title: Inhibition of phosphoinositide 3-kinase potentiates relaxation of porcine coronary arteries induced by nitroglycerin by decreasing phosphodiesterase type 5 activity.
abstract: BACKGROUND
  Vessel tension can be modulated by phosphoinositide 3-kinase (PI3K) acting on l-type calcium channel, rho kinase and phosphodiesterase (PDE) type 3 in smooth muscle cells. Inhibition of PI3K could increase the relaxation of porcine coronary arteries to nitroglycerin independent of this pathway, and the aim of the present study was therefore to determine the underlying mechanisms.
  
  
  RESULTS
  Isolated porcine coronary arteries were dissected from the heart and cut into rings in ice-cold modified Krebs-Ringer bicarbonate buffer. The response of these vessels was studied by using the organ chamber technique; the content of cyclic guanosine monophosphate (cGMP) was determined by using enzyme-linked immunosorbent assay kit; and PI3K and Akt activity were determined by measuring the phosphorylation level of their downstream signaling molecule on Western blot. Inhibition of PI3K with 2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride (LY294002) potentiated the relaxation of porcine coronary arteries to nitroglycerin and nitric oxide (NO), but not to 8-bromo-guanosine 3'5'-cyclic monophosphate, isoproterenol or (R)-(+)-trans-4-(1-Aminoethyl)-N-(4-Pyridyl)cyclohexanecarboxamide dihydrochloride monohydrate (Y27632). Increased relaxation induced by LY294002 was eliminated by Akt1/2 kinase inhibitor (Akt-I: 1,3-dihydro-1-(1-((4-(6-phenyl-1H-imidazo(4,5-g)quinoxalin-7-yl)phenyl)methyl)-4-piperidinyl)-2H-benzimidazol-2-one trifluoroacetate salt hydrate) or zaprinast, but was not affected by 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one, nifedipine or milrinone. Inhibition of Akt caused similar effects as LY294002. Incubation with LY294002 or Akt-I decreased the activity of PI3K and Akt but augmented the elevation of cGMP caused by NO. Enhanced cGMP elevation induced by LY294002 or Akt-I was also eliminated by zaprinast.
  
  
  CONCLUSIONS
  PI3K-Akt signaling may affect vascular tone through a stimulatory effect on PDE type 5.
authors: Department of Physiology and Pathophysiology, Peking University Health Science Center, Beijing, China. doudou@bjmu.edu.cn
authors: Dou
authors: D
authors: Dou
authors: Yixuan
authors: Y
authors: Guo
authors: Lei
authors: L
authors: Ying
authors: Juan
authors: J
authors: Liu
authors: Xiaojian
authors: X
authors: Xu
authors: Xiaoxing
authors: X
authors: Yu
authors: Yuansheng
authors: Y
authors: Gao
mesh_terms: D000818:Animals; D002867:Chromones / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D006152:Cyclic GMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020105:Milrinone / Q000494:pharmacology; D023421:Models, Animal; D009025:Morpholines / Q000494:pharmacology*; D009543:Nifedipine / Q000494:pharmacology; D005996:Nitroglycerin / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D011688:Purinones / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology; D013552:Swine; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D002867:Chromones; D006152:Cyclic GMP; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004791:Enzyme Inhibitors; D020105:Milrinone; D009025:Morpholines; D009543:Nifedipine; D005996:Nitroglycerin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011688:Purinones; D014665:Vasodilator Agents; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C011145:zaprinast