title: AMP-activated kinase relaxes agonist induced contractions in the mouse aorta via effects on PKC signaling and inhibits NO-induced relaxation.
abstract: Adenosine monophosphate activated kinase (AMPK), a regulator of cellular metabolism, has been shown to relax arterial smooth muscle via endothelium-dependent and independent mechanisms. We have examined the role of AMPK in different smooth muscles using the activating compound, 5-amino-4-imidazolecarboxamide riboside-1-β-d-ribofuranoside (AICAR). Isolated preparations of mouse aorta, saphenous artery, ileum and urinary bladder were compared. AICAR produced a reversible dose-dependent relaxation in aortic rings pre-incubated with AICAR and activated with phenylephrine. Less prominent relaxation was noted in the other tissues. This difference in sensitivity to AICAR was not due to differences in the expression levels of AMPK α1 mRNA. In the aorta, AICAR had a greater effect on contractions induced by phenylephrine, compared to high-K(+) induced contractions. Contractions of the aorta in response to the protein kinase C activator PDBu were prominently inhibited by AICAR. The AICAR relaxation observed in the aorta was not prevented by the NOS inhibitor L-NAME, Indomethacin or endothelium removal. Nitric oxide (NO) mediated relaxations in aortic preparations induced by acetylcholine or sodium nitroprusside (SNP) were attenuated by AICAR. In conclusion, AMPK induced relaxation of smooth muscle is tissue-dependent and most prominent in large elastic arteries. The smooth muscle relaxation is NO-independent and occurs downstream of PKC activation and is associated with attenuated relaxant responses to NO.
authors.affiliation: Department of Physiology & Pharmacology, Karolinska Institutet, Von Eulers väg 8, Stockholm, Sweden.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Davis
authors.forename: Awahan
authors.initials: A
authors.lastname: Rahman
authors.forename: Anders
authors.initials: A
authors.lastname: Arner
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000322:Adrenergic Agonists / Q000494:pharmacology; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018721:Muscarinic Agonists / Q000494:pharmacology; D009126:Muscle Relaxation / Q000187:drug effects*; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000494:pharmacology*; D010656:Phenylephrine / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology
chemical_list: D000322:Adrenergic Agonists; D018721:Muscarinic Agonists; D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D012265:Ribonucleotides; D010656:Phenylephrine; D009569:Nitric Oxide; D000620:Aminoimidazole Carboxamide; D011493:Protein Kinase C; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide