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J C McGiff

Publications and source records attributed to J C McGiff.

At least 19 recordsLinked to original sources
PubMed2001

20-hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acids and blood pressure.

The properties of 20-hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acids, vasoactivity and modulation of ion transport and mediation/modulation of the effects of vasoactive hormones, such as angiotensin II and endothelin, underscore their importance to renal vascular mechanisms and electrolyte excretion. 20-Hydroxyeicosatetraenoic acid is an integral component of renal autoregulation and tubuloglomerular feedback as well as cerebral autoregulation, eliciting vasoconstriction by the inhibition of potassium channels. Nitric oxide inhibits 20-hydroxyeicosatetraenoic acid formation, the removal of which contributes to the vasodilator effect of nitric oxide. In contrast, epoxyeicosatrienoic acids are generally vasodilatory by activating potassium channels and have been proposed as endothelium-derived hyperpolarizing factors. 20-Hydroxyeicosatetraenoic acid modulates ion transport in key nephron segments by influencing the activities of sodium--potassium-ATPase and the sodium--potassium--chloride co-transporter; however, the primacy of the various arachidonate oxygenases that generate products affecting these activities changes with age. The range and diversity of activity of 20-hydroxyeicosatetraenoic acid is influenced by its metabolism by cyclooxygenase to products affecting vasomotion and salt/water excretion. 20-Hydroxyeicosatetraenoic acid is the principal renal eicosanoid that interacts with several hormonal systems that are central to blood pressure regulation. This article reviews the most recent studies that address 20-hydroxyeicosatetraenoic acid and epoxyeicosatrienoic acids in vascular and renal tubular function and hypertension.

Animals↗
PubMed2001

CaR-mediated COX-2 expression in primary cultured mTAL cells.

Primary cultures of medullary thick ascending limb (mTAL) cells retain the capacity to express calcium-sensing receptor (CaR) mRNA and protein. Increases in cyclooxygenase-2 (COX-2) mRNA accumulation, protein expression, and PGE(2) synthesis were observed in a dose- and time-dependent manner after exposure of these cells to extracellular calcium (Ca(o)(2+)). Moreover, transfection of mTAL cells with a CaR overexpression vector significantly enhanced COX-2 expression and PGE(2) production in response to calcium compared with cells transfected with an empty vector. Challenge with the CaR-selective agonist poly-L-arginine (PLA) also increased COX-2 mRNA accumulation, protein expression, and PGE(2) synthesis. Furthermore, Ca(o)(2+)- and PLA-mediated PGE(2) production was abolished in the presence of NS-398 or nimesulide, two different COX-2-selective inhibitors. These data suggest that intracellular signaling mechanisms initiated via activation of CaR contribute to COX-2-dependent PGE(2) synthesis in the mTAL. Because Ca(o)(2+) concentration varies along Henle's loop, calcium may contribute to salt and water balance via a COX-2- and CaR-dependent mechanism. Thus novel calcimimetics might be useful in conditions such as hypertension in which manipulation of extracellular fluid volume provides beneficial effects.

Animals↗
PubMed2001

Epoxyeicosatrienoic acid-mediated renal vasodilation to arachidonic acid is enhanced in SHR.

We tested the hypothesis that cyclooxygenase-independent vasodilation produced by arachidonic acid (AA) is mediated by epoxyeicosatrienoic acids (EETs) and is blunted in the spontaneously hypertensive rat (SHR). At normal perfusion pressure (PP; 70 to 90 mm Hg), AA constricted the renal vasculature in both SHR and normotensive Wistar-Kyoto rats, an effect abolished by cyclooxygenase inhibition, and converted to vasodilation when PP was raised to approximately 200 mm Hg. Unexpectedly, renal vasodilation elicited by AA was greater in the SHR at high PP; for example, 2.5, 5, and 10 microg of AA produced PP declines of 54+/-9, 92+/-10, and 112+/-5 mm Hg, respectively, in SHR compared with 26+/-3, 45+/-5, and 77+/-6 mm Hg in Wistar-Kyoto rats (P:<0.01). However, the renal vasodilator responses to acetylcholine (0.1 microg) and sodium nitroprusside (1 microg) did not differ between strains, indicating that vascular responsiveness to AA was independent of intrinsic changes in vascular smooth muscle. Hyperresponsiveness of the renal vasculature to AA may be unique for the SHR, because it did not occur in Sprague-Dawley rats with angiotensin II-induced hypertension. 5,8,11,14-Eicosatetraynoic acid (ETYA; 4 micromol/L), an inhibitor of all AA pathways, attenuated the vasodilator responses to AA, as did treatment with stannous chloride, which depletes cytochrome P450 enzymes, suggesting that a cytochrome P450 AA metabolite mediated the renal vasodilation. N:-Methylsulfonyl-12,12-dibromododec-11-en-amide (DDMS; 2 micromol/L), a selective omega-hydroxylase inhibitor, did not affect AA-induced vasodilation, whereas selective inhibition of epoxygenases with either miconazole (0.3 micromol/L) or N:-methylsulfonyl-6-(2-propargyloxyphenyl) hexanamide (MS-PPOH; 12 micromol/L) did, indicating that one or more EETs were involved in the renal vasodilator action of AA at high PP. This conclusion was supported by the demonstration that AA greatly enhanced the renal efflux of EETs at high PP but not at basal PP.

