Relaxing effect of pharmacologic interventions increasing cAMP in rat heart

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Abstract
The relationship between cAMP and relaxation was studied in the isolated rat heart beating at constant rate and perfused at constant coronary flow. After 1 min treatment with different positive inotropic interventions, cyclic nucleotide levels (cAMP and cGMP) and cAMP-dependent protein kinase activity were determined in heart homogenates. Glucagon, norepinephrine and isoproterenol increased cAMP from 0.503 .+-. 0.025 pmol/mg wet wt to 1.051 .+-. 0.099, 0.900 .+-. 0.064 and 0.982 .+-. 0.138, respectively. Simultaneously glucagon, norepinephrine and isoproterenol increased cAMP-dependent protein kinase activity ratio from 0.21 .+-. 0.02 to 0.45 .+-. 0.04, 0.33 .+-. 0.02 and 0.34 .+-. 0.02, respectively. The ratio between maximal velocities of contraction and relaxation (+.ovrhdot.T/-.ovrhdot.T) was significantly decreased by these interventions; time to peak tension (TTP) was shortened by norepinephrine and isoproterenol. High Ca, ouabain and paired stimulation did not affect cAMP levels, TTP or +.ovrhdot.T/-.ovrhdot.T. A striking correlation was found between cAMP-dependent protein kinase activity and relaxation indices, i.e., TTP, -.ovrhdot.T or +.ovrhdot.T/-.ovrhdot.T (r = .+-.0.7 to -0.9). Results suggest that inotropic interventions increasing cAMP levels might be primarily affecting intracellular mechanisms causing relaxation.