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. Materials and methods: 8-Bromo-cGMP (2 μg/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 μg/kg/min) was infused, followed by 8 Br-cGMP. Regional myocardial work (force*shortening/min), and O₂ consumption (VO₂) (coronary blood flow*O₂ 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 VO₂ by 29% in control, but not in HYP (1073 ± 182 by -10%, VO₂ by -16%) or HYP-FAIL (495 ± 145 by -9%, VO₂ by 0%). Isoproterenol increased work by 43% and VO₂ by 48% in controls and in HYP (work by 54%, VO₂ by 39%), but not in HYP-FAIL (work by -28%, VO₂ by -5%). Subsequently, 8-Br-cGMP had no effect on work or VO₂ 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.