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Interaction between the opposing functional effects of cyclic AMP and cyclic GMP in hypertrophic cardiac myocytes
1Department of Physiology & Biophysics UMDNJ--Robert Wood Johnson Medical School, Piscataway, NJ 08854-5635, USA.
Insights
In cardiac cells, cyclic GMP
Area of Science:
- Cardiovascular Physiology
- Cellular Biology
Background:
- Cardiac myocytes regulate contractility through cyclic nucleotides, including cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP).
- Renal hypertension can lead to cardiac hypertrophy, altering myocyte function.
- The interaction between cAMP and cGMP in cardiac function, particularly in hypertrophic states, requires further elucidation.
Purpose of the Study:
- To investigate the hypothesis that elevated cyclic AMP levels blunt the negative functional effects of cyclic GMP in isolated cardiac myocytes.
- To determine if this interaction is altered in cardiac hypertrophy associated with one-kidney, one-clip (1K1C) renal hypertension.
- To assess the functional effects of 8-bromoguanosine cyclic monophosphate (8-Br-cGMP) and forskolin on myocyte shortening and cyclic nucleotide levels.
Main Methods:
- Isolated ventricular myocytes from control and 1K1C hypertensive rabbits were used.
- Cell shortening was measured after exposure to varying concentrations of 8-Br-cGMP.
- The effects of forskolin (an adenylate cyclase activator) followed by 8-Br-cGMP were assessed on cell shortening and cyclic AMP levels.
Main Results:
- 8-Br-cGMP decreased myocyte shortening in a dose-dependent manner in both control and hypertrophic myocytes.
- Forskolin increased shortening in control myocytes but not significantly in hypertrophic myocytes, despite increasing cyclic AMP levels in both.
- Forskolin attenuated the negative effects of 8-Br-cGMP in both groups; cyclic AMP levels increased after 8-Br-cGMP addition in control but not 1K1C myocytes.
Conclusions:
- In hypertrophic cardiac myocytes, the positive functional effects of cyclic AMP are blunted, while the negative effects of cyclic GMP remain similar to controls.
- The interaction between cyclic GMP and cyclic AMP in mediating cardiac myocyte function is altered in the context of renal hypertension-induced hypertrophy.
- The blunting of cyclic GMP effects by forskolin suggests a complex interplay, not solely dependent on cyclic AMP phosphodiesterase activity.
Abstract:
We tested the hypothesis that in isolated cardiac myocytes, the negative functional effects of cyclic GMP would be blunted when the level of cyclic AMP was increased and that this interaction would be altered in renal hypertensive (One-Kidney-One-Clip, 1K1C) cardiac hypertrophic rabbits. Using isolated control and 1K1C ventricular myocytes, cyclic AMP and cell shortening (%) data were collected: 1) at baseline, 2) after the addition of 8-Br-cGMP 10(-7), -6, -5 M, and 3) after forskolin (10(-6) M), an adenylate cyclase activator, followed by 8-Br-cGMP 10(-7), -6, -5 M. Basal levels of cyclic AMP were similar in control vs. 1K1C myocytes (10.2 +/- 1.6 vs. 11.3 +/- 2.6 pmol/10(5) myocytes). We found that 8-Br-cGMP decreased the percent shortening in a dose related manner in both control myocytes (5.1 +/- 0.6 to 3.2 +/- 0.4%) and hypertrophic myocytes (5.2 +/- 0.4 to 3.6 +/- 0.5). The level of cyclic AMP significantly increased after the addition of 8-Br-cGMP in control myocytes (14.1 +/- 2.1), but not in 1K1C myocytes. Forskolin increased the percent shortening in the control myocytes (3.8 +/- 0.1 to 4.8 +/- 0.4), but no significant increase was noted in the hypertrophic myocytes (3.6 +/- 0.3 to 3.7 +/- 0.3). The level of cyclic AMP significantly increased after the addition of forskolin in both control (13.9 +/- 2.0), and 1K1C cells (14.6 +/- 3.8). Forskolin attenuated the negative functional effects of 8-Br-cGMP in the control (4.8 +/- 0.4 to 3.2 +/- 0.1) and 1K1C myocytes (3.7 +/- 0.3 to 2.7 +/- 0.3). The addition of 8-Br-cGMP did not affect the level of cyclic AMP after forskolin in either control (13.9 +/- 2.0 to 14.8 +/- 2.5) or 1K1C myocytes (14.6 +/- 3.8 to 13.8 +/- 1.9). These data indicated that in hypertrophic cardiac myocytes the negative functional effects of 8-Br-cGMP were similar to control, but the positive functional effects of cyclic AMP were blunted. There was an increase in cyclic AMP levels after addition of 8-Br-cGMP in control but not 1K1C cells. We conclude that in control and hypertrophic myocytes, the effects of cyclic GMP were blunted after forskolin, but this did not seem to be related to cyclic AMP phosphodiesterase activity.