Jalowy, MDa,
Rainer Schulz, MDa,
Hilmar Dörge, MDa,
Matthias Behrends, MDa and
Gerd Heusch, MD, FESC, FACCa
a Abteilung für Pathophysiologie, Zentrum für Innere Medizin des Universitätsklinikums Essen, Essen, Germany
Manuscript received April 29, 1998;
revised manuscript received July 1, 1998,
accepted July 24, 1998.
Address for correspondence: Prof. Dr. Gerd Heusch, Abteilung für Pathophysiologie, Zentrum für Innere Medizin, Universitätsklinikum Essen, Hufelandstrasse 55, 45122 Essen, Federal Republic of Germany
gerd.heusch{at}uni-essen.de
Objective. We studied the effect of the angiotensin II type 1 (AT1)-receptor antagonist candesartan on infarct size resulting from regional myocardial ischemia in pigs.
Background. The effects of AT1-receptor blockade on infarct size in different species remain controversial and its potential cardioprotective mechanisms are still unclear. In pigs, infarct development closely resembles that observed in humans.
Methods. A total of 62 enflurane-anesthetized pigs underwent a protocol of 90-min low-flow ischemia and 120-min reperfusion. Systemic hemodynamics (micromanometer), regional myocardial function (sonomicrometry), regional myocardial blood flow (microspheres) and infarct size (TTC [triphenyl tetrazolium chloride]-staining) were determined.
Results. Left ventricular peak pressure decreased with candesartan (1 mg/kg i.v.) from 97 ± 2 standard error of the mean (SEM) to 86 ± 5 mm Hg and was then readjusted by aortic banding. In placebo pigs (n = 9), infarct size was 21.8 ± 4.8% of the area at risk. Candesartan (n = 7) reduced infarct size to 9.7 ± 2.5% (p < 0.05). Pretreatment with the AT2-receptor antagonist PD123319 (3 µg/kg/min intracoronarily [i.c.]; n = 8), the bradykinin B2-receptor antagonist HOE140 (0.01 µg/kg/min i.c.; n = 8) or the cyclooxygenase inhibitor indomethacin (10 mg/kg i.v.; n = 8) per se did not affect infarct size but did abolish the reduction of infarct size achieved by candesartan (PD123319 + candesartan (n = 7): 23.2 ± 4.7%; HOE140 + candesartan (n = 7): 18.2 ± 4.0%; indomethacin + candesartan (n = 8): 21.1 ± 5.2%). Hemodynamics, regional myocardial blood flow during ischemia and the area at risk were comparable among all groups of pigs.
Conclusions. Reduction of infarct size by the AT1-receptor antagonist candesartan in pigs involves angiotensin II type 2 receptor (AT2) activation, bradykinin and prostaglandins.
|
Abbreviations and Acronyms
| | ACE | = angiotensin-converting-enzyme | | AT1 | = angiotensin II type 1 receptor | | AT2 | = angiotensin II type 2 receptor | | LAD | = left anterior descending coronary artery | | LV | = left ventricular | | SEM | = standard error of the mean | | TTC | = triphenyl tetrazolium chloride |
|
This article has been cited by other articles:
|
|
|
|
 
G. Heusch and R. Schulz
Neglect of the coronary circulation: some critical remarks on problems in the translation of cardioprotection
Cardiovasc Res,
October 1, 2009;
84(1):
11 - 14.
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. Heusch, A. Skyschally, P. Gres, P. van Caster, D. Schilawa, and R. Schulz
Improvement of regional myocardial blood flow and function and reduction of infarct size with ivabradine: protection beyond heart rate reduction
Eur. Heart J.,
September 2, 2008;
29(18):
2265 - 2275.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Matsuhisa, H. Otani, T. Okazaki, K. Yamashita, Y. Akita, D. Sato, A. Moriguchi, H. Imamura, and T. Iwasaka
Angiotensin II type 1 receptor blocker preserves tolerance to ischemia-reperfusion injury in Dahl salt-sensitive rat heart
Am J Physiol Heart Circ Physiol,
June 1, 2008;
294(6):
H2473 - H2479.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Messadi-Laribi, V. Griol-Charhbili, A. Pizard, M.-P. Vincent, D. Heudes, P. Meneton, F. Alhenc-Gelas, and C. Richer
Tissue Kallikrein Is Involved in the Cardioprotective Effect of AT1-Receptor Blockade in Acute Myocardial Ischemia
J. Pharmacol. Exp. Ther.,
October 1, 2007;
323(1):
210 - 216.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Voros, Z. Yang, C. M. Bove, W. D. Gilson, F. H. Epstein, B. A. French, S. S. Berr, S. P. Bishop, M. R. Conaway, H. Matsubara, et al.
