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Phosphodiesterase PDE3 blunts the positive inotropic and cyclic AMP enhancing effects of CGP12177 but not of noradrenaline in rat ventricle
Author(s) -
Vargas Maria Luisa,
Hernandez Jesus,
Kaumann Alberto J
Publication year - 2006
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0706498
Subject(s) - rolipram , medicine , propranolol , endocrinology , inotrope , phosphodiesterase 3 , phosphodiesterase , chemistry , phosphodiesterase inhibitor , ventricle , ibmx , pharmacology , biology , forskolin , enzyme , receptor , biochemistry
The cardiostimulant effects of CGP12177, mediated through a β 1 ‐adrenoceptor site with low affinity for (−)‐propranolol, are potentiated by the nonselective PDE inhibitor IBMX but the role of PDE isoenzymes is unknown. We studied the effects of the PDE3‐selective inhibitor cilostamide (300 n M ) and PDE4‐selective inhibitor rolipram (1 μ M ) on the positive inotropic and cyclic AMP‐enhancing effects of CGP12177 and noradrenaline in right ventricular strips of rat. CGP12177 (under (−)‐propranolol 200 n M ) only increased contractile force in the presence of either cilostamide or rolipram with −logEC 50 M 6.7 ( E max =23% over basal) and 7.1 ( E max =50%) respectively. The combination of cilostamide and rolipram caused CGP12177 to enhance contractile force with −logEC 50 M=7.7 and E max =178%. The positive inotropic effects of noradrenaline (−logEC 50 M=6.9) were potentiated by rolipram (−logEC 50 M=7.4) but not by cilostamide (−logEC 50 M=7.0). In the presence of rolipram and (−)‐propranolol, noradrenaline (2 μ M ) and CGP12177 (10 μ M ) produced matching inotropic effects but failed to increase cyclic AMP levels. 20 μ M (−)‐noradrenaline increased cyclic AMP levels, a response further enhanced by rolipram. Both PDE3 and PDE4 of rat ventricle appear to hydrolyse cyclic AMP generated through the low‐affinity β 1 ‐adrenoceptor site, thereby preventing inotropic responses of CGP12177. When (−)‐noradrenaline interacts with the β 1 ‐adrenoceptor, the generated cyclic AMP is hydrolysed only by PDE4, thereby reducing cardiostimulation.British Journal of Pharmacology (2006) 147 , 158–163. doi: 10.1038/sj.bjp.0706498