Inhibition of the Na+/H+ exchanger attenuates the deterioration of ventricular function during pacing-induced heart failure in rabbits.
OBJECTIVE
Inhibition of the Na+/H+-exchanger (NHE) preserves myocardial morphology and function in rat and mouse models of hypertrophy and failure. The mechanism(s) involved in such cardioprotective effects remain(s) unclear, but might involve blockade of increased protein kinase activity as observed in untreated hearts.


RESULTS
We investigated the functional, morphological and biochemical consequences of NHE-inhibition with BIIB722 in rabbits with pacing-induced heart failure (HF). In sham rabbits treated with placebo (n = 9) or BIIB722 (30 mg/kg/day po, n = 9), LV end-diastolic diameter (LVEDD) and systolic fractional shortening (FS, %) remained unchanged. In HF rabbits (n = 9), LVEDD increased and FS decreased from 31.5 +/- 1.4 to 8.1 +/- 0.9 (p < 0.05) at 3 weeks of LV pacing (400 bpm). Apoptosis, fibrosis and myocyte cross-sectional area as well as p38MAPK phosphorylation and iNOS protein expression were significantly increased in HF compared to sham rabbits. The activity of the 90 kDa NHE-kinase was greater in HF than in sham rabbits. In HF rabbits receiving BIIB722 prior to (18.1 +/- 2.2, n = 9) or following 1 week (15.5 +/- 1.6, n = 7) of pacing, FS at 3 weeks was better preserved than in untreated HF rabbits (p < 0.05). Apoptosis, fibrosis, myocyte cross-sectional area, p38MAPK phosphorylation and iNOS protein expression were significantly reduced in HF rabbits receiving BIIB722.


CONCLUSIONS
NHE-inhibition attenuates the functional, morphological and biochemical derangements of pacing-induced HF in rabbits.
Aker
Stephanie
S
Institute of Pathophysiology, University of Essen Medical School, Hufelandstrasse 55, Essen 45122, Germany.
Snabaitis
Andrew K
AK
Konietzka
Ina
I
Van De Sand
Anita
A
Böngler
Kerstin
K
Avkiran
Metin
M
Heusch
Gerd
G
Schulz
Rainer
R
D000818:Animals; D004452:Echocardiography; D006146:Guanidines / Q000494:pharmacology*; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010766:Phosphorylation; D011817:Rabbits; D015398:Signal Transduction / Q000502:physiology*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018754:Ventricular Dysfunction / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000503:physiopathology; D048051:p38 Mitogen-Activated Protein Kinases
D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; C069139:growth factor-activatable Na-H exchanger NHE-1; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C476560:sabiporide