Compartmentation of receptor-mediated cAMP and cGMP signalling in normal and failing hearts. Implications for treatment of heart failure

With an average 5-year survival rate of only about 30% and with a prevalence of 1-2% in the general population and nearly 10% in the elderly, the personal and societal consequences of heart failure (HF) are dramatic. Better treatment of HF is needed, and must rest upon a better understanding of the mechanisms of myocardial function and HF development. Modern HF treatment aims to counteract detrimental compensatory mechanisms such as sympathetic stimulation, using e.g. beta-blockers, which reduce the beta-adrenergic signalling through the second messenger cyclic AMP (cAMP) in the heart. However, other receptors (e.g. 5-HT4 serotonin and prostaglandin receptors) also utilise cAMP as a second messenger, but with different effects on cardiac contractility. In this project we have investigated the mechanisms for the different effects of cAMP produced by these three receptor systems. We have also investigated the influence of the second messenger cyclic GMP, produced by receptors for natriuretic peptides, on cardiac contractility, both by interfering with cAMP signalling and by direct effects of cGMP on cardiac contractility. In addition to studying contractility of isolated heart muscle strips and single cells, we have developed and used fluorescent sensors to study localised intracellular production of cAMP and cGMP, as well as degradation of these messengers by different phosphodiesterases.

Better treatment of heart failure (HF) is needed, and must rest upon a better understanding of the mechanisms of myocardial function and HF development. It is well established that classical beta-adrenergic signalling is deleterious and increases mortalit y in chronic HF patients. Beta-adrenoceptors (AR) signal through cyclic AMP (cAMP) and several lines of evidence indicate that increasing cardiac contractility through cAMP-mediated signalling is energetically expensive and therefore should be avoided in chronic HF. However, other receptors (e.g. 5-HT4 serotonin receptors and prostaglandin receptors) also utilise cAMP as a second messenger. Whereas 5-HT4 receptors in many respects behave like beta-AR (but with important differences to be explored in this research), prostaglandin receptor stimulation gives different functional consequences, and recent research indicates that different receptors increase cAMP in different functional intracellular compartments. Our recent results indicate that cyclic GMP ( cGMP), produced in the heart by stimulation of receptors for natriuretic peptides as well as nitric oxide (NO), also displays differential functional compartmentation with different functional consequences. Specifically, cGMP produced following NPR-B rece ptor stimulation reduces the degradation of cAMP through phosphodiesterase inhibition and thus enhances potentially deleterious cAMP-mediated signalling. With new methodology allowing studies of cAMP and cGMP production at the subcellular level combined with studies of protein-protein interaction, we will now determine the intracellular compartmentation of cAMP and cGMP in cardiomyocytes following stimulation of different receptor systems and relate these different intracellular compartments of cAMP and cGMP to functional effects in the heart, primarily regulation of contractility. Results from animal experiments will be verified in human heart tissue and the research will have relevance for treatment of HF.