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(Stroke. 2003;34:544.)
© 2003 American Heart Association, Inc.

Original Contributions

Essential Role of Gap Junctions in NO- and Prostanoid-Independent Relaxations Evoked by Acetylcholine in Rabbit Intracerebral Arteries

From the Department of Diagnostic Radiology, Wales Heart Research Institute, University of Wales College of Medicine, Heath Park, Cardiff, UK. Dr Ujiie is now at the Department of Neurosurgery, Neurological Institute, Tokyo Women’s Medical University, Tokyo, Japan.

Correspondence to Tudor M. Griffith, MD, PhD, Department of Diagnostic Radiology, Wales Heart Research Institute, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK. E-mail Griffith{at}Cardiff.ac.uk

Background and Purpose— Direct intercellular communication via gap junctions may play a central role in endothelium-dependent relaxations that are mediated by a conducted hyperpolarization and do not involve the synthesis of NO and prostanoids. In the present study, inhibitory peptides homologous to the Gap27 domain of the second extracellular loop of connexin37/connexin43 and connexin40, designated as ^37,43Gap27 and ⁴⁰Gap27, respectively, were used to evaluate the role of this mechanism in intracerebral arteries.

Methods— Isolated rings of rabbit middle cerebral artery were constricted by histamine (10 µmol/L) in the presence of N^G-nitro-L-arginine methyl ester (300 µmol/L) and indomethacin (10 µmol/L). Concentration-relaxation curves for acetylcholine were constructed in the presence and absence of ^37,43Gap27 and ⁴⁰Gap27. Specific antibodies were used to delineate the distribution of connexin37, connexin40, connexin43, and connexin45 within the arterial wall.

Results— Individually, ^37,43Gap27 and ⁴⁰Gap27 minimally affected endothelium-dependent relaxations to acetylcholine at concentrations of 300 µmol/L, whereas their combination (at 300 µmol/L each) inhibited the maximal response by 70% and increased the EC₅₀ value for relaxation by 15-fold. In endothelium-denuded rings, this peptide combination did not attenuate responses to sodium nitroprusside, an exogenous source of NO. Gap junction plaques, whose incidence was highest in endothelium, were constructed from connexin40 and connexin43 in the media and connexin37, connexin40, and connexin43 in the endothelium.

Conclusions— The findings confirm that direct communication via gap junctions contributes to agonist-induced relaxations of intracerebral arteries. More than one connexin subtype appears to participate in such responses.

Key Words: acetylcholine • connexins • endothelium-derived hyperpolarizing factor • histamine

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