Abstract
Endothelial function refers to a multitude of physiological processes that maintain healthy homeostasis of the vascular wall. Exposure of the endothelium to cardiac risk factors results in endothelial dysfunction and is associated with an alteration in the balance of vasoactive substances produced by endothelial cells. These include a reduction in nitric oxide (NO), an increase in generation of potential vasoconstrictor substances and a potential compensatory increase in other mediators of vasodilation. The latter has been surmised from data demonstrating persistent endothelium-dependent vasodilatation despite complete inhibition of NO and prostaglandins. This remaining non-NO, non-prostaglandin mediated endothelium-dependent vasodilator response has been attributed to endothelium-derived hyperpolarizing factor/s (EDHF). Endothelial hyperpolarization is likely due to several factors that appear to be site and species specific. Experimental studies suggest that the contribution of the EDHFs increase as the vessel size decreases, with a predominance of EDHF activity in the resistance vessels, and a compensatory up-regulation of hyperpolarization in states characterized by reduced NO availability. Since endothelial dysfunction is a precursor for atherosclerosis development and its magnitude is a reflection of future risk, then the mechanisms underlying endothelial dysfunction need to be fully understood, so that adequate therapeutic interventions can be designed.
Highlights
Endothelial function refers to a multitude of physiological processes of the vascular endothelium that maintain healthy homeostasis of the vascular wall and may be used as a “barometer” of the injury/repair inflicted by multiple environmental and genetic factors [1,2,3]
We have demonstrated that cytochrome P450derived epoxyeicosatrienoic acids contribute to resting vasodilator tone in the healthy microcirculation with the use of fluconazole to block their action
Absence of consensus regarding the precise identity of endothelium-derived hyperpolarizing factor/s (EDHF) and a consequent lack of specific inhibitors has long hampered clinical translation of this phenomenon (Table 1)
Summary
Endothelial function refers to a multitude of physiological processes of the vascular endothelium that maintain healthy homeostasis of the vascular wall and may be used as a “barometer” of the injury/repair inflicted by multiple environmental and genetic factors [1,2,3]. Convincing evidence has been presented to suggest that a CYP450-dependent EDHF plays a significant role in the regulation of coronary arteriolar tone by KCa+ channel activation and smooth muscle hyperpolarization [8, 29]. By conducting experiments using single and combined blockade, we demonstrated that KCa+ channel activation contributes to microvascular dilator tone even after inhibition of epoxyeicosatrienoic acids This indicates that sources other than epoxyeicosatrienoic acids contribute to hyperpolarization of the resting human forearm microcirculation. Matoba et al utilized catalase, an endogenous peroxidase to show inhibition of EDHF-mediated, endothelium-dependent relaxations and hyperpolarizations, resistant to indomethacin or N(omega)nitro-l-arginine [71] These findings have been confirmed in piglet pial arteries, canine subepicardial coronary arteries and arterioles, and during flow-induced vasodilation in human mesenteric arteries and coronary microvessels [66, 72,73,74]. NO may tonically inhibit EDHF responses as some studies could only demonstrate EDHF responses once NO production had been inhibited [44]
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