Interaction between AT1 and AT2 receptors during postinfarction left ventricular remodeling
Am J Physiol Heart Circ Physiol,
March 1, 2006;
290(3):
H1004 - H1010.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. C. Hakam, A. H. Siddiqui, and T. Hussain
Renal angiotensin II AT2 receptors promote natriuresis in streptozotocin-induced diabetic rats
Am J Physiol Renal Physiol,
February 1, 2006;
290(2):
F503 - F508.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Jiang, E. Shi, Y. Nakajima, S. Sato, K. Ohno, and H. Yue
Cyclooxygenase-1 Mediates the Final Stage of Morphine-Induced Delayed Cardioprotection in Concert With Cyclooxygenase-2
J. Am. Coll. Cardiol.,
May 17, 2005;
45(10):
1707 - 1715.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. J. Campbell, H. Krum, and M. D. Esler
Losartan Increases Bradykinin Levels in Hypertensive Humans
Circulation,
January 25, 2005;
111(3):
315 - 320.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. F. Merrill, T. H. Rork, N. M. Spiler, and R. Golfetti
Acetaminophen and myocardial infarction in dogs
Am J Physiol Heart Circ Physiol,
November 1, 2004;
287(5):
H1913 - H1920.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
O. Johren, A. Dendorfer, and P. Dominiak
Cardiovascular and renal function of angiotensin II type-2 receptors
Cardiovasc Res,
June 1, 2004;
62(3):
460 - 467.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. P. Tiefenbacher, S. Friedrich, T. Bleeke, C. Vahl, X. Chen, and F. Niroomand
ACE inhibitors and statins acutely improve endothelial dysfunction of human coronary arterioles
Am J Physiol Heart Circ Physiol,
April 1, 2004;
286(4):
H1425 - H1432.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Kumar, V. Menon, W. R. Ford, A. S. Clanachan, and B. I. Jugdutt
Effect of Angiotensin II lype 2 Receptor Blockade on Activation of Mitogen-Activated Protein Kinases after Ischemia-Reperfusion in Isolated Working Rat Hearts
Journal of Cardiovascular Pharmacology and Therapeutics,
December 1, 2003;
8(4):
285 - 296.
[Abstract]
[PDF]
|
|
|
|
|
|
|
A. Jones, S. S. Dhamrait, J. R. Payne, E. Hawe, P. Li, I. S. Toor, L. Luong, P. T.E. Wootton, G. J. Miller, S. E. Humphries, et al.
Genetic Variants of Angiotensin II Receptors and Cardiovascular Risk in Hypertension
Hypertension,
October 1, 2003;
42(4):
500 - 506.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. I. Jugdutt and V. Menon
Upregulation of Angiotensin II Type 2 Receptor and Limitation of Myocardial Stunning by Angiotensin II Type 1 Receptor Blockers during Reperfused Myocardial Infarction in the Rat
Journal of Cardiovascular Pharmacology and Therapeutics,
September 1, 2003;
8(3):
217 - 226.
[Abstract]
[PDF]
|
|
|
|
|
|
|
N. Takahashi, J. R. Hagaman, H.-S. Kim, and O. Smithies
Minireview: Computer Simulations of Blood Pressure Regulation by the Renin-Angiotensin System
Endocrinology,
June 1, 2003;
144(6):
2184 - 2190.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Przyklenk and G. Heusch
Late preconditioning against myocardial stunning: Does aspirin close the "second window" of endogenous cardioprotection?
J. Am. Coll. Cardiol.,
April 2, 2003;
41(7):
1195 - 1197.
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. D. Solomon and M. A. Pfeffer
Renin-Angiotensin System and Cardiac Rupture After Myocardial Infarction
Circulation,
October 22, 2002;
106(17):
2167 - 2169.
