Heart Failure Reduces Both the Effects and Interaction Between Cyclic GMP and Cyclic AMP

BackgroundWe 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 methods8-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.Results8-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.ConclusionsIn 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.