Pharmacological evidence for involvement of phospholipase D, protein kinase C, and sodium-calcium exchanger in alpha-adrenoceptor-mediated negative inotropy in adult mouse ventricle.
The intracellular signalling pathway for alpha-adrenoceptor-mediated negative inotropy was studied pharmacologically in isolated adult mouse ventricle. The negative inotropy was inhibited by GF-109203X, a nonselective protein kinase C inhibitor. Phorbol 12-myristate 13-acetate also produced sustained negative inotropy, which was inhibited by KB-R7943, a Na(+)/Ca(2+) exchanger inhibitor. The alpha-adrenoceptor-mediated negative inotropy was augmented by RHC-80267, a diacylglycerol lipase inhibitor, but was inhibited either by C(2)-ceramide, a phospholipase D inhibitor, and high concentration of propranolol (50 micro M), which inhibits phosphatidate phosphohydrolase. The inotropy was not affected by U-73122, a phospholipase C inhibitor. Lavendustin-A, a tyrosine kinase inhibitor, also inhibited the negative inotropy. These findings suggest that alpha-adrenoceptor-mediated negative inotropy in adult mouse ventricle is mediated by activation of tyrosine kinase, the phospholipase D-phosphatidate phosphohydrolase pathway, and protein kinase C.
Nishimaru
Kazuhide
K
Department of Pharmacology, Toho University School of Pharmaceutical Sciences, Chiba, Japan.
Tanaka
Yoshio
Y
Tanaka
Hikaru
H
Shigenobu
Koki
K
D000818:Animals; D003864:Depression, Chemical; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D010739:Phospholipase D / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism*; D019831:Sodium-Calcium Exchanger / Q000819:agonists / Q000378:metabolism*; D016278:Ventricular Function, Right / Q000187:drug effects / Q000502:physiology
D004791:Enzyme Inhibitors; D011942:Receptors, Adrenergic, alpha; D019831:Sodium-Calcium Exchanger; D011493:Protein Kinase C; D010739:Phospholipase D