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. WALTHER, W.-E. SIEMS, D. HAUKE, F. SPILLMANN, A. DENDORFER, W. KRAUSE, H.-P. SCHULTHEISS, and C. TSCHOPE
AT1 receptor blockade increases cardiac bradykinin via neutral endopeptidase after induction of myocardial infarction in rats
FASEB J,
August 1, 2002;
16(10):
1237 - 1241.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Q.-D. Wang, J. Pernow, P.-O. Sjoquist, and L. Ryden
Pharmacological possibilities for protection against myocardial reperfusion injury
Cardiovasc Res,
July 1, 2002;
55(1):
25 - 37.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X.-Q. Jin, N. Fukuda, J.-Z. Su, Y.-M. Lai, R. Suzuki, Y. Tahira, H. Takagi, Y. Ikeda, K. Kanmatsuse, and H. Miyazaki
Angiotensin II Type 2 Receptor Gene Transfer Downregulates Angiotensin II Type 1a Receptor in Vascular Smooth Muscle Cells
Hypertension,
May 1, 2002;
39(5):
1021 - 1027.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Xu, D. Kumar, J. R. B. Dyck, W. R. Ford, A. S. Clanachan, G. D. Lopaschuk, and B. I. Jugdutt
AT1 and AT2 receptor expression and blockade after acute ischemia-reperfusion in isolated working rat hearts
Am J Physiol Heart Circ Physiol,
April 1, 2002;
282(4):
H1206 - H1215.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. Shinmura, Y.-T. Xuan, X.-L. Tang, E. Kodani, H. Han, Y. Zhu, and R. Bolli
Inducible Nitric Oxide Synthase Modulates Cyclooxygenase-2 Activity in the Heart of Conscious Rabbits During the Late Phase of Ischemic Preconditioning
Circ. Res.,
March 22, 2002;
90(5):
602 - 608.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Berry, R. Touyz, A. F. Dominiczak, R. C. Webb, and D. G. Johns
Angiotensin receptors: signaling, vascular pathophysiology, and interactions with ceramide
Am J Physiol Heart Circ Physiol,
December 1, 2001;
281(6):
H2337 - H2365.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Prasad, J. P. J. Halcox, M. A. Waclawiw, and A. A. Quyyumi
Angiotensin type 1 receptor antagonism reverses abnormal coronary vasomotion in atherosclerosis
J. Am. Coll. Cardiol.,
October 1, 2001;
38(4):
1089 - 1095.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Moudgil, Y. Xu, V. Menon, and B. I. Jugdutt
Effect of Chronic AT1 Receptor Antagonism on Postischemic Functional Recovery and AT1/AT2 Receptor Proteins in Isolated Working Rat Hearts
Journal of Cardiovascular Pharmacology and Therapeutics,
June 1, 2001;
6(2):
183 - 188.
[Abstract]
[PDF]
|
|
|
|
|
|
|
B. I Jugdutt and M. Balghith
Enhanced regional AT2-receptor and PKC{varepsilon} expression during cardioprotection induced by AT1-receptor blockade after reperfused myocardial infarction
Journal of Renin-Angiotensin-Aldosterone System,
June 1, 2001;
2(2):
134 - 140.
[Abstract]
[PDF]
|
|
|
|
|
|
|
L. Ryden, P.-O. Sjoquist, and Q.-D. Wang
Pharmacological tools for the limitation of myocardial reperfusion injury: Experimental evidence
Eur. Heart J. Suppl.,
June 1, 2001;
3(suppl_C):
C28 - C35.
[Abstract]
[PDF]
|
|
|
|
|
|
|
L. H. Opie and M. N. Sack
Enhanced Angiotensin II Activity in Heart Failure : Reevaluation of the Counterregulatory Hypothesis of Receptor Subtypes
Circ. Res.,
April 13, 2001;
88(7):
654 - 658.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Schulz and G. Heusch
Review: AT 1-receptor blockade in experimental myocardial ischaemia/reperfusion
Journal of Renin-Angiotensin-Aldosterone System,
March 1, 2001;
2(1_suppl):
S136 - S140.
[PDF]
|
|
|
|
|
|
|
B. I Jugdutt, Yi Xu, M. Balghith, and V. Menon
Cardioprotective effects of angiotensin II type 1 receptor blockade with candesartan after reperfused myocardial infarction: role of angiotensin II type 2 receptor
Journal of Renin-Angiotensin-Aldosterone System,
March 1, 2001;
2(1_suppl):
S162 - S166.
