PMID- 8904645
OWN - NLM
STAT- MEDLINE
DCOM- 19970218
LR  - 20190512
IS  - 0007-1188 (Print)
IS  - 0007-1188 (Linking)
VI  - 119
IP  - 4
DP  - 1996 Oct
TI  - Effect of cyclic GMP-dependent vasodilators on the expression of inducible nitric 
      oxide synthase in vascular smooth muscle cells: role of cyclic AMP.
PG  - 707-15
AB  - 1. In the present study we examined whether interleukin-1 beta (IL-1 beta) 
      increases the activity of adenylyl cyclase in vascular smooth muscle cells and 
      determined its role in the cytokine-induced expression of the inducible nitric 
      oxide synthase (iNOS) and activation of nuclear transcription factor-kappa B 
      (NF-kappa B). In addition the interaction between cyclic AMP- and cyclic 
      GMP-elevating agonists on the IL-1 beta-stimulated expression of iNOS was 
      examined. 2. Exposure of vascular smooth muscle cells to IL-1 beta stimulated the 
      formation of cyclic AMP but not of cyclic GMP. The intracellular level of cyclic 
      AMP reached a maximum within 1 h and then gradually declined over the next 5 h. 
      This IL-1 beta (60 u ml-1)-stimulated formation of cyclic AMP was modest (about 3 
      fold at 60 u ml-1 for 1 h) compared to that evoked by isoprenaline (about 9 fold 
      at 3 x 10(-6) M for 2 min). 3. The IL-1 beta (60 u ml-1 for 24 h)-stimulated 
      accumulation of nitrite, which was taken as an index of NO production, was 
      concentration-dependently increased by preferential inhibitors of cyclic 
      AMP-dependent phosphodiesterases (rolipram and trequinsin). This effect was 
      reproduced by a specific activator of the cyclic AMP-dependent protein kinase(s) 
      A, Sp-8-CPT-cAMPS (10(-4) M) but was prevented by a specific inhibitor of cyclic 
      AMP-dependent protein kinase(s) A, Rp-8-CPT-cAMPS (10(-4) M). These compounds 
      alone [rolipram (10(-6) M), trequinsin (3 x 10(-6) M) and Sp-8-CPT-cAMPS (10(-4) 
      M)] slightly but significantly increased the release of nitric oxide while 
      Rp-8-CPT-cAMPS elicited no such effect. 4. Inducible NOS protein was expressed in 
      IL-1 beta (30 u ml-1, 24 h)-stimulated smooth muscle cells as assessed by Western 
      blot analysis. The level of iNOS protein was markedly increased in smooth muscle 
      cells which had been exposed to IL-1 beta in combination with either rolipram (3 
      x 10(-6) M) or Sp-8-CPT-cAMPS (10(-4) M) but was reduced in those exposed to IL-1 
      beta and Rp-8-CPT-cAMPS (10(-4) M). A weak expression of iNOS protein was found 
      in smooth muscle cells which had been exposed to either Sp-8-CPT-cAMPS or 
      rolipram alone for 24 h while Rp-8-CPT-cAMPS elicited no such effect. 5. Exposure 
      of smooth muscle cells to IL-1 beta (30 u ml-1) for 30 min increased the level of 
      NF-kappa B-DNA complexes in nuclear extracts as detected by electrophoretic 
      mobility shift assay. Similar levels of NF-kappa B-DNA complexes were found in 
      cells which had been exposed to IL-1 beta in combination with either 
      Sp-8-CPT-cAMPS (10(-4) M), trequinsin (10(-6) M) or rolipram (10(-6) M). None of 
      the modulators alone affected the basal level of NF-kappa B binding activity. 6. 
      NO-donors [sodium nitroprusside (SNP) 10(-4) M; 
      dinitrosyl-iron-di-L-cysteine-complex (DNIC), 10(-4) M; 3-morpholino-sydnonimine 
      (SIN-1), 10(-4) M] and atrial natriuretic factor (10(-6) M) significantly 
      increased the IL-1 beta (30 or 60 u ml-1, 24 h)-stimulated expression of iNOS 
      protein and activity as assessed indirectly by the conversion of oxyhaemoglobin 
      to methaemoglobin. In the absence of IL-1 beta, SNP (10(-4) M, 24 h) but not the 
      other cyclic GMP-dependent vasodilators caused a modest expression of iNOS 
      protein. No such effect was found in smooth muscle cells exposed to SNP in 
      combination with Rp-8-CPT-cAMPS (10(-4) M) while an increased level of iNOS 
      protein was found in those exposed to SNP in combination with either 
      Sp-8-CPT-cAMPS (10(-4) M) or rolipram (3 x 10(-6) M). 7. Exposure of vascular 
      smooth muscle cells to either S-nitroso-L-cysteine (Cys-SNO, 10(-4) M), SNP 
      (10(-4) M) or SIN-1 (10(-4) M) for 35 min affected minimally the basal activation 
      of NF-kappa B but abolished that evoked by IL-1 beta (30 u ml-1 added during the 
      last 30 min). However, addition of Cys-SNO following the stimulation with IL-1 
      beta (during the last 5 min of the 30 min exposure period) reduced the level of 
      NF-kappa B-DNA complexes only slightly. 8. These data indicate that the cyclic 
      AMP-dependent pathway plays a decisi
FAU - Boese, M
AU  - Boese M
AD  - Zentrum der Physiologie, Klinikum der Johann Wolfgang Goethe Universitat, 
      Frankfurt/Main, Germany.
FAU - Busse, R
AU  - Busse R
FAU - Mulsch, A
AU  - Mulsch A
FAU - Schini-Kerth, V
AU  - Schini-Kerth V
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Br J Pharmacol
JT  - British journal of pharmacology
JID - 7502536
RN  - 0 (Interleukin-1)
RN  - 0 (NF-kappa B)
RN  - 0 (Nitrites)
RN  - 0 (Vasodilator Agents)
RN  - E0399OZS9N (Cyclic AMP)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase)
RN  - H2D2X058MU (Cyclic GMP)
SB  - IM
MH  - Animals
MH  - Cyclic AMP/*physiology
MH  - Cyclic GMP/*metabolism
MH  - Interleukin-1/pharmacology
MH  - Male
MH  - Muscle, Smooth, Vascular/cytology/*drug effects/enzymology
MH  - NF-kappa B/metabolism
MH  - Nitric Oxide Synthase/*biosynthesis/metabolism
MH  - Nitrites/metabolism
MH  - Rats
MH  - Rats, Inbred WKY
MH  - Vasodilator Agents/*pharmacology
PMC - PMC1915773
EDAT- 1996/10/01 00:00
MHDA- 1996/10/01 00:01
PMCR- 1997/10/01
CRDT- 1996/10/01 00:00
PHST- 1996/10/01 00:00 [pubmed]
PHST- 1996/10/01 00:01 [medline]
PHST- 1996/10/01 00:00 [entrez]
PHST- 1997/10/01 00:00 [pmc-release]
AID - 10.1111/j.1476-5381.1996.tb15730.x [doi]
PST - ppublish
SO  - Br J Pharmacol. 1996 Oct;119(4):707-15. doi: 10.1111/j.1476-5381.1996.tb15730.x.