title: Angiotensin II blockade followed by growth hormone as adjunctive therapy after experimental myocardial infarction.
abstract: BACKGROUND
  Recombinant human growth hormone (rhGH) has shown beneficial effects on cardiac function after myocardial infarction (MI) in rats. High-dose angiotensin II (AT1) receptor blockade in normal rats inhibited the hypertrophic effect of growth hormone (GH), therefore we investigated whether GH effects after MI would be enhanced by giving it in sequence after remodeling had been inhibited by prior AT1 blockade (losartan, L).
  
  
  RESULTS
  Rats given losartan for 10 weeks after MI followed by rhGH for 2 weeks (2 mg/kg twice a day, GH plus losartan) were compared with rats given losartan for 10 weeks followed by placebo for 2 weeks (placebo plus losartan group) and with untreated controls (n = 17-20/group). Average MI sizes and left ventricular (LV) end diastolic (ED) dimensions (echocardiography) did not differ between groups. In GH and losartan, body weight (BW) was increased but left ventricular weight (LVW)/BW was reduced, and the LV fractional shortening and LV dP/dtmax (catheter tip micromanometer) were increased compared with the control group (20.3 vs 15.4% and 5579 vs 4699 mmHg/s, respectively, P < .05). The cardiac index also was significantly increased. In the placebo plus losartan group, the LVW/BW was also reduced and the cardiac index increased versus controls. Stroke volume was increased in GH plus losartan group compared with both placebo plus losartan and controls, and the systemic vascular resistance was significantly decreased only in the GH plus losartan group. The ED posterior wall thickness (noninfarcted wall) was increased in GH plus losartan compared with both control and placebo plus losartan. Left ventricular end diastolic pressure reduction was not significant in GH plus losartan group versus controls but was reduced in placebo plus losartan group, whereas LV relaxation (tau) was improved in both groups versus control rats. Thus, persistent remodeling effects caused by prior AT1 blockade undoubtedly contributed to some responses, but short-term GH given in sequence after chronic AT1 blockade had favorable actions on the failing heart and peripheral circulation by increasing LV wall thickness with partial reversal of unfavorable remodeling, lowering of vascular resistance, improvement of LV contractility, and enhanced LV systolic function and cardiac index relatively late after experimental MI.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla 92093-0613, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hongo
authors.forename: E M
authors.initials: EM
authors.lastname: Sentianin
authors.forename: N
authors.initials: N
authors.lastname: Tanaka
authors.forename: L
authors.initials: L
authors.lastname: Mao
authors.forename: M D
authors.initials: MD
authors.lastname: McKirnan
authors.forename: R G
authors.initials: RG
authors.lastname: Clark
authors.forename: W
authors.initials: W
authors.lastname: Won
authors.forename: K R
authors.initials: KR
authors.lastname: Chien
authors.forename: J
authors.initials: J
authors.lastname: Ross
mesh_terms: D000804:Angiotensin II / Q000037:antagonists & inhibitors; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001783:Blood Flow Velocity / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003971:Diastole; D004359:Drug Therapy, Combination; D004452:Echocardiography; D005260:Female; D013006:Growth Hormone / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D006439:Hemodynamics / Q000187:drug effects; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy; D007668:Kidney / Q000473:pathology; D008099:Liver / Q000473:pathology; D019808:Losartan / Q000494:pharmacology* / Q000627:therapeutic use; D009203:Myocardial Infarction / Q000175:diagnosis / Q000188:drug therapy* / Q000503:physiopathology; D009206:Myocardium / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000473:pathology; D016277:Ventricular Function, Left / Q000187:drug effects; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D057911:Angiotensin Receptor Antagonists; D000889:Anti-Arrhythmia Agents; D000804:Angiotensin II; D013006:Growth Hormone; D019808:Losartan