Modulation by Cytochrome P450-4A ω-Hydroxylase Enzymes of Adrenergic Vasoconstriction and Response to Reduced PO2 in Mesenteric Resistance Arteries of Dahl Salt-Sensitive Rats

Raffai, Gábor; Wang, Jingli; Roman, Richard J.; Anjaiah, Siddam; Weinberg, Brian D.; Falck, John R.; Lombard, Julian H.

doi:10.1111/j.1549-8719.2010.00053.x

Cited by 8 publications

(9 citation statements)

References 64 publications

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“…In our preparation, inhibition of 20-HETE production using 10 μM DDMS inhibited vasoconstriction to high oxygen tension in a reversible manner, but did not affect vasodilation to low oxygen tension (Figure 5). Previous studies have shown that vessels maintain their reactivity to vasoconstrictors (norepinephrine) following addition of DDMS [26], and in the present study the vessels maintained some tone after addition of DDMS. It is therefore unlikely that the lack of response to high oxygen reflects a general failure of the VSMC to contract.…”

Section: Discussionsupporting

confidence: 73%

Significance of KATP channels, L-type Ca2+ channels and CYP450-4A enzymes in oxygen sensing in mouse cremaster muscle arterioles In vivo

et al. 2013

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BackgroundATP-sensitive K+ channels (KATP channels), NO, prostaglandins, 20-HETE and L-type Ca2+ channels have all been suggested to be involved in oxygen sensing in skeletal muscle arterioles, but the role of the individual mechanisms remain controversial. We aimed to establish the importance of these mechanisms for oxygen sensing in arterioles in an in vivo model of metabolically active skeletal muscle. For this purpose we utilized the exteriorized cremaster muscle of anesthetized mice, in which the cremaster muscle was exposed to controlled perturbation of tissue PO2.ResultsChange from “high” oxygen tension (PO2 = 153.4 ± 3.4 mmHg) to “low” oxygen tension (PO2 = 13.8 ± 1.3 mmHg) dilated cremaster muscle arterioles from 11.0 ± 0.4 μm to 32.9 ± 0.9 μm (n = 28, P < 0.05). Glibenclamide (KATP channel blocker) caused maximal vasoconstriction, and abolished the dilation to low oxygen, whereas the KATP channel opener cromakalim caused maximal dilation and prevented the constriction to high oxygen. When adding cromakalim on top of glibenclamide or vice versa, the reactivity to oxygen was gradually restored. Inhibition of L-type Ca2+ channels using 3 μM nifedipine did not fully block basal tone in the arterioles, but rendered them unresponsive to changes in PO2. Inhibition of the CYP450-4A enzyme using DDMS blocked vasoconstriction to an increase in PO2, but had no effect on dilation to low PO2.ConclusionsWe conclude that: 1) L-type Ca2+ channels are central to oxygen sensing, 2) KATP channels are permissive for the arteriolar response to oxygen, but are not directly involved in the oxygen sensing mechanism and 3) CYP450-4A mediated 20-HETE production is involved in vasoconstriction to high PO2.

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Section: Discussionsupporting

confidence: 73%

Significance of KATP channels, L-type Ca2+ channels and CYP450-4A enzymes in oxygen sensing in mouse cremaster muscle arterioles In vivo

et al. 2013

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“…In an in vitro study [25], the vasodilatation of mesenteric arteries induced by ACh in low-sodium-fed rats was similar to that in high-sodium-fed rats. Another study [26] showed that the vasoconstrictive response of small mesenteric arteries to NA in low-sodium-fed rats was strong and comparable to that in high-sodium-fed rats. In an in vitro study using mesenteric resistance arteries [27], a high-sodium diet did not affect NA-induced vasoconstriction, but did impair ACh-induced vasodilatation.…”

Section: Discussionmentioning

confidence: 99%

High Sodium Intake Impairs Small Artery Vasoreactivity in vivo in Dahl Salt-Sensitive Rats

