Dissociation between contraction and relaxation: the possible role of phospholamban phosphorylation.

Abstract

The relationship between myocardial relaxation and phosphorylation of phospholamban, an intrinsic protein of sarcoplasmic reticulum (SR), was studied in perfused rat hearts beating at constant rate and perfused at constant coronary flow. The positive inotropic effect (increase in developed tension, T, and maximal rate of rise of tension, +T) of 3 X 10(-9) and 3 X 10(-8) M isoproterenol (ISO) occurred together, with a proportionately greater increase in maximal velocity of relaxation, -T. Thus, the +T/-T ratio decreased 0.23 +/- 0.04 and 0.41 +/- 0.05 respectively. Time to half-relaxation (t1/2) and the time constant of relaxation (Tau) were also significantly decreased by ISO. Phospholamban phosphorylation (in pmol 32Pi/mg SR protein) increased from 23 +/- 3.3 (control) to 42 +/- 2.3 (3 X 10(-9) M ISO) and to 186 +/- 19.3 (3 X 10(-8) M ISO). When the negative inotropic action of nifedipine was just offset by either Ca2+ (N-Ca2+) or ISO (N-I), relaxation was faster when ISO was present. Perfusion with N-I significantly decreased +T/-T 0.18 +/- 0.05, t1/2 14 +/- 3 ms and Tau 1.4 +/- 0.2 ms. Phospholamban phosphorylation significantly increased from 23 +/- 3.3 to 40 +/- 4.9 pmol 32 Pi/mg SR protein. N-Ca2+ did not elicit any significant change in these parameters nor in phospholamban phosphorylation. Thus, phospholamban phosphorylation appears closely related to myocardial relaxation and may be one of the important mechanisms by which contractility and relaxation are dissociated in vivo.