5,8,11,14-Eicosatetraynoic Acid↗
PubMed2000

Angiotensin II releases 20-HETE from rat renal microvessels.

We studied hydroxyeicosatetraenoic acid (HETE) release in response to ANG II from preglomerular microvessels (PGMVs), the vascular segment governing changes in renal vascular resistance. PGMVs were isolated from Sprague-Dawley rats and incubated with NADPH and hormones at 37 degrees C. Eicosanoids were extracted, and cytochrome P-450 (CYP)-derived HETEs were purified and quantitated by negative chemical ionization gas chromatography-mass spectroscopy. PGMVs produced primarily 20- and 19-HETEs, namely, 7.9 +/- 1.7 and 2.2 +/- 0.5 ng/mg protein, respectively. ANG II (5 nM) increased CYP-HETE release by two- to threefold; bradykinin, phenylephrine, and Ca(2+) ionophore were without effect. [Sar(1)]ANG II (0.1-100 microM) dose dependently stimulated 19- and 20-HETEs, an effect blocked by the AT(2)-receptor antagonist PD-123319 as well as by U-73122, a phospholipase C inhibitor. Microvascular 20-HETE release was increased more than twofold by the third day in response to ANG II (120 ng. kg(-1). min(-1)) infused subcutaneously for 2 wk; it was not further enhanced after 14 days, although blood pressure continued to rise. Thus an AT(2)-phospholipse C effector unit is associated with synthesis of a vasoconstrictor product, 20-HETE, in a key renovascular segment.

Angiotensin II↗
PubMed2000

Regulation of cyclooxygenase isoforms in the renal thick ascending limb: effects of extracellular calcium.

We previously showed that primary cultures of mTAL cells express cyclooxygenase 2 (COX-2) when challenged with tumor necrosis factor alpha (TNFalpha) or phorbol myristate acetate (PMA). Moreover, expression of COX-2 was linked to decreases in TNFalpha-mediated 86Rb uptake, an in vitro correlate of natriuresis. mTAL cells in primary culture express calcium sensing receptor (CaR), a G-protein coupled receptor that senses changes in extracellular calcium concentration and ultimately increases intracellular calcium concentration ([Ca2+]i) and protein kinase C (PKC) activity. PGE2 synthesis by mTAL cells increases in a dose- and time-dependent manner after exposure of these cells to extracellular Ca2+. Similar effects were observed when cells were challenged with the CaR-selective agonist, poly-L-arginine. These data suggest that intracellular signaling mechanisms initiated via activation of CaR contribute to mTAL PGE2 synthesis. As TNF production is calcium-sensitive in some cells types, we postulate that these effects involve the regulation of COX-2 expression via a TNF-dependent mechanism. The functional implications of these studies relate to a cytokine-mediated mechanism that contributes to salt and water balance, and suggests that small changes in Ca(2+)o may contribute to the regulation of these events. The possibility that the effects of Ca(2+)o involve activation of CaR suggests that novel calcimimetic molecules might be useful in conditions, such as hypertension or other conditions, in which manipulation of extracellular fluid volume provides beneficial effects.

Animals↗
PubMed1999

Endothelin-1 and CYP450 arachidonate metabolites interact to promote tissue injury in DOCA-salt hypertension.

