Contribution of cytochrome P450 4A isoforms to renal functional response to inhibition of nitric oxide production in the rat

Hercule, Hantz C.; Wang, M.-H.; Oyekan, Adebayo

doi:10.1113/jphysiol.2003.049981

Cited by 23 publications

(23 citation statements)

References 30 publications

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“…Mice lacking the eNOS gene displayed increased vascular 20-HETE synthesis (Huang et al, 2005). Inhibition of 20-HETE synthesis attenuated the rise in blood pressure in N -nitro-L-arginine methyl estertreated rats (Hercule et al, 2003) and induced the NO/endothelium-dependent relaxation to acetylcholine (Kerkhof et al, 1999), whereas administration of a 20-HETE agonist prevented the fall in blood pressure after endotoxin shock (Tunctan et al, 2008). In all, these studies implicate NO in the regulation of 20-HETE synthesis.…”

Section: -Hete-mediated Ikk-dependent Endothelial Dysfunction 63mentioning

confidence: 79%

20-Hydroxy-5,8,11,14-eicosatetraenoic Acid Mediates Endothelial Dysfunction via IκB Kinase-Dependent Endothelial Nitric-Oxide Synthase Uncoupling

Cheng¹,

Wu²,

Gotlinger³

et al. 2009

J Pharmacol Exp Ther

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Endothelial dysfunction and activation occur in the vasculature and are believed to contribute to the pathogenesis of cardiovascular diseases. We have shown that 8,11,, a cytochrome P450 4A-derived eicosanoid that promotes vasoconstriction in the microcirculation, uncouples endothelial nitric-oxide synthase (eNOS) and reduces nitric oxide (NO) levels via the dissociation of the 90-kDa heat shock protein (HSP90) from eNOS. It also causes endothelial activation by stimulating nuclear factor-B (NF-B) and increasing levels of proinflammatory cytokines. In this study, we examined signaling mechanisms that may link 20-HETE-induced endothelial dysfunction and activation. Under conditions in which 20-HETE inhibited NO production, it also stimulated inhibitor of NF-B (IB) phosphorylation. Both effects were prevented by inhibition of tyrosine kinases and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK). It is noteworthy that inhibitor of IB kinase (IKK) activity negated the 20-HETE-mediated inhibition of NO production. Immunoprecipitation experiments revealed that treatment of ionophore-stimulated cells with 20-HETE brings about a decrease in HSP90-eNOS association and an increase in HSP90-IKK␤ association, suggesting that the activation by 20-HETE of NF-B is linked to its action on eNOS. Furthermore, addition of inhibitors of tyrosine kinase MAPK and IKK restored the 20-HETE-mediated impairment of acetylcholine-induced relaxation in rat renal interlobar arteries. The results indicate that 20-HETE mediates eNOS uncoupling and endothelial dysfunction via the activation of tyrosine kinase, MAPK, and IKK, and these effects are linked to 20-HETE-mediated endothelial activation.The integrity of the vascular endothelium is vital to the regulation of the cardiovascular system. The endothelium serves as a protective barrier between tissues and circulating blood and functions to maintain vascular homeostasis by releasing bioactive factors in response to hemodynamic changes and blood-borne signals. An uncontrolled endothelial cell response is involved in many disease processes, including hypertension, atherosclerosis, and diabetes. These diseases are related to endothelial injury, dysfunction and activation. Nitric oxide (NO), generated from L-arginine by endothelial nitric-oxide synthase (eNOS), is a key endothelial-derived factor, the bioavailability of which is essential to the integrity and function of the endothelium. Endothelial dysfunction occurs as a result of a loss of NO bioavailability that is due to either reduced formation or accelerated degradation of NO, and it is often associated with endothelial activation. NO actively mediates many functions of the endothelium. In addition to its Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.109.159863.ABBREVIATIONS: NO, nitric oxide; eNOS, endothelial nitric-oxide synthase; SMC, smooth muscle cell; 20-HETE, 20-hydroxyeicosatetraenoic acid; HSP90, 90-kDa heat shock prot...