[Abstract]
[PDF]
|
|
|
|
|
|
|
H. Peng, O. A. Carretero, M. E. Alfie, J. A. Masura, and N.-E. Rhaleb
Effects of Angiotensin-Converting Enzyme Inhibitor and Angiotensin Type 1 Receptor Antagonist in Deoxycorticosterone Acetate-Salt Hypertensive Mice Lacking Ren-2 Gene
Hypertension,
March 1, 2001;
37(3):
974 - 980.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. E. Schmieder, J. Erdmann, C. Delles, J. Jacobi, E. Fleck, K. Hilgers, and V. Regitz-Zagrosek
Effect of the angiotensin II type 2-receptor gene (+1675 G/A) on left ventricular structure in humans
J. Am. Coll. Cardiol.,
January 1, 2001;
37(1):
175 - 182.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Xu, A. S. Clanachan, and B. I. Jugdutt
Enhanced Expression of Angiotensin II Type 2 Receptor, Inositol 1,4,5-Trisphosphate Receptor, and Protein Kinase C{epsilon} During Cardioprotection Induced by Angiotensin II Type 2 Receptor Blockade
Hypertension,
October 1, 2000;
36(4):
506 - 510.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. S Weinberg, A. J Weinberg, and D. H Zappe
Effectively targetting the renin-angiotensin-aldosterone system in cardiovascular and renal disease: rationale for using angiotensin II receptor blockers in combination with angiotensin-converting enzyme inhibitors
Journal of Renin-Angiotensin-Aldosterone System,
September 1, 2000;
1(3):
217 - 233.
[PDF]
|
|
|
|
|
|
|
E. Chabielska, T. Matys, I. Kucharewicz, D. Pawlak, R. Rolkowski, and W. Buczko
The involvement of AT2-receptor in the antithrombotic effect of losartan in renal hypertensive rats
Journal of Renin-Angiotensin-Aldosterone System,
September 1, 2000;
1(3):
263 - 267.
[Abstract]
[PDF]
|
|
|
|
|
|
|
R. Maruyama, E. Hatta, K. Yasuda, N. C. E. Smith, and R. Levi
Angiotensin-Converting Enzyme-Independent Angiotensin Formation in a Human Model of Myocardial Ischemia: Modulation of Norepinephrine Release by Angiotensin Type 1 and Angiotensin Type 2 Receptors
J. Pharmacol. Exp. Ther.,
July 1, 2000;
294(1):
248 - 254.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
Yi Xu, V. Menon, and B. I Jugdutt
Cardioprotection after angiotensin II type 1 blockade involves angiotensin II type 2 receptor expression and activation of protein kinase C-{varepsilon} in acutely reperfused myocardial infarction in the dog: Effect of UP269-6 and losartan on AT1- and AT2-receptor expression and IP3 receptor and PKC{varepsilon} proteins
Journal of Renin-Angiotensin-Aldosterone System,
June 1, 2000;
1(2):
184 - 195.
[Abstract]
[PDF]
|
|
|
|
|
|
|
W. C. De Mello and A. H. J. Danser
Angiotensin II and the Heart : On the Intracrine Renin-Angiotensin System
Hypertension,
June 1, 2000;
35(6):
1183 - 1188.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Prasad, T. Tupas-Habib, W. H. Schenke, R. Mincemoyer, J. A. Panza, M. A. Waclawin, S. Ellahham, and A. A. Quyyumi
Acute and Chronic Angiotensin-1 Receptor Antagonism Reverses Endothelial Dysfunction in Atherosclerosis
Circulation,
May 23, 2000;
101(20):
2349 - 2354.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. W. O'Brien, Y. Xu, V. Menon, and B. I. Jugdutt
Efficacy of Pretreatment With the Angiotensin II Type 1 Receptor Blocker UP269-6 and Losartan in the Dog: Effect on Hemodynamics and Ischemia-Reperfusion
Journal of Cardiovascular Pharmacology and Therapeutics,
January 1, 2000;
5(2):
129 - 137.
[Abstract]
[PDF]
|
|
|
|
|
|
|
W. R. Ford, A. S. Clanachan, and B. I. Jugdutt
Characterization of Cardioprotection Mediated by AT2 Receptor Antagonism After Ischemia-Reperfusion in Isolated Working Rat Hearts
Journal of Cardiovascular Pharmacology and Therapeutics,
January 1, 2000;
5(3):
211 - 221.
[Abstract]
[PDF]
|
|
|
|
|
|
|
B. I. Jugdutt, Yi Xu, M. Balghith, R. Moudgil, and V. Menon
Cardioprotection Induced by AT1R Blockade After Reperfused Myocardial Infarction: Association With Regional Increase in AT2R, IP3R and PKC{varepsilon} Proteins and cGMP
Journal of Cardiovascular Pharmacology and Therapeutics,
January 1, 2000;
5(4):
301 - 311.
[Abstract]
[PDF]
|
|
|
|
|
|
|
K. Shinmura, Y.-T. Xuan, X.-L. Tang, E. Kodani, H. Han, Y. Zhu, and R. Bolli
Inducible Nitric Oxide Synthase Modulates Cyclooxygenase-2 Activity in the Heart of Conscious Rabbits During the Late Phase of Ischemic Preconditioning
Circ. Res.,
March 22, 2002;
90(5):
602 - 608.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
