Abstract
We studied the influence of prolonged administration of thebeta 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.
Footnotes
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Send reprint requests to: Dr. Bettina Linck, Institut für Pharmakologie und Toxikologie der Westfälischen Wilhelms-Universität, Domagkstraβe 12, D-48149 Münster, Germany.
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↵1 This work was supported by the Deutsche Forschungsgemeinschaft, the Deutsche Herzstiftung, the Deutsche Gesellschaft für Herz- und Kreislaufforschung and the IKF B1.
- Abbreviations:
- Iso
- (−)-isoproterenol
- TCT
- total contraction time
- TPT
- time to peak tension
- RT
- time of relaxation
- PLB
- phospholamban, Prop, propranolol
- SDS
- sodium dodecyl sulfate
- PAGE
- polyacrylamide gel electrophoresis, SERCA, sarcoplasmic reticulum Ca++-ATPase
- Received September 18, 1997.
- Accepted March 23, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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