Interaction between the opposing functional effects of cyclic AMP and cyclic GMP in hypertrophic cardiac myocytes

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), and 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/10⁵ 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 adition 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. Received: 12 October 1999, Returned for 1. revision: 24 November 1999, 1. Revision received: 23 March 2000, Returned for 2. revision: 26 May 2000, 2. received: 16 June 2000, Accepted: 12 July 2000