Intracellular mechanisms of specific beta-adrenoceptor antagonists involved in improved cardiac function and survival in a genetic model of heart failure.
beta-blockers, as class, improve cardiac function and survival in heart failure (HF). However, the molecular mechanisms underlying these beneficial effects remain elusive. In the present study, metoprolol and carvedilol were used in doses that display comparable heart rate reduction to assess their beneficial effects in a genetic model of sympathetic hyperactivity-induced HF (alpha(2A)/alpha(2C)-ARKO mice). Five month-old HF mice were randomly assigned to receive either saline, metoprolol or carvedilol for 8 weeks and age-matched wild-type mice (WT) were used as controls. HF mice displayed baseline tachycardia, systolic dysfunction evaluated by echocardiography, 50% mortality rate, increased cardiac myocyte width (50%) and ventricular fibrosis (3-fold) compared with WT. All these responses were significantly improved by both treatments. Cardiomyocytes from HF mice showed reduced peak [Ca(2+)](i) transient (13%) using confocal microscopy imaging. Interestingly, while metoprolol improved [Ca(2+)](i) transient, carvedilol had no effect on peak [Ca(2+)](i) transient but also increased [Ca(2+)] transient decay dynamics. We then examined the influence of carvedilol in cardiac oxidative stress as an alternative target to explain its beneficial effects. Indeed, HF mice showed 10-fold decrease in cardiac reduced/oxidized glutathione ratio compared with WT, which was significantly improved only by carvedilol treatment. Taken together, we provide direct evidence that the beneficial effects of metoprolol were mainly associated with improved cardiac Ca(2+) transients and the net balance of cardiac Ca(2+) handling proteins while carvedilol preferentially improved cardiac redox state.
Bartholomeu
Jan B
JB
School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil.
Vanzelli
Andréa S
AS
Rolim
Natale P L
NP
Ferreira
Julio C B
JC
Bechara
Luiz R G
LR
Tanaka
Leonardo Y
LY
Rosa
Kaleizu T
KT
Alves
Márcia M
MM
Medeiros
Alessandra
A
Mattos
Katt C
KC
Coelho
Marcele A
MA
Irigoyen
Maria C
MC
Krieger
Eduardo M
EM
Krieger
Jose E
JE
Negrão
Carlos E
CE
Ramires
Paulo R
PR
Guatimosim
Silvia
S
Brum
Patricia C
PC
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D002227:Carbazoles / Q000627:therapeutic use; D000077261:Carvedilol; D004195:Disease Models, Animal; D006333:Heart Failure / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000503:physiopathology*; D006334:Heart Function Tests; D006439:Hemodynamics / Q000187:drug effects / Q000235:genetics; D007424:Intracellular Fluid / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008790:Metoprolol / Q000627:therapeutic use; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects / Q000235:genetics; D011412:Propanolamines / Q000627:therapeutic use; D011897:Random Allocation; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*
D000319:Adrenergic beta-Antagonists; D002227:Carbazoles; D011412:Propanolamines; D011943:Receptors, Adrenergic, beta; D000077261:Carvedilol; D008790:Metoprolol