Selective type 1 angiotensin II receptor blockade attenuates oxidative stress and regulates angiotensin II receptors in the canine failing heart.
OBJECTIVE
Angiotensin II type 1 receptor (AT(1)R) blockade reduces vascular oxidative stress but whether myocardial oxidative stress represents a mechanism for the beneficial effect of AT(1)R blockade in heart failure is unclear. Furthermore, the impact of AT(1)R blockade on the expression of angiotensin II receptors in heart failure has not been well documented. Accordingly, we examined the impact of the AT(1)R blocker candesartan on hemodynamics, left ventricular (LV) remodeling (echocardiography), oxidative stress, and tissue expression of AT(1)Rs and angiotensin II type 2 receptors (AT(2)Rs) in a canine model of pacing-induced heart failure.


RESULTS
Animals were randomized to rapid right ventricular-pacing (250 beats/min for 3 weeks) to severe heart failure and treated with candesartan (10 mg/kg daily, n = 8) or placebo (n = 8) from day 3 onwards, or no pacing (sham, n = 7). Candesartan significantly reduced mean pulmonary arterial and LV diastolic pressure, LV end-diastolic and end-systolic volume and ascites, increased cardiac output, dP/dt, and ejection fraction, while reversing the marked increase in aldehydes, a marker of oxidative stress, observed in the placebo group. Although candesartan did not alter LV AT(1)R protein expression compared to placebo or sham, it reversed the decrease in AT(2)R protein observed in the placebo group.


CONCLUSIONS
Our results indicate that in the pacing model of heart failure, chronic AT(1)R blockade attenuates hemodynamic deterioration and limits LV remodeling and dysfunction, in part by reversing oxidative stress and AT(2)R downregulation.
Division of Cardiology, St. Michael's Hospital, University of Toronto, 30 Bond Street, Suite-6-040, Toronto, ON, Canada, M5B 1W8. moeg@smh.toronto.on.ca
Gordon
G
Moe
Andrea
A
Konig
Peter
P
Liu
Bodh I
BI
Jugdutt
D000447:Aldehydes / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology*; D001713:Biphenyl Compounds; D004285:Dogs; D004452:Echocardiography; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D018384:Oxidative Stress / Q000187:drug effects*; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D044139:Receptor, Angiotensin, Type 2 / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology; D020257:Ventricular Remodeling / Q000187:drug effects
D000447:Aldehydes; D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D013777:Tetrazoles; D000804:Angiotensin II; C081643:candesartan