Phorbol 12,13-diacetate-induced contraction of the canine basilar artery: role of protein kinase C.
The pharmacological and biochemical mechanisms of contractile responses to the protein kinase C (PKC) activator phorbol-12,13-diacetate (PDA) were investigated in canine basilar arteries. In the normal medium, PDA elicited a strong, dose-related, and slow-developing sustained contraction. Among the constrictors examined, including serotonin, prostaglandin F2 alpha, and endothelin, only PDA yielded contractions in a Ca2(+)-free medium. In both media, the PDA-induced contractions were virtually inhibited by either staurosporine, H-7, or quinacrine, while neither neurotransmitter blockades nor R24571 (calmidazolium) exerted significant effects. In addition, it was shown that 8-bromocyclic GMP, but not 8-bromocyclic AMP, markedly curtailed the PDA-induced contractions. Biochemical analysis, furthermore, showed that PDA induced increased phosphorylations of 27- and 96-kDa and proteins other than the myosin light chain (MLC) 20-kDa protein. Thus, the present results open up a novel mechanism of sustained cerebral artery contractions, where PKC activation rather than Ca2+/calmodulin/MLC system plays a key role that is regulated both by phospholipase A2 and by cyclic GMP.
Sugawa
M
M
Department of Pharmacology, Research Laboratories of Chugai Pharmaceutical Company Ltd., Komakado, Japan.
Koide
T
T
Naitoh
S
S
Takato
M
M
Matsui
T
T
Asano
T
T
D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D001488:Basilar Artery / Q000187:drug effects / Q000502:physiology*; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D015237:Dinoprost / Q000494:pharmacology; D004285:Dogs; D016232:Endothelins / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D010703:Phorbol Esters / Q000494:pharmacology*; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D011796:Quinacrine / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology; D019311:Staurosporine
D000470:Alkaloids; D016232:Endothelins; D007093:Imidazoles; D007546:Isoquinolines; D010703:Phorbol Esters; D010879:Piperazines; C008874:phorbol-12,13-diacetate; C016276:8-bromocyclic GMP; D012701:Serotonin; C031938:calmidazolium; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D015237:Dinoprost; D011493:Protein Kinase C; D011796:Quinacrine; D006152:Cyclic GMP; D019311:Staurosporine