Comparison of adenosine and muscarinic receptor-mediated effects on protein phosphatase inhibitor-1 activity in the heart.

Langendorff-perfused guinea pig ventricles were used to examine the effects of the adenosine agonists, (-)-N-6-phenylisopropyl-adenosine (PIA) and 5'-N-ethylcarboxamidoadenosine and the muscarinic cholinergic agonist, acetylcholine, on the rate of tension development, protein phosphatase inhibitor-1 (PPI-1) activity, and cyclic AMP-dependent protein kinase (PKA) activity ratio. Isoproterenol (10 nM) and forskolin (1 microM) stimulated rate of tension development, PKA activity ratio and PPI-1 activity each approximately 2-fold. Acetylcholine (1 microM) by itself was not effective, but when administered with isoproterenol for forskolin reduced the rate of tension development and PPI-1 activity without decreasing PKA activity ratio. Similarly, both PIA and 5'-N-ethylcarboxamidoadenosine alone were ineffective, but when simultaneously applied with isoproterenol attenuated the isoproterenol-stimulated rate of tension development and PPI-1 activity. PIA reduced PKA activity ratio, whereas 5'-N-ethylcarboxyamidoadenosine failed to do so. However, the effect of PIA on PKA activity ratio was smaller than those seen on rate of tension development and PPI-1 activity. Hence, the present data do not support a cyclic AMP-dependent regulation of PPI-1 activity by adenosine and muscarinic agonists. It is tempting to speculate that adenosine and muscarinic agonists reduce PPI-1 activity by a cyclic AMP-independent mechanism.