Phosphatase inhibitor cantharidin blocks adenosine A(1) receptor anti-adrenergic effect in rat cardiac myocytes.
Experiments were performed to examine whether the protein phosphatase inhibitor cantharidin blocks the anti-adrenergic effect of adenosine A(1) receptor stimulation. In electrically stimulated adult rat ventricular myocytes loaded with the intracellular calcium concentration ([Ca(2+)](i)) indicator fluo-3, isoproterenol (10 nM) increased systolic [Ca(2+)](i) by 46%, increased twitch amplitude by 56%, and increased total cellular cAMP content by 140%. The adenosine A(1) receptor agonist 2-chloro-N(6)-cyclopentlyadenosine (CCPA) reduced isoproterenol-stimulated [Ca(2+)](i) and contractility by 87 and 80%, respectively, but reduced cAMP content by only 18%. Cantharidin had no effects on myocyte [Ca(2+)](i), contractility, or cAMP in the absence or presence of isoproterenol but blocked the effects of CCPA on [Ca(2+)](i) and contractility by approximately 44%. Cantharidin had no effect on CCPA attenuation of isoproterenol-induced increases in cAMP. Pretreatment with CCPA also reduced the increase in contractile parameters produced by the direct cAMP-dependent protein kinase A (PKA) activator 8-bromocAMP. These results suggest that activation of protein phosphatases mediate, in part, the anti-adrenergic effect of adenosine A(1) receptor activation in ventricular myocardium.
Narayan
P
P
Department of Surgery, University of Kentucky College of Medicine, Lexington, Kentucky 40536, USA. pnaraya@pop.uky.edu
Mentzer
R M
RM
Lasley
R D
RD
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000241:Adenosine / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002193:Cantharidin / Q000494:pharmacology*; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007425:Intracellular Membranes / Q000378:metabolism; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors*; D058906:Purinergic P1 Receptor Agonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D018047:Receptors, Purinergic P1 / Q000502:physiology*
D000318:Adrenergic beta-Agonists; D004791:Enzyme Inhibitors; D058906:Purinergic P1 Receptor Agonists; D018047:Receptors, Purinergic P1; D015124:8-Bromo Cyclic Adenosine Monophosphate; C058394:2-chloro-N(6)cyclopentyladenosine; D000242:Cyclic AMP; D010744:Phosphoric Monoester Hydrolases; D002193:Cantharidin; D000241:Adenosine; D007545:Isoproterenol; D002118:Calcium