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Section: -Hete-mediated Ikk-dependent Endothelial Dysfunction 63mentioning

confidence: 79%

20-Hydroxy-5,8,11,14-eicosatetraenoic Acid Mediates Endothelial Dysfunction via IκB Kinase-Dependent Endothelial Nitric-Oxide Synthase Uncoupling

Cheng¹,

Wu²,

Gotlinger³

et al. 2009

J Pharmacol Exp Ther

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“…We have also shown that NO induced activation of the K Ca channels in rat renal interlobular arteries and in the middle cerebral artery of the rat is cGMP independent and is associated with inhibition of the endogenous formation of 20-HETE in VSM cells (47,48). Further studies have shown that inhibitors of the synthesis of 20-HETE reduce the vasodilator response to NO in renal and cerebral arteries by 50 -75% (1, 3) and the pressor response of rats to blockade of NO synthesis with L-NAME in vivo (17). Thus the present data suggest that the vasoconstrictor response in the cerebral vessels to scavenging of NO by Hb (at least in vitro) is due, in part, to an increase in 20-HETE production in cerebral arteries, which blocks K Ca channels and depolarizes VSM cells.…”

Section: Discussionmentioning

confidence: 99%

“…The levels of endothelin (46), thromboxane (36), ATP (31), isoprostanes (44), glutamate (4), platelet-activating factor (PAF) (17) and serotonin (5-HT) (6,43) in CSF all increase after SAH, and the response of cerebral arteries to most of these constrictors is enhanced. Cerebral vasospasm after SAH has been reported to be attenuated by inhibitors of endothelin synthesis or receptors (10,12), by 5-HT receptor antagonists (6), and by inhibitors of the downstream effectors of these vasoconstrictors, including Ras, Rho, mitogen-activated protein kinase (MAPK), and protein kinase C (PKC) (25,26,33,52).…”

mentioning

confidence: 99%

Hemoglobin, NO, and 20-HETE interactions in mediating cerebral vasoconstriction following SAH

Takeuchi¹,

Miyata²,

Renić³

et al. 2006

American Journal of Physiology-Regulatory, Integrative and Comp

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Recent studies have indicated that 20-hydroxyeicosatetraenoic acid (20-HETE) contributes to the fall in cerebral blood flow (CBF) after subarachnoid hemorrhage (SAH), but the factors that stimulate the production of 20-HETE are unknown. This study examines the role of vasoactive factors released by clotting blood vs. the scavenging of nitric oxide (NO) by hemoglobin (Hb) in the fall in CBF after SAH. Intracisternal (icv) injection of blood produced a greater and more prolonged (120 vs. 30 min) decrease in CBF than that produced by a 4% solution of Hb. Pretreating rats with N -nitro-L-arginine methyl ester (L-NAME; 10 mg/kg iv) to block the synthesis of NO had no effect on the fall in CBF produced by an icv injection of blood. L-NAME enhanced rather than attenuated the fall in CBF produced by an icv injection of Hb. Blockade of the synthesis of 20-HETE with TS-011 (0.1 mg/kg iv) prevented the sustained fall in CBF produced by an icv injection of blood and the transient vasoconstrictor response to Hb. Hb (0.1%) reduced the diameter of the basilar artery (BA) of rats in vitro by 10 Ϯ 2%. This response was reversed by TS-011 (100 nM). Pretreatment of vessels with L-NAME (300 M) reduced the diameter of BA and blocked the subsequent vasoconstrictor response to the addition of Hb to the bath. TS-011 returned the diameter of vessels exposed to L-NAME and Hb to that of control. These results suggest that the fall in CBF after SAH is largely due to the release of vasoactive factors by clotting blood rather than the scavenging of NO by Hb and that 20-HETE contributes the vasoconstrictor response of cerebral vessels to both Hb and blood. subarachnoid hemorrhage; nitric oxide; 20-hydroxyeicosatetraenoic acid CEREBRAL VASOSPASM IS A CRITICAL complication of subarachnoid hemorrhage (SAH). Vasospasm occurs in 70% of patients with aneurysmal SAH and leads to ischemic deficits in 36% of patients (5). Despite extensive investigation, the factors that trigger the decline in cerebral blood flow (CBF) after SAH remain to be determined.The fall in CBF after SAH correlates with the amount of hemoglobin (Hb) released into cerebrospinal fluid (CSF), and vasospasm can be triggered by an injection of Hb alone into the CSF (31, 51). Hb induces hemeoxygenase-1 (24) that increases iron levels, which generate superoxide radicals (30). Superoxide radicals at low concentration have been reported to constrict vessels in several vascular beds in part by decreasing the levels of nitric oxide (NO) (13, 42), and there is a recent report that supports a similar mechanism in cerebral arteries (55). Free radicals also increase the production of lipid peroxides and isoprostanes (20, 44) that are potent constrictors of cerebral arteries (19).Previous studies have focused on the role of various vasoconstrictor pathways in the development of cerebral vasospasm. The levels of endothelin (46), thromboxane (36), ATP (31), isoprostanes (44), glutamate (4), platelet-activating factor (PAF) (17) and serotonin (5-HT) (6, 43) in CSF all increase after SAH, and the ...

