Abstract
Although β-adrenoceptor (β-AR) blockers are used for the treatment of ischemic heart disease, the mechanisms of their beneficial actions have not been fully elucidated. In view of the role of sarcoplasmic reticular (SR) abnormalities in cardiac dysfunction due to ischemia-reperfusion (I/R), we examined the effects of β-AR blockers on the I/R-induced changes in SR Ca2+ uptake and release, as well as the protein contents and gene expression of ryanodine receptor, SR Ca2+-pump, phospholamban, and calsequestrin. I/R in isolated rat hearts was induced by stopping the perfusion for 30 min and then reperfusing the ischemic hearts for 60 min. Hearts were treated with or without 10 μM atenolol, a β1-specific blocker, or 10 μM propranolol, a nonspecific β-blocker, 10 min before inducing ischemia as well as during the reperfusion period. I/R depressed cardiac performance, SR Ca2+ uptake, and Ca2+ release activities, protein contents, as well as Ca2+/calmodulin-dependent protein kinase and cAMP-dependent protein kinase-mediated phosphorylations, significantly. The mRNA levels for SR Ca2+ pump, ryanodine receptors, phospholamban, and calsequestrin were also reduced by I/R. All these changes due to I/R were partially prevented by β-AR blocker treatment. The results indicate that the beneficial effects of β-AR blockers on cardiac performance in the I/R hearts may be related to the prevention of changes in SR Ca2+ uptake and release activities, protein contents, as well as Ca2+/calmodulin-dependent protein kinase and cAMP-dependent protein kinase phosphorylations of SR proteins. On the other hand, the protection of I/R-induced alterations in mRNA levels for SR proteins by β-AR blockers suggests cardiac SR gene expression as a molecular site of their cardioprotective action.
Footnotes
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Send reprint requests to: Dr. Naranjan S. Dhalla, Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, 351 Taché Ave., Winnipeg, Manitoba R2H 2A6 Canada. E-mail: cvso{at}sbrc.umanitoba.ca
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↵1 This study was supported by a grant from the Medical Research Council of Canada (MRC Group in Experimental Cardiology. Rana M. Temsah received studentship award of the University of Manitoba; Chadwyn Dyck received support from the B. Sc. (Med) program at the Faculty of Medicine. Dr. Naranjan S. Dhalla holds MRC/Pharmaceutical Research and Development Chair in Cardiovascular Research supported by Merck Frosst, Canada.
- Abbreviations:
- β-AR
- β-adrenoceptors
- SR
- sarcoplasmic reticular/reticulum
- I/R
- ischemia-reperfusion
- CaMK
- Ca2+/calmodulin-dependent protein kinase
- PKA
- cAMP-dependent protein kinase
- SERCA2a
- Ca2+-pump ATPase
- PLB
- phospholamban
- RyR
- ryanodine receptor
- CQS
- calsequestrin
- LVDP
- left ventricular developed pressure
- LVEDP
- left ventricular end diastolic pressure
- +dP/dt
- rate of ventricular pressure development
- −dP/dt
- rate of ventricular pressure decline
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- α-MHC
- α-myosin heavy chain
- PAGE
- polyacrylamide gel electrophoresis
- Received August 3, 1999.
- Accepted January 6, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
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