Vol. 286, Issue 1, 531-538, July 1998

Long-term Beta Adrenoceptor-Mediated Alteration in Contractility and Expression of Phospholamban and Sarcoplasmic Reticulum Ca⁺⁺-ATPase in Mammalian Ventricle¹

Bettina Linck, Peter Bokník, Hideo A. Baba, Thomas Eschenhagen, Uta Haverkamp, Elmar Jäckel, Larry R. Jones, Uwe Kirchhefer, Jörg Knapp, Stephanie Läer, Frank U. Müller, Wilhelm Schmitz, Hasso Scholz, Annemarie Syska, Ute Vahlensieck and Joachim Neumann

Institut für Pharmakologie und Toxikologie der Westfälischen Wilhelms-Universität, Domagkstrae 12, D-48149 Münster, Germany (B.L., P.B., U.H., U.K., J.K., F.U.M., W.S., A.S., U.V., J.N.); Institut für Pathologie der Westfälischen Wilhelms-Universität, Domagkstrae 17, D-48149 Münster, Germany (H.A.B.); Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Martinistrae 52, D-20246 Hamburg, Germany (T.E., E.J., S.L., H.S); and Department of Medicine and Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana (L.R.J.)

We studied the influence of prolonged administration of the beta adrenoceptor agonist isoproterenol on contractile parameters and expression of sarcoplasmic reticulum (SR) Ca⁺⁺-ATPase and phospholamban, genes important 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 and 26 days, respectively. The positive inotropic effect of Iso was impaired in rats pretreated with Iso in vivo. Iso pretreatment shortened time to peak tension (TPT) by 28%, time of relaxation (RT) by 27% and total contraction time (TCT) by 27% compared with the appropriate controls (day 2). The shortening of time-dependent contractile indices started after 1 day of Iso pretreatment, reached a maximum after 2 days and remained reduced for 4 days. Longer treatment by Iso failed to affect time parameters, whereas the positive inotropic effect of Iso added to the isolated muscles persisted. The shortened contractile time parameters were accompanied by diminished mRNA and protein expression of phospholamban (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 the Iso-pretreated group (2 days) respectively. The reduced mRNA levels were accompanied by reduced levels of the corresponding proteins. It is concluded that altered levels of PLB and SERCA probably account for the noted changes in contractile time parameters in the mammalian heart.