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“…20-HETE is one of the most potent vasoconstrictive eicosanoids in existence and is known as a counter-regulator of nitric oxide in the cerebromicrovasculature (Hercule et al, 2003;Sun et al, 2000). In addition to the vasoconstrictive effects, inhibition of 20-HETE has also been shown to play an important role in mediating the angiogenic effects of vascular endothelial growth factor (VEGF) (Amaral et al, 2003;Chen et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Protective Effect of the 20-HETE Inhibitor HET0016 on Brain Damage after Temporary Focal Ischemia

Poloyac

Zhang

Bies

et al. 2006

J Cereb Blood Flow Metab

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Cytochrome P450 metabolism of arachidonic acid produces the potent vasoconstrictive metabolite, 20-hydroxyeicosatetraenoic acid (20-HETE). Recent studies have implicated 20-HETE as a vasoconstrictive mediator in hemorrhagic stroke. The purpose of this study was to determine the effect of the 20-HETE inhibitor, HET0016, on lesion volume and cerebral blood flow (CBF) after temporary middle cerebral artery occlusion (MCAO) in rats. Plasma pharmacokinetics and tissue concentrations of HET0016 were determined after a 10 mg/kg intraperitoneal dose. Separate rats were treated with HET0016 or vehicle before 90 mins of MCAO. Lesion volume was assessed by 2,3,5-triphenyl-tetrazolium-chloride and cerebral flow was determined using laser Doppler flow. The effect of MCAO on in vitro microsomal formation of mono-oxygenated arachidonic acid metabolites was also determined. Results show that HET0016 has a short biologic half-life, distributes into the brain, and is associated with a 79.6% reduction in 20-HETE concentration in the cortex. Lesion volume was greatly reduced in HET0016-treated (9.1%64.9%) versus vehicle-treated (57.4%69.8%; n = 6; P < 0.001) rats. An attenuation of the observed decrease in CBF was observed in HET0016-treated (180 mins 89.2%66.2%; 240 mins 88.1%65.7% of baseline flow) versus vehicle control (180 mins 57.6%619.0%; 240 mins 53.8%620.0% of baseline flow; n = 6; P < 0.05). Brain cortical microsomal formation rate of 20-HETE was also reduced at 24 h in the ipsilateral hemisphere after MCAO. These data support a significant role for 20-HETE in the pathogenesis of ischemic stroke.

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Contribution of cytochrome P450 4A isoforms to renal functional response to inhibition of nitric oxide production in the rat

Cited by 23 publications

References 30 publications

20-Hydroxy-5,8,11,14-eicosatetraenoic Acid Mediates Endothelial Dysfunction via IκB Kinase-Dependent Endothelial Nitric-Oxide Synthase Uncoupling

20-Hydroxy-5,8,11,14-eicosatetraenoic Acid Mediates Endothelial Dysfunction via IκB Kinase-Dependent Endothelial Nitric-Oxide Synthase Uncoupling

Hemoglobin, NO, and 20-HETE interactions in mediating cerebral vasoconstriction following SAH

Protective Effect of the 20-HETE Inhibitor HET0016 on Brain Damage after Temporary Focal Ischemia

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