[Effects of combination therapy with angiotensin I-converting enzyme inhibitor and angiotensin 1 receptor antagonist on ventricular remodeling and expression of endothelial nitric oxide synthase].
OBJECTIVE
To evaluate the effects of ACEI, AT1 receptor antagonism, and combination of these two drugs on ventricular remodeling, and the vary of eNOS in rats with myocardial infarction (MI).


METHODS
Eighty-six rats were randomly divided into four groups at twenty-four hours after MI, and treated for 2 weeks and 6 weeks. (1) MI-placebo (n = 22); (2) MI-Fosinopril (n = 20, 10 mg.kg(-1).d(-1)); (3) MI-Irbesartan (n = 23, 50 mg.kg(-1).d(-1)); (4) MI-Fosinopril + Irbesartan (n = 21, 10 mg.kg(-1).d(-1) + 50 mg.kg(-1).d(-1)); and sham-ligation. Mean blood pressure and left ventricular end diastolic pressure (LVEDP) were evaluated, as well as ventricular weight (VW)/body weight (BW) ratio. The total collagen was quantified by histomorphometry. The expressions of eNOS mRNA and protein within the noninfarction zone were determined by RT-PCR and histomorphometry.


RESULTS
Acute myocardial infarction resulted in a significant increase of LVEDP (P < 0.05), LVDd (P < 0.01), and VW/BW (P < 0.01), and total collagen (at 2 weeks 6.1 +/- 0.7 vs 3.6 +/- 0.5 and at 6 weeks 5.1 +/- 0.8 vs 3.6 +/- 0.4, P < 0.01) in noninfarcted region. Treatment with fosinopril, irbesartan and combination of these two drugs improved them. At the sixth week, irbesartan and combination therapy decreased more significantly total collagen compared with fosinopril (3.4 +/- 0.7 and 3.3 +/- 0.7 vs 4.2 +/- 0.6, P < 0.05). The level of eNOS mRNA expression increased more significantly in combination therapy group than in fosinopril or irbesartan group alone (at 2 weeks 1.55 +/- 0.17, at 6 weeks 1.61 +/- 0.16, P < 0.01). eNOS protein increased.


CONCLUSIONS
Fosinopril or irbesartan alone, and combination of these two drugs can improve hemodynamics, limited myocardial hypertrophy, attenuated the development of myocardial interstitial fibrosis in the noninfarcted left ventricule. The use of irbesartan, especially combined with fosinopril was more effective than fosinopril alone in the suppression interstitial fibrosis. Combination therapy was more effective than fosinopril and irbesartan alone in enhancing eNOS mRNA and protein expression.
Zhang
Rui-ying
RY
Department of Cardiology, First Hospital of Harbin Medical University, Harbin 150001, China.
Huang
Yong-lin
YL
Sun
Yi-hong
YH
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D017328:Fosinopril / Q000494:pharmacology / Q000627:therapeutic use; D000077405:Irbesartan; D008297:Male; D009203:Myocardial Infarction / Q000201:enzymology* / Q000503:physiopathology; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000096:biosynthesis; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000494:pharmacology / Q000627:therapeutic use; D020257:Ventricular Remodeling / Q000187:drug effects
D047228:Angiotensin II Type 1 Receptor Blockers; D000806:Angiotensin-Converting Enzyme Inhibitors; D001713:Biphenyl Compounds; D012333:RNA, Messenger; D013777:Tetrazoles; D052250:Nitric Oxide Synthase Type III; D000077405:Irbesartan; D017328:Fosinopril