Kynurenic acid attenuates NMDA-induced pial arteriolar dilation in newborn pigs.
The excitatory amino acid glutamate is a potent vasodilator in the central nervous system. Glutamate-induced vasodilation is mediated primarily by N-methyl-D-aspartate (NMDA) and AMPA/kainate (KAIN) receptors. We have now tested whether two metabolites of the kynurenine pathway of tryptophan degradation acting at the NMDA receptor, the antagonist kynurenic acid (KYNA) and the agonist quinolinic acid (QUIN), are capable of modulating the dilation of pial arterioles. The closed cranial window technique was used, and changes in vessel diameter ( approximately 100 microm) were analyzed in anesthetized newborn piglets. Topical application of NMDA (10(-4) M) or KAIN (5 x 10(-5) M) resulted in marked vasodilation (44 +/- 5% and 39 +/- 4%, respectively). Neither KYNA nor QUIN (both at 10(-5) to 10(-3) M) affected the vessel diameter when applied alone. Co-application of KYNA dose-dependently reduced the vasodilation caused by 10(-4) M NMDA and also attenuated the KAIN-induced response. Ten minutes of global cerebral ischemia did not modify the interaction between KAIN and KYNA. In contrast, KYNA did not affect vasodilation to hypercapnia, elicited by the inhalation of 10% CO2. Moreover, endogenous levels of KYNA and QUIN in the cerebral cortex, hippocampus and thalamus were found to be essentially unchanged during the early reperfusion period (0.5-2 h) following an episode of cerebral ischemia. Our data are relevant for the use of drugs that target the kynurenine pathway for therapeutic interventions in cerebrovascular diseases.
Bari
Ferenc
F
Department of Physiology, Faculty of Medicine, University of Szeged, Dóm tér 10, H-6720 Szeged, Hungary. BARI@phys.szote.u-szeged.hu
Nagy
Krisztina
K
Guidetti
Paolo
P
Schwarcz
Robert
R
Busija
David W
DW
Domoki
Ferenc
F
D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002545:Brain Ischemia / Q000188:drug therapy; D002536:Cerebral Arteries / Q000187:drug effects* / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005260:Female; D006935:Hypercapnia / Q000188:drug therapy / Q000503:physiopathology; D007736:Kynurenic Acid / Q000494:pharmacology*; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology*; D017378:Quinolinic Acid / Q000494:pharmacology; D013552:Swine; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects*
D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D016202:N-Methylaspartate; D017378:Quinolinic Acid; D007736:Kynurenic Acid