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(Stroke. 2002;33:2285.)
© 2002 American Heart Association, Inc.

Original Contributions

Altered Endothelial Ca²⁺ Regulation After Ischemia/Reperfusion Produces Potentiated Endothelium-Derived Hyperpolarizing Factor–Mediated Dilations

Sean P. Marrelli, PhD

From the Department of Anesthesiology, Baylor College of Medicine, Houston, Tex.

Correspondence to Sean P. Marrelli, PhD, Department of Anesthesiology, Baylor College of Medicine, One Baylor Plaza, Suite 434-D, Houston, TX 77030. E-mail marrelli{at}bcm.tmc.edu

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.

Key Words: brain • calcium • cerebral arteries • cerebral ischemia, transient • endothelium • endothelium-derived hyperpolarizing factor • middle cerebral artery • middle cerebral artery occlusion • rats

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