Cyclic AMP but not phosphorylation of phospholamban contributes to the slow inotropic response to stretch in ferret papillary muscle

cAMP has been suggested to mediate the increased intracellular Ca2+ transie nt and contraction seen during the slow response to stretch in cardiac musc le. We measured cAMP in ferret papillary muscles stretched from 80-85% to 9 8% of their length at which maximum active tension is produced (L-max) for 15 min. cAMP was significantly (P<0.05) increased by 53% in muscles at the longer length which showed the slow response compared with controls. By con trast, in a population of muscles that were stretched but did not show the slow response, cAMP was not significantly different from that in muscles at the short length. Although cAMP can increase sarcoplasmic reticulum (SR) C a2+ uptake by phosphorylation of phospholamban, we found no:significant eff ect of stretch on phosphorylation of phospholamban at either Ser(16) or Thr (17). Further support for the hypothesis that cAMP is a mediator of the slo w response was obtained by exposure of some muscles to the cell-permeable c AMP antagonist 8-bromo, adenosine 3',5'-cyclic monophosphorothioate, Rp iso mer (Rp-8-Br-cAMPS, (2.5-10 mu M). The slow response was reduced by 30% (P< 0.05) in the presence of this antagonist. Our results not only provide evid ence for the mediation of the slow response to stretch by cAMP, they also s uggest that cAMP may rise in an intracellular compartment inaccessible to t he SR.