Inhibition of cytochrome P-450 (CYP450) enzymes with cobalt chloride (CoCl2) prevented hypertension, organ hypertrophy, and renal injury induced by DOCA and salt (1% NaCl) in uninephrectomized (UNx) rats. Systolic blood pressure (SBP) rose to 193 +/- 6 mmHg by day 21 from control levels of 150 +/- 7 mmHg in response to DOCA-salt treatment, a rise that was prevented by CoCl2 (24 mg. kg-1. 24 h-1). The effects of DOCA-salt treatment, which increased protein excretion to 88.3 +/- 6.9 mg/24 h on day 21 from 9.0 +/- 1.1 mg/24 h on day 3, were prevented by CoCl2. CoCl2 also attenuated the renal and left ventricular hypertrophy and the increase in media-to-lumen ratio in hypertensive rats. DOCA-salt treatment increased excretion of endothelin (ET)-1 from 81 +/- 17 to 277 +/- 104 pg. 100 g body wt-1. 24 h-1 associated with a fourfold increase in 20-hydroxyeicosatetraenoic acid (20-HETE) excretion from 3.0 +/- 1.1 to 12.2 +/- 1.9 ng. 100 g body wt-1. 24 h-1 (days 3 vs. 21). CoCl2 blunted these increases by 58 and 72%, respectively. In aortic rings pulsed with [3H]thymidine, ET-1 increased its incorporation. Dibromododec-11-enoic acid, an inhibitor of 20-HETE synthesis, attenuated ET-1-induced increases in [3H]thymidine incorporation. We distinguished effects of CoCl2 acting via CO generation vs. suppression of CYP450-arachidonic acid metabolism by treating UNx-salt-DOCA rats with 1-aminobenzotriazole (ABT), which suppresses CYP450 enzyme activity, and compared these results to those produced by CoCl2. ABT reduced hypertension, as did CoCl2. Unlike CoCl2, ABT did not prevent organ hypertrophy and proteinuria, suggesting that these effects were partially related to CO formation. Blockade of the ETA receptor with BMS-182874 reduced SBP, organ hypertrophy, and proteinuria, indicating the importance of ET-initiated abnormalities to the progression of lesions in UNx-salt-DOCA.

Animals↗
PubMed1999

20-HETE and the kidney: resolution of old problems and new beginnings.

The protean properties of 20-hydroxyeicosatetraenoic acid (HETE), vasoactivity, mitogenicity, and modulation of transport in key nephron segments, serve as the basis for the essential roles of 20-HETE in the regulation of the renal circulation and electrolyte excretion and as a second messenger for endothelin-1 and mediator of selective renal effects of ANG II. Renal autoregulation and tubular glomerular feedback are mediated by 20-HETE through constriction of preglomerular arterioles, responses that are maintained by 20-HETE inhibition of calcium-activated potassium channels. 20-HETE modulates ion transport in the proximal tubules and the thick ascending limb by affecting the activities of Na+-K+-ATPase and the Na+-K+-2Cl- cotransporter, respectively. The range and diversity of activity of 20-HETE derives in large measure from COX-dependent transformation of 20-HETE to products affecting vasomotion and salt and water excretion. Nitric oxide (NO) exerts a negative modulatory effect on 20-HETE formation; inhibition of NO synthesis produces marked perturbation of renal function resulting from increased 20-HETE production. 20-HETE is an essential component of interactions involving several hormonal systems that have central roles in blood pressure homeostasis, including angiotensins, endothelins, NO, and cytokines. 20-HETE is the preeminent renal eicosanoid, overshadowing PGE2 and PGI2. This review is intended to provide evidence for the physiological roles for cytochrome P-450-derived eicosanoids, particularly 20-HETE, and seeks to extend this knowledge to a conceptual framework for overall cardiovascular function.

Animals↗
PubMed1999

Cyclooxygenase-2 expression and function in the medullary thick ascending limb.

The medullary thick ascending limb (MTAL) metabolizes arachidonic acid (AA) via cytochrome P-450 (CyP450)- and cyclooxygenase (COX)-dependent pathways. In the present study, we demonstrated that the COX-2-selective inhibitor, NS-398, prevented tumor necrosis factor-alpha (TNF)- and phorbol myristate acetate (PMA)-mediated increases in PGE(2) production by cultured MTAL cells. Accumulation of COX-2, but not COX-1, mRNA increased when cells were challenged with TNF (1 nM) or PMA (1 microM). Pretreatment of cells for 30 min with actinomycin D (AcD, 1 microM) had little effect on COX-2 mRNA accumulation in unstimulated cells or in cells challenged with either TNF or PMA. Moreover, a posttranscriptional mechanism(s) appears to contribute significantly to COX-2 mRNA accumulation as pretreatment for 15 min with cycloheximide (CHX, 1 microM) caused a superinduction of COX-2 mRNA accumulation in unstimulated cells as well as in cells challenged with either TNF or PMA. Expression of COX-2 protein in unstimulated MTAL cells was attenuated by preincubation for 2 h with dexamethasone (Dex, 2 microM); however, Dex had little or no effect on COX-2 expression in cells challenged with either PMA or TNF. The time-dependent inhibition of 86Rb uptake by MTAL cells challenged with TNF was diminished by pretreating cells with NS-398. These data suggest that TNF-mediated induction of COX-2 protein expression accounted for the lag-time required for this cytokine to inhibit 86Rb uptake in MTAL cells.

Animals↗
PubMed1999

Renal cytochrome P450 omega-hydroxylase and epoxygenase activity are differentially modified by nitric oxide and sodium chloride.

