Efficacy of angiotensin II type 1 receptor blockade on reperfusion-induced arrhythmias and mortality early after myocardial infarction is increased in transgenic rats with cardiac angiotensin II type 1 overexpression.
Angiotensin II induces ischemia/reperfusion (I/R)-induced arrhythmias and blockade of the angiotensin II type 1 receptor (AT1R) may therefore be beneficial in preventing arrhythmias and decreasing mortality after myocardial infarction (MI). Because the AT1R is upregulated after myocardial ischemia, it was hypothesized that the level of AT1R expression would mediate the response to AT1R blockade. Transgenic (TGR) rats that overexpress the human AT1R and Sprague-Dawley rats were used as controls. Total duration of arrhythmia (seconds) after I/R injury was similar in TGR and SD rats (433 +/- 109 vs. 376 +/- 117, p = n.s.). AT1R blockade with losartan decreased total duration of arrhythmia in the TGR rats (433 +/- 110 s-164 +/- 48 s; p < 0.05), whereas it caused a nonsignificant increase in the SD rats (376 +/- 117 s-497 +/- 97). In vivo, survival in the first 24 hours after MI was impaired in TGR rats (39%; SD, 63%). Losartan improved survival significantly in TGR rats (from 39% to 80%, p < 0.05). A smaller, nonsignificant effect was observed in SD rats (63% to 81%). AT1R blockade is beneficial only when the AT1R was overexpressed, both in reducing the reperfusion-induced arrhythmias and mortality early after MI.
de Boer
Rudolf A
RA
Thoraxcenter, Department of Cardiology, University Hospital Groningen, P.O. Box 30.001, Groningen, The Netherlands. r.a.de.boer@thorax.azg.nl
van Geel
Peter P
PP
Pinto
Yigal M
YM
Suurmeijer
Albert J H
AJ
Crijns
Harry J G M
HJ
van Gilst
Wiek H
WH
van Veldhuisen
Dirk J
DJ
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D030801:Animals, Genetically Modified; D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D006801:Humans; D019808:Losartan / Q000627:therapeutic use*; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000235:genetics; D015427:Reperfusion Injury / Q000150:complications*; D016277:Ventricular Function, Left / Q000187:drug effects
D057911:Angiotensin Receptor Antagonists; D000889:Anti-Arrhythmia Agents; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D019808:Losartan