ABSTRACT

The endothelium controls vascular tone by releasing various vasoactive substances. Additionally, another pathway associated with the hyperpolarization of both endothelial and vascular smooth muscle cells contributes also to endothelium-dependent relaxations (EDHF-mediated responses). These responses involve an increase in the intracellular Ca²⁺ concentration of the endothelial cells followed by the opening of Ca²⁺-activated K⁺ channels of small and intermediate conductances (SK_Ca and IK_Ca). These channels show a distinct subcellular distribution, suggesting that their activation could be elicited by distinct stimuli. Following K_Ca activation, the endothelial hyperpolarization can be conducted to the underlying smooth muscle cells by electrical coupling through myo-endothelial gap junctions. In addition, the potassium efflux can lead to the accumulation of potassium ions in the intercellular space and the subsequent activation of smooth muscle Kir2.1 and/or Na⁺/K⁺-ATPase. The hyperpolarization of the smooth muscle cells produces vascular relaxation, predominantly by closing voltage-gated calcium channels, and vasodilatation. EDHF-mediated responses are altered in various pathologies or, conversely, act as a compensating mechanism when other endothelial pathways are impaired. A better characterization of EDHF-mediated responses should allow determining whether or not new drugable targets can be identified within this endothelial pathway for the treatment of cardiovascular diseases.

Contents

• 1. Endothelium-Dependent Hyperpolarizations: The Classical “EDHF” Pathway
  • 1.1 THE CLASSICAL “EDHF” PATHWAY: HISTORICAL NOTES
  • 1.2 EARLY CHARACTERIZATION OF EDHF-MEDIATED RESPONSES
  • 1.3 IDENTIFICATION AND LOCALIZATION OF THE POTASSIUM CHANNELS INVOLVED IN EDHF-MEDIATED RESPONSES
  • 1.4 FUNDAMENTAL ROLE OF ENDOTHELIAL CELL HYPERPOLARIZATION
  • 1.5 BEYOND ENDOTHELIAL CELL HYPERPOLARIZATION
  • 1.6 WHY TWO POPULATIONS OF ENDOTHELIAL POTASSIUM CHANNELS: SK_Ca AND IK_Ca?
  • 1.7 LESSONS FROM GENETICALLY MODIFIED ANIMALS
  • 1.8 PHYSIOLOGICAL ROLE OF EDHF-MEDIATED RESPONSES
  • 1.9 CARDIOVASCULAR DISEASES AND ALTERATIONS IN EDHF-MEDIATED RESPONSES
  • 1.10 POTENTIAL THERAPEUTIC INTERVENTIONS
• Conclusion
• References
• Author Biography