Endothelium-derived hyperpolarising factors and associated pathways: a synopsis

Abstract

The term endothelium-derived hyperpolarising factor (EDHF) was introduced in 1987 to describe the hypothetical factor responsible for myocyte hyperpolarisations not associated with nitric oxide (EDRF) or prostacyclin. Two broad categories of EDHF response exist. The classical EDHF pathway is blocked by apamin plus TRAM-34 but not by apamin plus iberiotoxin and is associated with endothelial cell hyperpolarisation. This follows an increase in intracellular [Ca(2+)] and the opening of endothelial SK(Ca) and IK(Ca) channels preferentially located in caveolae and in endothelial cell projections through the internal elastic lamina, respectively. In some vessels, endothelial hyperpolarisations are transmitted to myocytes through myoendothelial gap junctions without involving any EDHF. In others, the K(+) that effluxes through SK(Ca) activates myocytic and endothelial Ba(2+)-sensitive K(IR) channels leading to myocyte hyperpolarisation. K(+) effluxing through IK(Ca) activates ouabain-sensitive Na(+)/K(+)-ATPases generating further myocyte hyperpolarisation. For the classical pathway, the hyperpolarising "factor" involved is the K(+) that effluxes through endothelial K(Ca) channels. During vessel contraction, K(+) efflux through activated myocyte BK(Ca) channels generates intravascular K(+) clouds. These compromise activation of Na(+)/K(+)-ATPases and K(IR) channels by endothelium-derived K(+) and increase the importance of gap junctional electrical coupling in myocyte hyperpolarisations. The second category of EDHF pathway does not require endothelial hyperpolarisation. It involves the endothelial release of factors that include NO, HNO, H(2)O(2) and vasoactive peptides as well as prostacyclin and epoxyeicosatrienoic acids. These hyperpolarise myocytes by opening various populations of myocyte potassium channels, but predominantly BK(Ca) and/or K(ATP), which are sensitive to blockade by iberiotoxin or glibenclamide, respectively.

Contraction by Ca2+ Influx via the L-Type Ca2+ Channel Voltage Window in Mouse Aortic Segments is Modulated by Nitric Oxide

“…NO has been described to activate voltage-gated K + channels, to hyperpolarize VSMCs and to decrease the intracellular Ca 2+ concentration (Edwards et al, 2010;Quignard et al, 2000;Yuan et al, 1996). To compensate for the hyperpolarizing effects of NO or depolarizing effects of eNOS inhibition, 1 µM levcromakalim was added to set Vm of all the segments to VK (figure 9).…”

Pharmacotherapy and analysis of gaseous mediators in hypertensive patients

“…It inhibits key events in the development of atherosclerosis, such as adhesion and platelet aggregation, leukocyte adhesion and migration, proliferation of smooth muscle cells (13) . Several studies are documenting that antihypertensive drugs medications contribute to the elevation of NO in plasma levels, such as Enalapril and Captopril (angiotensin-converting enzyme inhibitors) (14) and the Nisoldipina (calcium channel antagonist) (15) .…”

Spasmolytic effect of galetin 3,6-dimethyl ether, a flavonoid obtained from Piptadenia stipulacea (Benth) Ducke

“…The airway epithelial cells modulate the basal tone and reactivity of smooth muscle by releasing epithelium derived relaxant factors (EDRF) (Hashiba et al, 1999), such as nitric oxide (NO) (Nijkamp et al, 1993) and prostaglandins (Farmer et al, 1987). The FGAL relaxant effect in the guinea pig trachea pre-contracted with CCh is concentration-dependent and occurs in both the (Edwards et al, 2010). Consequently, drugs which act on vascular smooth muscle represent an alternative in treating these diseases.…”