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

• Published in: Journal of cardiovascular pharmacology Vol. 43; no. 4; p. 574
• Main Authors: Asanuma, Hiroshi, Sanada, Shoji, Ogai, Akiko, Minamino, Tetsuo, Takashima, Seiji, Asakura, Masanori, Ogita, Hisakazu, Shinozaki, Yoshiro, Mori, Hidezo, Node, Koichi, Tomoike, Hitonobu, Hori, Masatsugu, Kitakaze, Masafumi
• Format: Journal Article
• Language: English
• Published: United States 01.04.2004
• Subjects: 2-Aminoadipic Acid - analogs & derivatives; 2-Aminoadipic Acid - therapeutic use; Adenosine - antagonists & inhibitors; Adenosine - physiology; Animals; Cardiotonic Agents - therapeutic use; Dogs; Methotrexate - analogs & derivatives; Methotrexate - therapeutic use; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Myocardial Infarction - prevention & control; Purinergic P1 Receptor Antagonists; Receptors, Purinergic P1 - physiology; Theophylline - analogs & derivatives; Theophylline - pharmacology
• ISSN: 0160-2446; 1533-4023
• DOI: 10.1097/00005344-200404000-00013

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.