TY - JOUR
T1 - Hyperpolarizing factors
AU - Quilley, John
AU - Fulton, David
AU - McGiff, John C.
N1 - Funding Information:
This work was supported by NIH Grants HL492750 and RO1 HL 25394 and by AHA Grant 940-318.
PY - 1997/11/15
Y1 - 1997/11/15
N2 - There is now overwhelming evidence for factors, other than nitric oxide (NO), chat mediate endothelium-dependent vasodilation by hyperpolarizing the underlying smooth muscle via activation of Ca2+-activated K+ channels. Although the identity of endothelium derived hyperpolarizing factor (EDHF) remains to be established, cytochrome P450 (CYP) dependent metabolites of arachidonic acid (AA), namely, the eposides, fulfill several of the criteria required for consideration as putative mediators of endothelium-dependent hyperpolarization. They are produced by the endothelium, released in response to vasoactive hormones, and elicit vasorelaxation via stimulation of Ca2+-activated K+ channels. Our studies in the rat indicate that of the epoxides, 5,6- epoxyeicosatrienoic acid (5,6-EET) is the most likely mediator of NO-independent, but CYP-dependent coronary vasodilation in response to bradykinin. Studies in the rat kidney, however, support the existence of additional EDHFs as acetylcholine also exhibits NO-independent vasodilation that is unaffected by CYP inhibitors in concentrations that attenuate responses to bradykinin. In some blood vessels, NO may tonically suppress the expression of CYP dependent EDHF. In the event of impaired NO synthesis, therefore, a CYP dependent vasodilator mechanism may serve as a backup to a primary NO-dependent mechanism, although they may act in concert. In other vessels, particularly microvessels, an EDHF may constitute the major vasodilator mechanism for hormones and other physiological stimuli. EDHFs appear to he important regulators of vascular tone; alterations in this system can be demonstrated in hypertension and diabetes, conditions associated with altered endothelium dependent vasodilator responsiveness.
AB - There is now overwhelming evidence for factors, other than nitric oxide (NO), chat mediate endothelium-dependent vasodilation by hyperpolarizing the underlying smooth muscle via activation of Ca2+-activated K+ channels. Although the identity of endothelium derived hyperpolarizing factor (EDHF) remains to be established, cytochrome P450 (CYP) dependent metabolites of arachidonic acid (AA), namely, the eposides, fulfill several of the criteria required for consideration as putative mediators of endothelium-dependent hyperpolarization. They are produced by the endothelium, released in response to vasoactive hormones, and elicit vasorelaxation via stimulation of Ca2+-activated K+ channels. Our studies in the rat indicate that of the epoxides, 5,6- epoxyeicosatrienoic acid (5,6-EET) is the most likely mediator of NO-independent, but CYP-dependent coronary vasodilation in response to bradykinin. Studies in the rat kidney, however, support the existence of additional EDHFs as acetylcholine also exhibits NO-independent vasodilation that is unaffected by CYP inhibitors in concentrations that attenuate responses to bradykinin. In some blood vessels, NO may tonically suppress the expression of CYP dependent EDHF. In the event of impaired NO synthesis, therefore, a CYP dependent vasodilator mechanism may serve as a backup to a primary NO-dependent mechanism, although they may act in concert. In other vessels, particularly microvessels, an EDHF may constitute the major vasodilator mechanism for hormones and other physiological stimuli. EDHFs appear to he important regulators of vascular tone; alterations in this system can be demonstrated in hypertension and diabetes, conditions associated with altered endothelium dependent vasodilator responsiveness.
KW - Arachidonic acid
KW - Bradykinin
KW - Cytochrome P450-AA
KW - Endothelium
KW - Endothelium-derived hyperpolarizing factor
KW - Nitric oxide
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U2 - 10.1016/S0006-2952(97)00039-7
DO - 10.1016/S0006-2952(97)00039-7
M3 - Article
C2 - 9464448
AN - SCOPUS:0030669283
SN - 0006-2952
VL - 54
SP - 1059
EP - 1070
JO - Biochemical Pharmacology
JF - Biochemical Pharmacology
IS - 10
ER -