Treatment of heart failure by a methanocarba derivative of adenosine monophosphate: implication for a role of cardiac purinergic P2X receptors.
Evidence is accumulating to support a potentially important role for purinergic (P2X) receptors in heart failure (HF). We tested the hypothesis that a hydrolysis-resistant nucleotide analog with agonist activity at myocardial P2X receptors (P2XRs) improves the systolic HF phenotype in mouse and dog models. We developed a hydrolysis-resistant adenosine monophosphate derivative, (1'S,2R,3S,4'R,5'S)-4-(6-amino-2-chloro-9H-purin-9-yl)-1-[phosphoryloxymethyl] bicycle[3.1.0]hexane-2,3-diol) (MRS2339), with agonist activity at native cardiac P2XRs. Chronic MRS2339 infusion in postinfarct and calsequestrin (CSQ) mice with HF resulted in higher rates of pressure change (+dP/dt), left ventricle (LV)-developed pressure, and cardiac output in an in vitro working heart model. Heart function in vivo, as determined by echocardiography-derived fractional shortening, was also improved in MRS2339-infused mice. The beneficial effect of MRS2339 was dose-dependent and was identical to that produced by cardiac myocyte-specific overexpression of the P2X(4) receptor. The HF improvement was associated with the preservation of LV wall thickness in both systole and diastole in postinfarct and CSQ mice. In dogs with pacing-induced HF, MRS2339 infusion reduced left ventricular end-diastolic pressure, improved arterial oxygenation, and increased +dP/dt. MRS2339 treatment also decreased LV chamber size in mice and dogs with HF. In murine and canine models of systolic HF, in vivo administration of a P2X nucleotide agonist improved contractile function and cardiac performance. These actions were associated with preserved LV wall thickness and decreased LV remodeling. The data are consistent with a role of cardiac P2XRs in mediating the beneficial effect of this agonist.
Zhou
Si-Yuan
SY
The Pat and Jim Calhoun Cardiology Center, University of Connecticut Health Center, Farmington, Connecticut 06030, USA.
Mamdani
Mohammed
M
Qanud
Khaled
K
Shen
Jian-Bing
JB
Pappano
Achilles J
AJ
Kumar
T Santhosh
TS
Jacobson
Kenneth A
KA
Hintze
Thomas
T
Recchia
Fabio A
FA
Liang
Bruce T
BT
D000249:Adenosine Monophosphate / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D000818:Animals; D002304:Cardiac Pacing, Artificial; D002311:Cardiomyopathy, Dilated / Q000188:drug therapy; D004285:Dogs; D006321:Heart / Q000187:drug effects*; D006333:Heart Failure / Q000000981:diagnostic imaging / Q000188:drug therapy*; D006334:Heart Function Tests; D006439:Hemodynamics / Q000187:drug effects; D007262:Infusions, Intravenous; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D018048:Receptors, Purinergic P2 / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D013610:Tachycardia / Q000188:drug therapy; D014463:Ultrasonography; D016277:Ventricular Function, Left / Q000187:drug effects
C549055:MRS 2339; D018048:Receptors, Purinergic P2; D000249:Adenosine Monophosphate