Methotrexate and MX-68, a new derivative of methotrexate, limit infarct size via adenosine-dependent mechanisms in canine hearts.

Abstract

Methotrexate, an anti-rheumatic agent, has recently been reported to show an anti-inflammatory action via ecto-5'-nucleotidase- and adenosine-dependent mechanisms. Because ecto-5'-nucleotidase contributes to the production of adenosine and adenosine has a potent cardioprotective effect against ischemia/reperfusion injury, we investigated whether methotrexate or MX-68 [N-1-((2,4-diamino-6-pteridinyl) methyl)-3,4-dihydro-2H-1,4-benzothiazine-7- carbonyl]-N-2- aminoadipic acid] could reduce infarct size via adenosine-dependent mechanisms. In beagle dogs, the left anterior descending coronary artery was perfused through a bypass tube, which was occluded for 90 minutes followed by 6 hours of reperfusion. The size of infarcts was assessed by TTC staining. MX-68 reduced infarct size compared with that in untreated dogs (13.7 +/- 1.9 versus 38.6 +/- 5.3%, P < 0.01). This effect was completely blunted by either the adenosine receptor antagonist 8-sulfophenyltheophylline (8-SPT) (45.0 +/- 4.6% and 46.8 +/- 5.8% in the 8-SPT and MX-68 + 8-SPT groups, respectively) or by the ecto-5'-nucleotidase inhibitoralpha,beta-methylenadenosine 5'-diphosphate (AMP-CP) (44.0 +/- 4.5% and 46.7 +/- 5.8% in the AMP-CP and MX-68 + AMP-CP groups, respectively). Methotrexate also reduced infarct size to a level comparable with that in the MX-68 group, and its effect was also blunted by 8-SPT. There were no significant differences of collateral blood flow or risk area between the groups. We conclude that methotrexate and its derivative (MX-68) both limit infarct size via adenosine-dependent mechanisms.

• Authors: Hiroshi Asanuma, Shoji Sanada, Akiko Ogai, Tetsuo Minamino, Seiji Takashima, Masanori Asakura, Hisakazu Ogita, Yoshiro Shinozaki, Hidezo Mori, Koichi Node, Hitonobu Tomoike, Masatsugu Hori, Masafumi Kitakaze
• Journal: Journal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 43 Issue 4 Pg. 574-9 (Apr 2004) ISSN: 0160-2446 [Print] United States
• PMID: 15085069 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cardiotonic Agents
• N-(1-((2,4-diamino-6-pteridinyl)methyl)-3,4-dihydro -2H-1,4-benzothiazine-7-carbonyl)-L-2-aminoadipic acid
• Purinergic P1 Receptor Antagonists
• Receptors, Purinergic P1
• 2-Aminoadipic Acid
• 8-(4-sulfophenyl)theophylline
• Theophylline
• Adenosine
• Methotrexate

Topics

• 2-Aminoadipic Acid (analogs & derivatives, therapeutic use)
• Adenosine (antagonists & inhibitors, physiology)
• Animals
• Cardiotonic Agents (therapeutic use)
• Dogs
• Methotrexate (analogs & derivatives, therapeutic use)
• Myocardial Infarction (pathology, physiopathology, prevention & control)
• Purinergic P1 Receptor Antagonists
• Receptors, Purinergic P1 (physiology)
• Theophylline (analogs & derivatives, pharmacology)