Endothelium-Derived Hyperpolarizing Factor in the Brain

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 hyperpolarizing 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, noncyclooxygenase 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) hyperpolarizing the vascular smooth muscle (VSM), and (4) involving calcium-activated potassium (KCa) channels.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 cyclooxygenase.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, …