LONG-TERM BETA-ADRENOCEPTOR-MEDIATED ALTERATION IN CONTRACTILITY AND EXPRESSION OF PHOSPHOLAMBAN AND SARCOPLASMIC-RETICULUM CA-ATPASE IN MAMMALIAN VENTRICLE(+)

We studied the influence of prolonged administration of the beta adren oceptor agonist isoproterenol on contractile parameters and expression of sarcoplasmic reticulum (SR) Ca++-ATPase and phospholamban, genes i mportant for Ca++ uptake into the SR. Isoproterenol (Iso), 0.9% NaCl ( Ctr), propranolol (Prop) or Iso plus Prop were administered to rats by subcutaneous infusion with osmotic minipumps for 1, 2, 3, 4, 8, 13 an d 26 days, respectively. The positive inotropic effect of Iso was impa ired in rats pretreated with Iso in vivo. Iso pretreatment shortened t ime to peak tension (TPT) by 28%, time of relaxation (RT) by 27% and t otal contraction time (TCT) by 27% compared with the appropriate contr ols (day 2). The shortening of time-dependent contractile indices star ted after 1 day of Iso pretreatment, reached a maximum after 2 days an d remained reduced for 4 days. Longer treatment by Iso failed to affec t time parameters, whereas the positive inotropic effect of Iso added to the isolated muscles persisted. The shortened contractile time para meters were accompanied by diminished mRNA and protein expression of p hospholamban (PLB) and SR-Ca++-ATPase (SERCA). The mRNA levels for PLB and SERCA were maximally reduced by 31 +/- 1.3% and 41 +/- 1.4% in th e Iso-pretreated group (2 days) respectively. The reduced mRNA levels were accompanied by reduced levels of the corresponding proteins. It i s concluded that altered levels of PLB and SERCA probably account for the noted changes in contractile time parameters in the mammalian hear t.