Relationship between protein kinase C alterations and nitric oxide overproduction in cirrhotic rat aortas.
BACKGROUND
Although nitric oxide (NO) overproduction and protein kinase C (PKC) alterations may play a role in systemic haemodynamic changes in cirrhotic rat aortas, the relationship between NO synthase (NOS) hyperactivation and PKC hypoactivation is unknown. Therefore, the relationships between NOS and PKC activities were studied in cirrhotic rat aortas.


METHODS
The effects of NOS inhibition by Nw-nitro-L-arginine (LNNA) on the contractile response to phorbol myristate acetate (PMA), a PKC activator, were studied. The effects of NOS inhibition and those of S-nitroso-N acetyl-DL-penicillamine (SNAP), an NO donor, on PKC activity were also evaluated. The effects of PKC activation and inhibition on total NOS and inducible NOS (iNOS) activities were measured. Nitric oxide synthase inhibition caused an increase in PMA-induced contraction and an increase in PKC activity in cirrhotic rat aortas. S-nitroso-N acetyl-DL-penicillamine induced downregulation of PKC activity. Total basal aortic NOS activity was significantly higher in cirrhotic rats than in control rats and activation of PKC by PMA induced a decrease in total aortic NOS activity. Protein kinase C downregulation caused an increase in both total aortic NOS and iNOS activities only in control rats, whereas only iNOS activity increased in cirrhotic rats.


CONCLUSIONS
In cirrhotic rat aortas, NO overproduction plays a role in the decreased PKC activation that leads to reduced aortic contraction. Overactivation of aortic NOS in cirrhotic rats may be because of, in part, the reduced PKC activity.
Tazi
Khalid A
KA
Laboratoire d'Hémodynamique Splanchnique et de Biologie Vasculaire, INSERM U-481, Hôpital Beaujon, Clichy, France. ktazi@bichat.inserm.fr
Barrière
Eric
E
Moreau
Richard
R
Poirel
Odile
O
Lebrec
Didier
D
D000818:Animals; D001013:Aorta, Thoracic / Q000378:metabolism*; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D008105:Liver Cirrhosis, Biliary / Q000209:etiology / Q000378:metabolism; D008106:Liver Cirrhosis, Experimental / Q000209:etiology / Q000378:metabolism; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D010396:Penicillamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D004791:Enzyme Inhibitors; D020030:Nitric Oxide Donors; C110881:S-nitro-N-acetylpenicillamine; D019323:omega-N-Methylarginine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D011493:Protein Kinase C; D010396:Penicillamine; D013755:Tetradecanoylphorbol Acetate