PMID- 9440704
OWN - NLM
STAT- MEDLINE
DCOM- 19980205
LR  - 20190706
IS  - 0009-7330 (Print)
IS  - 0009-7330 (Linking)
VI  - 82
IP  - 1
DP  - 1998 Jan 9-23
TI  - Adenosine inhibits lipopolysaccharide-induced cardiac expression of tumor 
      necrosis factor-alpha.
PG  - 47-56
AB  - Tumor necrosis factor-alpha (TNF-alpha) is elevated in the failing heart. Very 
      little is known about regulation of TNF-alpha in cardiomyocytes. TNF-alpha 
      expression by macrophages is diminished by adenosine. Therefore, we hypothesized 
      that a similar mechanism might occur in the heart. Neonatal rat myocytes were 
      stimulated with lipopolysaccharide (LPS), and TNF-alpha was measured by ELISA. In 
      the absence of LPS, myocytes did not release TNF-alpha in the medium. After 
      exposure to LPS, TNF-alpha increased to 70.1+/-3.5 pg/mL at 6 hours. 
      Immunofluorescent staining confirmed that TNF-alpha was expressed in myocytes. 
      Adenosine decreased TNF-alpha in a dose-dependent manner (1 to 100 micromol/L, 
      37% to 65% decrease, P<.01). Adenosine also decreased TNF-alpha in cell 
      homogenates by 78% (P<.0001). The effect of adenosine could be replicated by the 
      A2 agonist PD-125944 (DPMA), by cAMP agonists 8-bromo-cAMP, forskolin, and Ro 
      20-1724, but not by A1 and A3 agonists. Conversely, the effect of adenosine could 
      be suppressed by the adenylate cyclase inhibitor MDL-12,330. Adenosine also 
      inhibited TNF-alpha in adult rat ventricular myocytes (-60%, P<.005) and rat 
      papillary muscles (-55%, P<.05). In neonatal myocytes, adenosine normalized 
      LPS-induced calcium changes and improved LPS-induced negative inotropic (P<.01) 
      and negative lusitropic (P<.01) effects. Our results demonstrate that adenosine 
      can significantly diminish TNF-alpha levels in the heart. The effect appears to 
      be mediated by the A2 receptor and transduced through a G protein-adenylyl 
      cyclase pathway. These results may explain some cardioprotective effects of 
      adenosine and provide a novel pharmacological intervention in congestive heart 
      failure.
FAU - Wagner, D R
AU  - Wagner DR
AD  - Division of Cardiology, University of Pittsburgh Medical Center, PA 15213, USA.
FAU - Combes, A
AU  - Combes A
FAU - McTiernan, C
AU  - McTiernan C
FAU - Sanders, V J
AU  - Sanders VJ
FAU - Lemster, B
AU  - Lemster B
FAU - Feldman, A M
AU  - Feldman AM
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Circ Res
JT  - Circulation research
JID - 0047103
RN  - 0 (Cardiovascular Agents)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Platelet Aggregation Inhibitors)
RN  - 0 (Purinergic P1 Receptor Agonists)
RN  - 0 (Purinergic P1 Receptor Antagonists)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 64ALC7F90C (Dipyridamole)
RN  - K72T3FS567 (Adenosine)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - Adenosine/analogs & derivatives/antagonists & inhibitors/*pharmacology
MH  - Animals
MH  - Animals, Newborn
MH  - Calcium/metabolism
MH  - Cardiovascular Agents/administration & dosage/*pharmacology
MH  - Cells, Cultured
MH  - Cytosol/chemistry/drug effects/metabolism
MH  - Dipyridamole/pharmacology
MH  - Dose-Response Relationship, Drug
MH  - Enzyme Inhibitors/pharmacology
MH  - Female
MH  - Fibroblasts/cytology/drug effects/metabolism
MH  - Heart/*drug effects
MH  - Heart Ventricles/cytology/drug effects/metabolism
MH  - Immunohistochemistry
MH  - Lipopolysaccharides/antagonists & inhibitors/pharmacology
MH  - Muscle Contraction/drug effects
MH  - Myocardium/cytology/*metabolism
MH  - Papillary Muscles/cytology/drug effects/metabolism
MH  - Platelet Aggregation Inhibitors/pharmacology
MH  - Purinergic P1 Receptor Agonists
MH  - Purinergic P1 Receptor Antagonists
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Signal Transduction/drug effects
MH  - Tumor Necrosis Factor-alpha/*antagonists & inhibitors/*biosynthesis/drug effects
EDAT- 1998/01/24 00:00
MHDA- 1998/01/24 00:01
CRDT- 1998/01/24 00:00
PHST- 1998/01/24 00:00 [pubmed]
PHST- 1998/01/24 00:01 [medline]
PHST- 1998/01/24 00:00 [entrez]
AID - 10.1161/01.res.82.1.47 [doi]
PST - ppublish
SO  - Circ Res. 1998 Jan 9-23;82(1):47-56. doi: 10.1161/01.res.82.1.47.