Modulation of the renin-angiotensin pathway through enzyme inhibition and specific receptor blockade in pacing-induced heart failure: II. Effects on myocyte contractile processes.
BACKGROUND
The goal of this study was to determine the effects of ACE inhibition alone, AT1 angiotensin (Ang) II receptor blockade alone, and combined ACEI and AT1 Ang II receptor blockade in a model of congestive heart failure (CHF) on isolated LV myocyte function and fundamental components of the excitation-contraction coupling process.


RESULTS
Pigs were randomly assigned to one of five groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n=9), (2) concomitant ACEI (benazeprilat, 0.187 mg x kg(-1) x d(-1)) and rapid pacing (n=9), (3) concomitant AT1 Ang II receptor blockade (valsartan, 3 mg/kg/d) and rapid pacing (n=9), (4) concomitant ACEI and AT1 Ang II receptor blockade (benazeprilat/valsartan, 0.05/3 mg x kg(-1) x d(-1)) and rapid pacing (n=9), and (5) sham controls (n=10). LV myocyte shortening velocity was reduced with chronic rapid pacing compared with control (27.2+/-0.6 versus 58.6+/-1.2 microm/s, P<.05) and remained reduced with AT1 Ang II receptor blockade and rapid pacing (28.0+/-0.5 microm/s, P<.05). Myocyte shortening velocity increased with ACEI or combination treatment compared with rapid pacing only (36.9+/-0.7 and 42.3+/-0.8 microm/s, respectively, P<.05). Myocyte beta-adrenergic response was reduced by >50% in both the rapid pacing group and the AT1 Ang II blockade group and improved by 25% with ACEI and increased by 54% with combined treatment. Both L-type Ca2+ channel density and the relative abundance of sarcoplasmic reticulum Ca2+ ATPase density were reduced with rapid pacing and returned to control levels in the combined ACEI and AT1 Ang II blockade group.


CONCLUSIONS
The unique findings of this study were twofold. First, basic defects in specific components of the myocyte excitation-contraction coupling process that occur with CHF are reversible. Second, combined ACEI and AT1 Ang II blockade may provide unique benefits on myocyte contractile processes in the setting of CHF.
Spinale
F G
FG
Division of Cardiothoracic Surgery, Medical University of South Carolina, Charleston 29425, USA.
Mukherjee
R
R
Iannini
J P
JP
Whitebread
S
S
Hebbar
L
L
Clair
M J
MJ
Melton
D M
DM
Cox
M H
MH
Thomas
P B
PB
de Gasparo
M
M
D000704:Analysis of Variance; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001552:Benzazepines / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000502:physiology; D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002304:Cardiac Pacing, Artificial; D002462:Cell Membrane / Q000502:physiology; D002478:Cells, Cultured; D004095:Dihydropyridines / Q000378:metabolism; D006333:Heart Failure / Q000503:physiopathology*; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000502:physiology; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D000254:Sodium-Potassium-Exchanging ATPase / Q000032:analysis; D013552:Swine; D013777:Tetrazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology; D000099211:Phospholamban
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001552:Benzazepines; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D004095:Dihydropyridines; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D000254:Sodium-Potassium-Exchanging ATPase; D013777:Tetrazoles; D014633:Valine; D000068756:Valsartan; D000099211:Phospholamban; C038806:1,4-dihydropyridine; C052133:benazeprilat