The obligatory link: role of gap junctional communication in endothelium-dependent smooth muscle hyperpolarization.
Although an endothelium-derived hyperpolarizing factor (EDHF) has often been hypothesized to underpin vascular relaxations that are independent of nitric oxide (NO) and prostanoids, bioassay techniques have failed to confirm the existence of a freely transferable EDHF in a consistent fashion. Indeed, observations that inhibitors of direct cell-cell coupling such as connexin-mimetic peptides (e.g. Gap 26 and 27) and glycyrrhetinic acid derivatives attenuate "EDHF-type" smooth muscle hyperpolarizations and relaxations suggest that an electrotonic spread of endothelial hyperpolarization via myoendothelial and homocellular smooth muscle gap junctions plays an obligatory role in such responses. The endothelial hyperpolarization that initiates relaxation results from the opening of K(Ca) channels and is sustained by capacitative Ca(2+) entry triggered by the depletion of intracellular Ca(2+) stores in the endoplasmic reticulum. EDHF-type relaxations are also associated with a prostanoid-independent synthesis of cAMP that increases the conductance of gap junction channels and enhances the transmission of endothelial hyperpolarization through the vascular wall in a permissive fashion. This review will discuss the roles of these interacting signalling pathways in the mediation of the EDHF phenomenon.
Griffith
Tudor M
TM
Department of Diagnostic Radiology, Wales Heart Research Institute, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK. griffith@cardiff.ac.uk
Chaytor
Andrew T
AT
Edwards
David H
DH
D000595:Amino Acid Sequence; D000818:Animals; D001685:Biological Factors / Q000502:physiology*; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D017629:Gap Junctions / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology*
D001685:Biological Factors; C067410:endothelium-dependent hyperpolarization factor