PMID- 10435033
OWN - NLM
STAT- MEDLINE
DCOM- 19990819
LR  - 20190513
IS  - 0008-6363 (Print)
IS  - 0008-6363 (Linking)
VI  - 41
IP  - 3
DP  - 1999 Mar
TI  - Role of nitric oxide and platelet-activating factor in cardiac alterations 
      induced by tumor necrosis factor-alpha in the guinea-pig papillary muscle.
PG  - 611-9
AB  - OBJECTIVE: Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine 
      with negative inotropic properties, is implicated in several pathophysiological 
      events. To clarify the mechanism of action of TNF-alpha on myocardium, we 
      investigated the possible role of platelet-activating factor (PAF) and nitric 
      oxide (NO) as secondary mediators of the depressant effect of this cytokine. 
      METHODS: Isometric twitches and intracellular action potentials were recorded 
      from guinea pig papillary muscles. The effects of TNF-alpha (1-10 ng/ml) were 
      studied in controlled conditions and after treatment with 0.5% Triton X-100, to 
      destroy the endocardial endothelium NG-nitro-L-arginine methyl ester (L-NAME), 
      D-NAME (1 mM) and the two different PAF-receptor antagonists WEB 2170 (3 microM) 
      and CV 3988 (5 microM) were used to study the role of NO and PAF in cardiac 
      depression induced by TNF-alpha. To study the role of NO in cardiac alterations 
      induced by PAF, papillary muscles were pretreated with L-NAME or D-NAME and then 
      challenged with PAF (0.1-1 microM). Nitrite production by papillary muscles 
      challenged with TNF-alpha alone. TNF-alpha in the presence of WEB 2170 or CV 
      3988, or PAF was studied with the Greiss reagent method. PAF production by 
      papillary muscles stimulated by TNF-alpha was studied by a bioassay method. 
      RESULTS: TNF-alpha induced an initial, transient positive inotropic effect, then 
      reduced the contractility and the action potential duration in a 
      concentration-dependent manner. Treatment of papillary muscle with Triton X-100 
      did not modify the response to TNF-alpha, suggesting that the effect of TNF-alpha 
      is not mediated by endocardial endothelial cells. Pretreatment with indomethacin 
      reduced the negative effect of TNF-alpha, while propranolol abolished the initial 
      increase of contractility. The role of PAF and NO as mediators of TNF-alpha was 
      suggested by: (1) the protective effect of L-NAME, but not of D-NAME, on 
      electrical and mechanical alterations; (2) the stimulatory effect of TNF-alpha on 
      nitrite production; (3) the inhibitory effect of WEB 2170 and CV 3988, on both 
      the electromechanical alterations and the nitrite production; (4) the synthesis 
      of PAF induced by TNF-alpha. L-NAME blocked the negative effect of PAF and PAF 
      enhanced nitrite production by papillary muscle. CONCLUSIONS: The present results 
      suggest that in cardiac muscle: (1) the release of PAF triggered by TNF-alpha may 
      account for the stimulation of NO production; (2) both PAF and NO contribute to 
      the development of the electrical and mechanical alterations induced by 
      TNF-alpha; (3) NO production was down-stream to the synthesis of PAF.
FAU - Alloatti, G
AU  - Alloatti G
AD  - Dipartimento di Biologia Animale e dell'Uomo, Universita degli Studi di Torino, 
      Turin, Italy.
FAU - Penna, C
AU  - Penna C
FAU - De Martino, A
AU  - De Martino A
FAU - Montrucchio, G
AU  - Montrucchio G
FAU - Camussi, G
AU  - Camussi G
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Cardiovasc Res
JT  - Cardiovascular research
JID - 0077427
RN  - 0 (Adrenergic beta-Antagonists)
RN  - 0 (Azepines)
RN  - 0 (Cyclooxygenase Inhibitors)
RN  - 0 (Phospholipid Ethers)
RN  - 0 (Platelet Activating Factor)
RN  - 0 (Platelet Aggregation Inhibitors)
RN  - 0 (Triazoles)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 31C4KY9ESH (Nitric Oxide)
RN  - 85703-73-7 (CV 3988)
RN  - 9Y8NXQ24VQ (Propranolol)
RN  - CKS724B66O (bepafant)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase)
RN  - V55S2QJN2X (NG-Nitroarginine Methyl Ester)
RN  - XXE1CET956 (Indomethacin)
SB  - IM
MH  - Action Potentials/drug effects
MH  - Adrenergic beta-Antagonists/pharmacology
MH  - Analysis of Variance
MH  - Animals
MH  - Azepines/pharmacology
MH  - Cyclooxygenase Inhibitors/pharmacology
MH  - Depression, Chemical
MH  - Guinea Pigs
MH  - Heart/*drug effects
MH  - In Vitro Techniques
MH  - Indomethacin/pharmacology
MH  - Myocardial Contraction/*drug effects
MH  - NG-Nitroarginine Methyl Ester/pharmacology
MH  - Nitric Oxide/*physiology
MH  - Nitric Oxide Synthase/antagonists & inhibitors
MH  - Phospholipid Ethers/pharmacology
MH  - Platelet Activating Factor/antagonists & inhibitors/*physiology
MH  - Platelet Aggregation Inhibitors/pharmacology
MH  - Propranolol/pharmacology
MH  - Triazoles/pharmacology
MH  - Tumor Necrosis Factor-alpha/*pharmacology
EDAT- 1999/08/06 00:00
MHDA- 1999/08/06 00:01
CRDT- 1999/08/06 00:00
PHST- 1999/08/06 00:00 [pubmed]
PHST- 1999/08/06 00:01 [medline]
PHST- 1999/08/06 00:00 [entrez]
AID - S0008-6363(98)00250-8 [pii]
AID - 10.1016/s0008-6363(98)00250-8 [doi]
PST - ppublish
SO  - Cardiovasc Res. 1999 Mar;41(3):611-9. doi: 10.1016/s0008-6363(98)00250-8.