20-HETE is an endogenous inhibitor of the large-conductance Ca(2+)-activated K+ channel in renal arterioles

Abstract

The present study examined the effects of 20-hydroxyeicosatetraenoic acid (20-HETE) and 17-octadecynoic acid (17-ODYA), an inhibitor of the metabolism of arachidonic acid by P-450, on K(+)-channel activity in vascular smooth muscle cells (VSM) isolated from renal arterioles of the rat. Two types of K+ channels were characterized using inside-out excised membrane patches. One channel exhibited a large conductance (250.3 +/- 5 pS), was activated by membrane depolarization and elevations in cytoplasmic Ca2+ concentration, and was blocked by low concentrations (< 1 mM) of tetraethylammonium (TEA). The other K+ channel exhibited an intermediate conductance (46.3 +/- pS), was activated by membrane depolarization but not by changes in intracellular Ca2+ concentration, and was blocked by 4-aminopyridine (5 mM). Addition of 20-HETE to the bath (1-100 nM), reduced the frequency of opening of the large-conductance Ca(2+)-activated K+ channel recorded using cell-attached patches on VSM. It had no effect on the intermediate-conductance K+ channel: 17-ODYA (1 microM) increased the activity of the large-conductance Ca(2+)-activated K+ channel, and this effect was reversed by 20-HETE (10 nM). 20-HETE (1-1000 nM) reduced the diameter of isolated perfused small renal arteries of the rat by approximately 15% TEA (1 mM) blocked the vasoconstrictor response to 20-HETE (100 nM). These studies suggest that 20-HETE is an endogenously formed vasoconstrictor that acts in part by inhibiting the opening of the large-conductance Ca(2+)-activated K+ channel in renal arteriolar VSM.

Inversion of neurovascular coupling by subarachnoid blood depends on large-conductance Ca 2+ -activated K + (BK) channels

“…This model is based on studies demonstrating that, under certain conditions, vessel constrictions in response to evoked increases in astrocytic soma Ca 2+ were prevented by high concentrations of an inhibitor of cytochrome P450 enzyme (CYP4a), which is responsible for the conversion of arachidonic acid to 20-HETE (23,28). Previous work also has demonstrated that 20-HETE can inhibit BK channels in renal and pial artery smooth muscle cells (29), and increased 20-HETE synthesis has been implicated in vascular pathologies associated with SAH (30). To examine the involvement of 20-HETE in EFS-induced vasoconstriction after SAH, we exposed brain slices to the CYP4a inhibitor, N-hydroxy-N′-(4-n-butyl-2-methylphenyl)formamidine (HET0016, 100 nM) (31,32), before EFS.…”

Hydrogen peroxide stimulates the Ca2+-activated big-conductance K channels (BK) through cGMP signaling pathway in cultured human endothelial cells

“…BK channels are located in both smooth muscle cells and endothelial cells [3,19] and play an important role in the regulation of vasoactivity. The regulation of BK channels in smooth muscle cells is intensively studied and has been demonstrated to be stimulated by NO, CO and epoxyeicosatrienoic acid (EET) and to be inhibited by 20-hydroxyeicosatetraenoic acid (20-HETE) [19][20][21][22][23]. In contrast, the regulatory mechanism of BK channels in endothelial cells is poorly understood.…”

Long-term modifications of blood pressure in normotensive and spontaneously hypertensive rats by gene delivery of rAAV-mediated cytochrome P450 arachidonic acid hydroxylase

“…All of the isoforms catalyze the ω-and ω-1 hydroxylation of arachidonic acid to produce 20-HETE [2,5,[25][26][27]. Ito et al [28] used isoform specific primers to amplify 4A isoforms individually and found that the expression of CYP4A1 mRNA was very low but that CYP 4A2 and 4A3 mRNA are constitutively expressed throughout various nephron segments and the renal vessels in male SD rats.…”