Heart failure reduces both the effects and interaction between cyclic GMP and cyclic AMP.
BACKGROUND
We tested the hypothesis that the negative functional effects of cyclic GMP would be attenuated by cyclic AMP and this interaction would be reduced in pacing-induced failure of hypertrophic hearts.


METHODS
8-Bromo-cGMP (2 microg/kg/min) was infused into a coronary artery in eight control, eight ventricular hypertrophy (HYP), and eight hypertrophic failure (HYP-FAIL) dogs. Then isoproterenol (0.1 microg/kg/min) was infused, followed by 8 Br-cGMP. Regional myocardial work (force*shortening/min), and O(2) consumption (VO(2)) (coronary blood flow*O(2) extraction) were measured. Cyclic GMP levels were determined by radioimmunoassay.


RESULTS
8-Br-cGMP significantly decreased regional work from 3812 +/- 839 g*mm/min by 17% and VO(2) by 29% in control, but not in HYP (1073 +/- 182 by -10%, VO(2) by -16%) or HYP-FAIL (495 +/- 145 by -9%, VO(2) by 0%). Isoproterenol increased work by 43% and VO(2) by 48% in controls and in HYP (work by 54%, VO(2) by 39%), but not in HYP-FAIL (work by -28%, VO(2) by -5%). Subsequently, 8-Br-cGMP had no effect on work or VO(2) in control (-2%, -13%), HYP (-12%, -30%), or HYP-FAIL (+13%, +14%). Cyclic AMP levels were elevated by isoproterenol in control (381 +/- 115 versus 553 +/- 119 pmol/g) and HYP (313 +/- 55 versus 486 +/- 227), but not in HYP-FAIL (300 +/- 60 versus 284 +/- 126). After isoproterenol, 8-Br-cGMP further elevated cyclic AMP in control (687 +/- 122), but not in HYP or HYP-FAIL.


CONCLUSIONS
In controls, cyclic AMP attenuated cyclic GMPs negative functional and metabolic effects. The effects and the interaction were blunted in the HYP and HYP-FAIL groups.
Department of Surgery, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey, USA.
Jacob
J
Moalem
Harvey R
HR
Weiss
Tomer
T
Davidov
Roberto
R
Rodriguez
Bruno
B
Molino
Michael J
MJ
Lazar
Peter M
PM
Scholz
D000818:Animals; D002303:Cardiac Output, Low / Q000503:physiopathology*; D002316:Cardiotonic Agents / Q000008:administration & dosage; D003326:Coronary Circulation; D003331:Coronary Vessels / Q000187:drug effects; D000242:Cyclic AMP / Q000032:analysis / Q000502:physiology*; D006152:Cyclic GMP / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000032:analysis / Q000502:physiology*; D004195:Disease Models, Animal; D004285:Dogs; D017379:Hypertrophy, Left Ventricular / Q000209:etiology / Q000503:physiopathology; D007545:Isoproterenol / Q000008:administration & dosage; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000737:chemistry; D010101:Oxygen Consumption / Q000187:drug effects
D002316:Cardiotonic Agents; C016276:8-bromocyclic GMP; D000242:Cyclic AMP; D006152:Cyclic GMP; D007545:Isoproterenol