Reduction in interaction between cGMP and cAMP in dog ventricular myocytes with hypertrophic failure.
Baseline function and signal transduction are depressed in hearts with hypertrophic failure. We tested the hypothesis that the effects of cGMP and its interaction with cAMP would be reduced in cardiac myocytes from hypertrophic failing hearts. Ventricular myocytes were isolated from control dogs, dogs with aortic valve stenosis hypertrophy, and dogs with pacing hypertrophic failure. Myocyte function was measured using a video edge detector. Cell contraction data were obtained at baseline, with 8-bromo-cGMP (10(-7), 10(-6), and 10(-5) M), with erythro-9-(2-hydroxy-3-nonyl)adenine [EHNA; a cAMP phosphodiesterase (PDE(2)) inhibitor] plus 8-bromo-cGMP, or milrinone (a PDE(3) inhibitor) plus 8-bromo-cGMP. Baseline percent shortening and maximal rates of shortening (R(max)) and relaxation were slightly reduced in hypertrophic myocytes and were significantly lower in failing myocytes (R(max): control dogs, 95.3 +/- 17.3; hypertrophy dogs, 88.2 +/- 5.5; failure dogs, 53.2 +/- 6.4 mum/s). 8-Bromo-cGMP dose dependently reduced myocyte function in all groups. However, EHNA (10(-6) M) and milrinone (10(-6) M) significantly reduced the negative effects of cGMP on cell contractility in control and hypertrophy but not in failing myocytes (R(max) for control dogs: cGMP, -46%; +EHNA, -21%; +milrinone, -19%; for hypertrophy dogs: cGMP, -40%; +EHNA, -13%; +milrinone, -20%; for failure dogs: cGMP, -40%; +EHNA, -29%; +milrinone, -32%). Both combinations of EHNA-cGMP and milrinone-cGMP significantly increased intracellular cAMP in control, hypertrophic, and failing myocytes. These data indicated that the cGMP signaling pathway was preserved in hypertrophic failing cardiac myocytes. However, the interaction of cGMP with the cAMP signaling pathway was impaired in these failing myocytes.
Zhang
Qihang
Q
Department of Surgery, UMDNJ-Robert Wood Johnson Medical School, One Robert Wood Johnson Place, CN-19, New Brunswick, NJ 08903-0019, USA.
Lazar
Michael
M
Molino
Bruno
B
Rodriguez
Roberto
R
Davidov
Tomer
T
Su
Jun
J
Tse
James
J
Weiss
Harvey R
HR
Scholz
Peter M
PM
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D001835:Body Weight; D002316:Cardiotonic Agents / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism* / Q000494:pharmacology; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D004285:Dogs; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006333:Heart Failure / Q000378:metabolism* / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000378:metabolism* / Q000473:pathology; D020105:Milrinone / Q000494:pharmacology; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D009929:Organ Size; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; C016276:8-bromocyclic GMP; C010192:9-(2-hydroxy-3-nonyl)adenine; D000242:Cyclic AMP; D006152:Cyclic GMP; D000225:Adenine; D020105:Milrinone