Post-beta-receptor impairment in the regulation of myofibrillar Ca2+ sensitivity in tachypacing-induced canine failing heart.
Although one of the salient abnormalities in signal transduction of failing myocardium is downregulation of the beta-adrenergic receptor, the extent of presentation of downstream pathways distal to beta-receptors is misunderstood. We addressed this question in tachypacing-induced canine failing heart by assessing changes in myofibrillar Ca2+ sensitivity and troponin I phosphorylation. At a basal state, no significant difference in myofibrillar Ca2+ sensitivity was found between normal and failing hearts. Isoproterenol 8-bromo-cylic adenosine monophosphate (cAMP), and 8-bromo-cAMP isobutylmethylxantine all significantly decreased the Ca2+ sensitivity in the normal, but not in the failing, heart. EMD57033 (10 microM ), a myofibrillar Ca2+ sensitizer increased the Ca2+ sensitivity to a similar extent in both groups. The troponin I phosphorylation levels were significantly decreased in the failing heart. These results suggest that abnormalities of the beta-adrenergic signaling system exist not only at the receptor level but also at downstream steps after cAMP production.
Satoh
Shinji
S
Department of Bioclimatology and Medicine, Medical Institute of Bioregulation, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan. satoshin@tsurumi.beppu.kyshu-u.ac.jp
Suematsu
Nobuhiro
N
Ueda
Yasuko
Y
Tsutsui
Hiroyuki
H
Egashira
Kensuke
K
Takeshita
Akira
A
Makino
Naoki
N
D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D048429:Cell Size; D000242:Cyclic AMP / Q000096:biosynthesis; D004285:Dogs; D004591:Electrophoresis, Polyacrylamide Gel; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D009200:Myocardial Contraction; D009206:Myocardium / Q000473:pathology; D009210:Myofibrils / Q000378:metabolism*; D010138:Pacemaker, Artificial; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010766:Phosphorylation; D011804:Quinolines / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction; D013829:Thiadiazines / Q000494:pharmacology; D019210:Troponin I / Q000378:metabolism; D016277:Ventricular Function, Left
D010726:Phosphodiesterase Inhibitors; D011804:Quinolines; D011943:Receptors, Adrenergic, beta; D013829:Thiadiazines; D019210:Troponin I; C070609:EMD 53998; D000242:Cyclic AMP; D002118:Calcium