Endothelium-Derived Hyperpolarizing Factor in the Brain

Abstract

EDHF Defined It is well established that stimulation of receptors on the endothelium can elicit dilation of arteries and arterioles by initiating the synthesis and release of nitric oxide (NO) and/or metabolites of the cyclooxygenase pathway (most often prostacyclin). Recent evidence now suggests that there is at least one other endothelium-dependent dilator mechanism that does not involve NO or a cyclooxygenase metabolite. This mechanism has been termed "endothelium-derived hy-perpolarizing factor" (EDHF). (Note that EDHF is different from endothelium-derived relaxing factor [EDRF], which is often associated with NO. It should also be noted that recent studies suggest that EDHF may not be a "factor" but rather a process or mechanism. To be more accurate, the term "EDHF" should be referred to as a non-NO, noncyclooxy-genase endothelium-dependent hyperpolarization. However, in order to maintain consistency in the literature, we will refer to it as "EDHF.") We believe that EDHF is a major regulator of cerebral blood flow during physiological states and may become even more important following pathological insults such as ischemia or traumatic brain injury. The purpose of this editorial is to familiarize the reader with EDHF and to highlight the potential importance of EDHF in the cerebral circulation. While the defining criteria for EDHF or the mechanism of endothelium-dependent hyperpolarizations can vary, we will characterize the process as (1) requiring endothelium, (2) being distinct from NO and a cyclooxygenase metabolite, (3) hyper-polarizing the vascular smooth muscle (VSM), and (4) involving calcium-activated potassium (K Ca) channels. EDHF in the Periphery The existence of a third pathway was alluded to in the late 1980s, when some endothelium-dependent relaxations were shown to be resistant to inhibitors of NO and cyclooxygen-ase. 1,2 Although it has been suggested that EDHF-dependent dilations reflect incomplete inhibition of nitric oxide synthase (NOS), 3 there is now convincing evidence of the existence of a non-NO, noncyclooxygenase pathway. In cerebral vessels, extensive studies with a combination of inhibitors 4 and eNOS knockout mice 5 demonstrate that a pathway independent from NO is involved. These relaxations were further characterized by hyperpolarization of the VSM and sensitivity to some inhibitors of K Ca channels. The VSM hyperpolarization serves to close voltage-gated calcium channels, resulting in decreased concentrations of cytoplasmic Ca 2 and ultimately VSM relaxation (or dilation). Over the past 10 years, there has been much debate as to the mechanism associated with the EDHF-mediated dilations. The first idea involved epoxyeicosatrienoic acids (EETs), a product of arachidonic acid metabolism through the cyto-chrome P 450 epoxygenase pathway. 6-8 EETs, which are either stored in the endothelium or synthesized on demand, were proposed to diffuse to the VSM, open K Ca channels, and hyperpolarize the VSM. 9 The second idea is that the potassium ion (K) is EDHF. 10 On stimulation of endothelial receptors, the K conductance of endothelial cells would increase by opening K Ca channels. This would be followed by an efflux of K from endothelial cells as a result of the electrochemical gradient causing K to increase from 3 mmol/L to 12 mmol/L in the extracellular space between the endothelial and VSM cells. 10 The increase in potassium would hyperpolarize the VSM by activating inwardly rectifying potassium channels and the Na /K pump. As stated above, the hyperpolarization would then lead to dilation. A third line of studies implicate gap junctions that couple endothelial cells and VSM cells (myoendothelial gap junctions). These myoendothelial junctions would provide a conduit for either the EDHF or an electrical current to move between the endothelium and VSM. 11 If the process involves only the movement of current, then "EDHF" would not be a factor per se but rather a process. Consequently, "endotheli-um-dependent hyperpolarization" might best describe the phenomenon. Additionally, there is evidence that hydrogen peroxide, 12 anandamide, 13 or products of the lipoxygenase pathway 14,15 are involved with the EDHF dilations. Although these latter mediators have been less studied and, therefore, less scrutinized , they may be no less significant. In all likelihood, several EDHFs and/or EDHF-like processes exist and are dependent on the vascular bed, species, and physiological state. For more in-depth reviews of the EDHF mechanisms in peripheral vessels see the previous works by Feletou and Vanhoutte 16 and McGuire et al. 17 EDHF in the Brain Although it was previously known that cerebrovascular smooth muscle could be hyperpolarized by endothelial mechanisms , 18 it was not until 1995 that evidence began to emerge