Combined angiotensin converting enzyme inhibition and angiotensin AT(1) receptor blockade up-regulates myocardial AT(2) receptors in remodeled myocardium post-infarction.
OBJECTIVE
In an ovine model of left ventricular (LV) remodeling after transmural anteroapical myocardial infarction (MI), we have previously demonstrated that the combination of angiotensin converting enzyme (ACE) inhibition and AT(1) receptor blockade is more effective at limiting LV remodeling than either therapy alone. We hypothesized that the beneficial effect of combined therapy is due in part to upregulation of AT(2) receptor levels.


METHODS
Two days after transmural anteroapical MI by coronary ligation, 16 sheep were randomized to losartan (50 mg/day), ramipril (10 mg/day), ramipril+losartan (combined therapy), or no therapy. At 8 weeks after MI, radioligand receptor assay were deployed with homogenates from regional LV tissues.


RESULTS
We found that AT receptors in normal sheep myocardium are predominantly of the AT(2) receptor subtype. Binding studies of remodeled myocardium 8 weeks later showed that the apparent maximum binding (B(max)) was increased from 23 to 48 fmol/mg protein only in animals with combined therapy. The AT(2)/AT(1) proportion was increased significantly in animals with combined therapy compared to infarcted controls (18.0 vs. 5.17).


CONCLUSIONS
These results indicate that AT(2) receptor expression increased significantly during LV remodeling with combined therapy but not with either therapy alone. In combination with prior work demonstrating the effectiveness of combined therapy in limiting LV remodeling, this study is consistent with the hypothesis that AT(2) receptors play a cardioprotective role in LV remodeling after MI.
Lee
S
S
Department of Medicine and Physiology, Georgetown University Medical Center, 394 Building D, 4000 Reservoir Road NW, Washington, DC 20007, USA.
Kramer
C M
CM
Mankad
S
S
Yoo
S E
SE
Sandberg
K
K
D000704:Analysis of Variance; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000818:Animals; D004359:Drug Therapy, Combination; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan / Q000627:therapeutic use*; D023421:Models, Animal; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology; D009206:Myocardium / Q000737:chemistry; D011725:Pyridines / Q000494:pharmacology; D011869:Radioligand Assay; D017257:Ramipril / Q000627:therapeutic use*; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000032:analysis / Q000378:metabolism*; D012044:Regression Analysis; D012756:Sheep; D020257:Ventricular Remodeling
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; C073402:PD 123319; D019808:Losartan; D017257:Ramipril