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Cyclic GMP attenuates cyclic AMP-stimulated inotropy and oxygen consumption in control and hypertrophic hearts
R J Leone1, M Straznicka, P M Scholz
1Heart and Brain Circulation Laboratory, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway 08854-5635, USA.
Insights
Increasing cyclic GMP levels can reduce cyclic AMP-mediated increases in heart contractility and oxygen consumption. However, this effect is diminished in cardiac hypertrophy.
Area of Science:
- Cardiovascular Physiology
- Cellular Signaling
- Cardiac Metabolism
Background:
- Cardiac hypertrophy alters myocardial function and energy metabolism.
- Cyclic nucleotides, cyclic AMP and cyclic GMP, play critical roles in regulating cardiac contractility and oxygen consumption.
- Investigating the interplay between cyclic GMP and cyclic AMP is crucial for understanding cardiac function, especially in disease states.
Purpose of the Study:
- To test if increasing myocardial cyclic GMP attenuates cyclic AMP-induced positive inotropy and oxygen consumption.
- To determine if cardiac hypertrophy affects the relationship between cyclic GMP, cyclic AMP, and cardiac function.
- To elucidate the role of cyclic GMP in modulating cyclic AMP levels in normal and hypertrophied hearts.
Main Methods:
- Utilized anesthetized, open-chest rabbits divided into control and hypertension-induced cardiac hypertrophy (HYP) groups.
- Administered isoproterenol (ISO) to increase cyclic AMP and 3-morpholinosyndnonimine (SIN-1) to increase cyclic GMP.
- Measured coronary blood flow and oxygen extraction to determine myocardial oxygen consumption (MVO2) in subepicardium and subendocardium.
- Quantified cyclic GMP and cyclic AMP levels in myocardial tissue.
Main Results:
- Isoproterenol significantly increased cardiac contractility and MVO2 in both control and HYP groups.
- Increasing cyclic GMP with SIN-1 alone did not affect MVO2 but increased cyclic GMP levels.
- Combined ISO+SIN-1 attenuated isoproterenol-induced increases in MVO2 and cyclic AMP levels in control animals.
- The attenuation of isoproterenol's effects by SIN-1 was less pronounced or absent in HYP animals, particularly for cyclic AMP modulation.
Conclusions:
- Increasing myocardial cyclic GMP can attenuate cyclic AMP-mediated increases in contractility and oxygen consumption.
- This attenuation appears partly mediated by a reduction in cyclic AMP levels.
- Cardiac hypertrophy impairs the ability of cyclic GMP to modulate cyclic AMP levels and its downstream effects on cardiac function.
Abstract:
We tested the hypothesis that increasing myocardial cyclic GMP would attenuate cyclic AMP induced positive inotropy and O2 consumption, in part, through changes in cyclic AMP and that renal hypertension-induced cardiac hypertrophy (HYP) would alter this relationship. Anesthetized, open chest rabbits (N = 48) were divided into four groups of control (CON) and HYP animals which received vehicle (VEH), isoproterenol 10(-6)M (ISO), 3-morpholinosyndnonimine 10(-4)M, (SIN-1), or a combination of ISO+SIN-1. Coronary blood flow (microspheres) and O2 extraction (microspectrophotometry) were used to determine O2 consumption in both subepicardium (EPI) and subendocardium (ENDO). Left ventricular change in wall thickness (%) was increased significantly by ISO in both CON (16 +/- 4 to 31 +/- 6) and HYP (17 +/- 2 to 24 +/- 3). Percent change in wall thickness was similar in the CON, SIN-1, and ISO+SIN-1 groups. Myocardial O2 consumption (ml O2/min/100 g) was increased by ISO in CON (10.3 +/- 1.0 to 13.6 +/- 2.0 EPI; 10.9 +/- 1.0 17.1 +/- 1.7 ENDO) and HYP (8.2 +/- 1.4 to 12.3 +/- 2.2 EPI; 6.6 +/- 1.4 to 14.8 +/- 1.8 ENDO). Oxygen consumption was unaffected by SIN-1 in CON and HYP animals. ISO+SIN-1 caused attenuated ISO-induced increases in O2 consumption in CON in EPI and ENDO, and in EPI in HYP. Cyclic GMP (pmol/g) was unchanged by ISO in CON and HYP, and increased by SIN-1 in CON (8.1 +/- 1.3 to 19.2 +/- 2.3 EPI) and HYP (9.1 +/- 1.5 to 12.8 +/- 2.0 EPI). Cyclic GMP remained elevated with ISO+SIN-1 in both groups. Cyclic AMP (pmol/g) was increased significantly by ISO in CON (496 +/- 43 to 725 +/- 106 EPI; 534 +/- 44 to 756 +/- 148 ENDO) and insignificantly in HYP (435 +/- 50 to 566 +/- 35 EPI; 497 +/- 51 to 583 +/- 47 ENDO). Cyclic AMP levels were unaffected by SIN-1 in either group. Isoproterenol induced increases in cyclic AMP were blunted by ISO+SIN-1 in CON (496 +/- 43 to 537 +/- 59 EPI) and not affected in HYP. The current study demonstrated attenuation of cyclic AMP mediated increased inotropy and O2 consumption by increasing cyclic GMP, which appeared, in part, related to cyclic GMP-induced reduction in cyclic AMP. This effect of cyclic GMP on cyclic AMP was not observed in myocardial hypertrophy.