Altered dose response to beta-agonists in SERCA1a-expressing hearts ex vivo and in vivo.
In this study we evaluated the contractile characteristics of sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA)1a-expressing hearts ex vivo and in vivo and in particular their response to beta-adrenergic stimulation. Analysis of isolated, work-performing hearts revealed that transgenic (TG) hearts develop much higher maximal rates of contraction and relaxation than wild-type (WT) hearts. Addition of isoproterenol only moderately increased the maximal rate of relaxation (+20%) but did not increase contractility or decrease relaxation time in TG hearts. Perfusion with varied buffer Ca(2+) concentrations indicated an altered dose response to Ca(2+). In vivo TG hearts displayed fairly higher maximal rates of contraction (+ 25%) but unchanged relaxation parameters and a blunted but significant response to dobutamine. Our study also shows that the phospholamban (PLB) level was decreased (-40%) and its phosphorylation status modified in TG hearts. This study clearly demonstrates that increases in SERCA protein level alter the beta-adrenergic response and affect the phosphorylation of PLB. Interestingly, the overall cardiac function in the live animal is only slightly enhanced, suggesting that (neuro)hormonal regulations may play an important role in controlling in vivo heart function.
Department of Physiology and Cell Biology, Ohio State University College of Medicine and Public Health, Columbus 43210, Ohio, USA.
Sabine
S
Huke
Vikram
V
Prasad
Michelle L
ML
Nieman
Kalpana J
KJ
Nattamai
Ingrid L
IL
Grupp
John N
JN
Lorenz
Muthu
M
Periasamy
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D004280:Dobutamine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D009206:Myocardium / Q000378:metabolism*; D010766:Phosphorylation; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban
D000318:Adrenergic beta-Agonists; D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D004280:Dobutamine; D007545:Isoproterenol; D011943:Receptors, Adrenergic, beta; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban