This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pierre, L. N. Articles by Katusic, Z. S. Search for Related Content PubMed PubMed Citation Articles by Pierre, L. N. Articles by Katusic, Z. S. Related Collections Acute Stroke Syndromes Other imaging Other Stroke Treatment - Medical

(Stroke. 1999;30:638-643.)
© 1999 American Heart Association, Inc.

Original Contributions

Blockade and Reversal of Endothelin-Induced Constriction in Pial Arteries From Human Brain

Lisa N. Pierre, PhD Anthony P. Davenport, PhD

From the Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

Correspondence to Dr A.P. Davenport, Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2QQ, UK. E-mail apd10{at}medschl.cam.ac.uk

Background and Purpose—Substantial evidence now implicates endothelin (ET) in the pathophysiology of cerebrovascular disorders such as the delayed vasospasm associated with subarachnoid hemorrhage and ischemic stroke. We investigated the ET receptor subtypes mediating vasoconstriction in human pial arteries.

Methods—ET receptors on human pial and intracerebral arteries were visualized with the use of autoradiography, and the subtypes mediating vasoconstriction were identified by means of wire myography.

Results—ET-1 was more potent than ET-3 as a vasoconstrictor, indicating an ET_A-mediated effect. Similarly, the selective ET_B agonist sarafotoxin S6c had no effect on contractile action at concentrations up to 30 nmol/L. The nonpeptide ET_A receptor antagonist PD156707 (3 to 30 nmol/L) caused a parallel rightward shift of the ET-1–induced response, yielding a pA₂ of 9.2. Consistent with these results, PD156707 (30 nmol/L) fully reversed an established constriction in pial arteries induced by 1 nmol/L ET-1, while the selective ET_B receptor antagonist BQ788 (1 µmol/L) had little effect. The calcium channel blocker nimodipine (0.3 to 3 µmol/L) significantly attenuated the maximum response to ET-1 in a concentration-dependent manner without changing potency. In agreement with the functional data, specific binding of [¹²⁵I]PD151242 to ET_A receptors was localized to the smooth muscle layer of pial and intracerebral blood vessels. In contrast, little or no [¹²⁵I]BQ3020 binding to ET_B receptors was detected.

Conclusions—These data indicate an important role for ET_A receptors in ET-1–induced constriction of human pial arteries and suggest that ET_A receptor antagonists may provide additional dilatory benefit in cerebrovascular disorders associated with raised ET levels.

Editorial Comment

Zvonimir S. Katusic, MD, PhD, Guest Editor

Anesthesia Research, Mayo Clinic, Rochester, Minnesota

This article has been cited by other articles:

				G. Michelson, S. Warntges, S. Leidig, J. Lotsch, and G. Geisslinger Nimodipine plasma concentration and retinal blood flow in healthy subjects. Invest. Ophthalmol. Vis. Sci., August 1, 2006; 47(8): 3479 - 3486. [Abstract] [Full Text] [PDF]

				J. Andresen, N. I. Shafi, and R. M. Bryan Jr. Endothelial influences on cerebrovascular tone J Appl Physiol, January 1, 2006; 100(1): 318 - 327. [Abstract] [Full Text] [PDF]

				J. Chuquet, K. Benchenane, J. Toutain, E. T. MacKenzie, S. Roussel, and O. Touzani Selective Blockade of Endothelin-B Receptors Exacerbates Ischemic Brain Damage in the Rat Stroke, December 1, 2002; 33(12): 3019 - 3025. [Abstract] [Full Text] [PDF]

				R Flemming, A Cheong, A M Dedman, and D J Beech Discrete store-operated calcium influx into an intracellular compartment in rabbit arteriolar smooth muscle J. Physiol., September 1, 2002; 543(2): 455 - 464. [Abstract] [Full Text] [PDF]

				C. C. Docherty, J. Kalmar-Nagy, M. Engelen, S. V. Koenen, M. Nijland, R. E. Kuc, A. P. Davenport, and P. W. Nathanielsz Effect of in vivo fetal infusion of dexamethasone at 0.75 GA on fetal ovine resistance artery responses to ET-1 Am J Physiol Regulatory Integrative Comp Physiol, July 1, 2001; 281(1): R261 - R268. [Abstract] [Full Text] [PDF]