Altered endothelial Ca2+ regulation after ischemia/reperfusion produces potentiated endothelium-derived hyperpolarizing factor-mediated dilations.

Abstract

BACKGROUND AND PURPOSE:

Endothelium-derived hyperpolarizing factor (EDHF)-mediated dilations are potentiated after several pathologies, including ischemia/reperfusion (I/R). However, no study to date has addressed the mechanism by which this potentiation occurs. This study tested the hypothesis that potentiated EDHF-mediated dilations are due to altered endothelial Ca2+ handling after I/R.

METHODS:

Rat middle cerebral arteries (MCAs) were isolated after 2 hours of MCA occlusion and 24 hours of reperfusion (or sham surgery). This model has been previously demonstrated to produce potentiated EDHF-mediated dilations. MCAs were studied in a pressurized/perfused vessel chamber equipped for the simultaneous measurement of endothelial Ca2+ (with fura 2) and artery diameter. Measures were made after luminal administration of UTP (P2Y2 purinoceptor agonist), 2 MeS-ATP (P2Y1 purinoceptor agonist), and Br-A23187 (receptor-independent Ca2+ ionophore) for sham and I/R MCAs.

RESULTS:

I/R resulted in significantly potentiated UTP-mediated dilations (through a P2Y2 purinoceptor) and endothelial Ca2+ responses in the presence of N(G)-nitro-L-arginine methyl ester (L-NAME) and indomethacin. Endothelial Ca2+ and diameter responses were also significantly potentiated with 2 MeS-ATP (through a P2Y1 purinoceptor) when L-NAME and indomethacin were absent. Br-A23187, a receptor-independent Ca2+ ionophore, produced significantly potentiated endothelial Ca2+ responses after I/R in the presence of L-NAME/indomethacin. Evaluation of artery diameter as a function of endothelial Ca2+ demonstrated no differences between sham and I/R groups.

CONCLUSIONS:

These findings demonstrate that I/R results in augmented endothelial Ca2+ responses that appear to be downstream of the receptor level. Moreover, these data suggest that this augmented Ca2+ response contributes to the potentiated EDHF-mediated dilations after I/R.

• Authors: Sean P Marrelli
• Journal: Stroke (Stroke) Vol. 33 Issue 9 Pg. 2285-91 (Sep 2002) ISSN: 1524-4628 [Electronic] United States
• PMID: 12215600 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Biological Factors
• Enzyme Inhibitors
• Fluorescent Dyes
• Ionophores
• P2ry1 protein, rat
• P2ry2 protein, rat
• Receptors, Purinergic P2
• Receptors, Purinergic P2Y1
• Receptors, Purinergic P2Y2
• Thionucleotides
• endothelium-dependent hyperpolarization factor
• Adenosine Triphosphate
• Calcium
• Uridine Triphosphate
• 2-methylthio-ATP

Topics

• Adenosine Triphosphate (analogs & derivatives, pharmacology)
• Animals
• Biological Factors (metabolism, pharmacology)
• Brain Ischemia (etiology, physiopathology)
• Calcium (metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Endothelium, Vascular (drug effects, physiopathology)
• Enzyme Inhibitors (pharmacology)
• Fluorescent Dyes
• In Vitro Techniques
• Infarction, Middle Cerebral Artery (complications)
• Ionophores (pharmacology)
• Male
• Middle Cerebral Artery (drug effects, physiopathology)
• Rats
• Rats, Long-Evans
• Receptors, Purinergic P2 (metabolism)
• Receptors, Purinergic P2Y1
• Receptors, Purinergic P2Y2
• Reperfusion
• Thionucleotides (pharmacology)
• Uridine Triphosphate (pharmacology)
• Vascular Patency (drug effects)
• Vasodilation (drug effects, physiology)