Effect of denopamine on the phosphorylation of cardiac muscle proteins in the perfused guinea-pig heart. Comparison with isoproterenol.
Effects of the new selectively beta 1-adrenergic cardiotonic drug denopamine (TA-064) on the phosphorylation of cardiac muscle proteins in the perfused guinea-pig heart were investigated in comparison with isoproterenol. Denopamine at 3 X 10(-6) M and isoproterenol at 10(-7) M were equipotent in their effects on the contractile force and + (dF/dt). Under these conditions, the increases in heart rate and tissue c-AMP levels by denopamine were significantly less than those by isoproterenol. Isoproterenol exerted a greater effect on -(dF/dt) than on +(dF/dt), whereas denopamine influenced both to the same extent. Denopamine (3 X 10(-6) M) and isoproterenol (10(-7) M) both stimulated 32P incorporation into the proteins of molecular weights of 150,000, 30,000, 19,000, 15,000 and 11,000 daltons. Among these proteins, the 30,000 and 11,000 dalton proteins, probably troponin-I and phospholamban, were phosphorylated to significantly lesser extents by denopamine than by isoproterenol. The above differences in the effects on c-AMP levels and protein phosphorylation between denopamine and isoproterenol may be causally related to the differences in their pharmacological properties such as the weaker arrhythmogenicity and comparatively less marked relaxation effect of denopamine compared with isoproterenol in the presence of similar cardiotonic effects.
Sasaki
Y
Y
Biological Research Laboratory, Tanabe Seiyaku Co. Ltd., Saitama, Japan.
Yabana
H
H
Nagao
T
T
Takeyama
S
S
D000255:Adenosine Triphosphate / Q000032:analysis; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000242:Cyclic AMP / Q000032:analysis; D004983:Ethanolamines / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology*; D008970:Molecular Weight; D009124:Muscle Proteins / Q000378:metabolism*; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D010477:Perfusion; D010766:Phosphorylation
D002316:Cardiotonic Agents; D004983:Ethanolamines; D009124:Muscle Proteins; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D007545:Isoproterenol; C037293:denopamine