Wang

Chen

et al. 2019

J Vasc Res

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The effects of high sodium intake on the functionality of resistance arteries have been repeatedly studied in vitro, but no study has focused on salt-sensitive hypertension in vivo. We studied the in vivo reactivity of mesenteric small arteries (MSAs) to vasoactive agents in Dahl salt-sensitive (DS) rats with various sodium diets. Twenty-four male DS rats were randomized into 3 groups: LS (0.3% NaCl diet), NS (0.6% NaCl diet), and HS (8% NaCl diet). After a 12-week intervention, the diameter changes of the MSAs after noradrenaline (NA) and acetylcholine (ACh) exposure were detected by a microscope, and changes in blood perfusion through the MSAs were measured by full-field laser perfusion imaging. HS enhanced the constrictive response of the MSAs to NA and attenuated the relaxing response to ACh. Low sodium intake reduced the response of the MSAs to NA and promoted ACh-induced vasodilatation. HS also aggravated NA-induced blood perfusion reduction and impaired ACh-induced hyperperfusion of the MSAs. Pathologically, HS was associated with arteriolar structural damage and fibrosis of the MSAs. We conclude that sodium intake affects the responsiveness of the MSAs to vasoactive agents in DS rats and might play important roles in modulating blood pressure in hypertensive individuals.

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“…As such, increases in the CYP4A/20-HETE system may be independent of dietary sodium. [14–16] In order to determine the direct effects of salt on the CYP4A/20-HETE pathway independent of changes in arterial pressure, the present study evaluated the effect of short-term (three days) elevated dietary salt intake as the Dahl SS rat does not demonstrate salt-induced pressure changes within this limited time frame. [16] In addition, we evaluated vascular function in a novel cosomic rat strain (SS-5 BN ) carrying CYP4A alleles from the Brown Norway (BN) rat in the Dahl SS genetic background that exhibits dramatic attenuation of salt-sensitivity of blood pressure.…”

Section: Introductionmentioning

confidence: 99%

Introgression of Brown Norway CYP4A genes on to the Dahl salt-sensitive background restores vascular function in SS-5BN consomic rats

et al. 2012

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This study tested the hypothesis that the Dahl salt-sensitive (SS) rat has vascular dysfunction due, in part, to the upregulation of the cytochrome P450-4A ω-hydroxylase (CYP4A)/20-hydroxyeicosatetraenoic acid (20-HETE) system. To assess the role of vascular 20-HETE, SS were compared to SS-5BN consomic rats, carrying CYP4A alleles on chromosome 5 from the normotensive Brown Norway introgressed onto the SS genetic background. Cerebral arteries from SS-5BN had less CYP4A protein than arteries from SS rats fed either normal salt (NS, 0.4% NaCl) or high salt (HS, 4.0% NaCl) diet. Acetylcholine (ACh)-induced dilation of middle cerebral arteries (MCA) from SS and SS-5BN was present in MCA of SS-5BN fed either NS or HS diet, but absent in SS. In SS fed either diet, ACh-induced dilation was restored by acute treatment with the CYP4A inhibitor DDMS or the 20-HETE antagonist 20-HEDE. The restored response to ACh in DDMS-treated SS was inhibited by L-NAME and unaffected by indomethacin or MS-PPOH. Vascular relaxation responses to the nitric oxide (NO) donor sodium nitroprusside were intact in both SS and SS-5BN rats and unaffected by the acute addition of DDMS, indicating the vascular dysfunction of the SS rat is due to a reduced bioavailability of NO instead of failure the vascular smooth muscle cells to respond to the vasodilator. Superoxide levels in cerebral arteries of SS-5BN rats (evaluated semi-quantitatively by DHE fluorescence) were lower than those in arteries of SS rats. These findings indicate SS rats have an upregulation of the CYP4A/20-HETE pathway resulting in elevated ROS and reduced NO bioavailability resulting in vascular dysfunction.

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Modulation by Cytochrome P450-4A ω-Hydroxylase Enzymes of Adrenergic Vasoconstriction and Response to Reduced PO2 in Mesenteric Resistance Arteries of Dahl Salt-Sensitive Rats

Cited by 8 publications

References 64 publications

Significance of KATP channels, L-type Ca2+ channels and CYP450-4A enzymes in oxygen sensing in mouse cremaster muscle arterioles In vivo

Significance of KATP channels, L-type Ca2+ channels and CYP450-4A enzymes in oxygen sensing in mouse cremaster muscle arterioles In vivo

High Sodium Intake Impairs Small Artery Vasoreactivity in vivo in Dahl Salt-Sensitive Rats

Introgression of Brown Norway CYP4A genes on to the Dahl salt-sensitive background restores vascular function in SS-5BN consomic rats

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