Renal function is perturbed by inhibition of nitric oxide synthase (NOS). To probe the basis of this effect, we characterized the effects of nitric oxide (NO), a known suppressor of cytochrome P450 (CYP) enzymes, on metabolism of arachidonic acid (AA), the expression of omega-hydroxylase, and the efflux of 20-hydroxyeicosatetraenoic acid (20-HETE) from the isolated kidney. The capacity to convert [(14)C]AA to HETEs and epoxides (EETs) was greater in cortical microsomes than in medullary microsomes. Sodium nitroprusside (10-100 microM), an NO donor, inhibited renal microsomal conversion of [(14)C]AA to HETEs and EETs in a dose-dependent manner. 8-bromo cGMP (100 microM), the cell-permeable analogue of cGMP, did not affect conversion of [(14)C]AA. Inhibition of NOS with N(omega)-nitro-L-arginine-methyl ester (L-NAME) significantly increased conversion of [(14)C]AA to HETE and greatly increased the expression of omega-hydroxylase protein, but this treatment had only a modest effect on epoxygenase activity. L-NAME induced a 4-fold increase in renal efflux of 20-HETE, as did L-nitroarginine. Oral treatment with 2% sodium chloride (NaCl) for 7 days increased renal epoxygenase activity, both in the cortex and the medulla. In contrast, cortical omega-hydroxylase activity was reduced by treatment with 2% NaCl. Coadministration of L-NAME and 2% NaCl decreased conversion of [(14)C]AA to HETEs without affecting epoxygenase activity. Thus, inhibition of NOS increased omega-hydroxylase activity, CYP4A expression, and renal efflux of 20-HETE, whereas 2% NaCl stimulated epoxygenase activity.

Animals↗
PubMed1998

Functional response of the rat kidney to inhibition of nitric oxide synthesis: role of cytochrome p450-derived arachidonate metabolites.

1. We tested the hypothesis that nitric oxide (NO) exerts a tonic inhibitory influence on cytochrome P450 (CYP450)-dependent metabolism of arachidonic acid (AA). 2. N(omega)-nitro-L-Arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase (NOS), increased mean blood pressure (MBP), from 91+/-6 to 137+/-5 mmHg, renal vascular resistance (RVR), from 9.9+/-0.6 to 27.4+/-2.5 mmHg ml(-1) min(-1), and reduced renal blood flow (RBF), from 9.8+/-0.7 to 6.5+/-0.6 ml min(-1)) and GFR from 1.2+/-0.2 to 0.6+/-0.2 ml 100 g(-1) min(-1)) accompanied by diuresis (UV, 1.7+/-0.3 to 4.3+/-0.8 microl 100 g(-1) min (-1)), and natriuresis (U(Na)V, 0.36+/-0.04 to 1.25+/-0.032 micromol 100 g(-1) min(-1)). 3. 12, 12 dibromododec-enoic acid (DBDD), an inhibitor of omega hydroxylase, blunted L-NAME-induced changes in MBP, RVR, UV and U(Na)V by 63+/-8, 70+/-5, 45+/-8 and 42+/-9%, respectively, and fully reversed the reduction in GFR by L-NAME. Clotrimazole, an inhibitor of the epoxygenase pathway of CYP450-dependent AA metabolism, was without effect. 4. BMS182874 (5-dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfo namide), an endothelin (ET)A receptor antagonist, also blunted the increases in MBP and RVR and the diuresis/natriuresis elicited by L-NAME without affecting GFR. 5. Indomethacin blunted L-NAME-induced increases in RVR, UV and U(Na)V. BMS180291 (1S-(1alpha,2alpha,3alpha,4alpha)]-2-[[3-[4-[(++ +pentylamino)carbonyl]-2-oxazolyl]-7-oxabicyclo[2.2.1]hept-2-yl ]methyl]benzenepropanoic acid), an endoperoxide receptor antagonist, attenuated the pressor and renal haemodynamic but not the renal tubular effects of L-NAME. 6. In conclusion, the renal functional effects of the CYP450-derived mediator(s) expressed after inhibition of NOS with L-NAME were prevented by inhibiting either CYP450 omega hydroxylase or cyclooxygenase or by antagonizing either ET(A) or endoperoxide receptors. 20-hydroxyeicosatetraenoic acid (20-HETE) fulfils the salient properties of this mediator.

Animals↗
PubMed1998

Cytochrome P-450-derived eicosanoids participate in the renal functional effects of ET-1 in the anesthetized rat.

We evaluated the contribution of cytochrome P-450 (CYP450)-dependent arachidonic acid (AA) metabolites and prostanoids to the renal hemodynamic and tubular effects of endothelin-1 (ET-1) in anesthetized rats. Either ET-1 (0.3, 1.0, and 3 pmol.kg-1.min-1) or vehicle was infused intravenously during two to three 30-min clearance experimental periods. Only high-dose ET-1 increased mean arterial pressure: control, 75 +/- 3 mmHg vs. experimental, 84 +/- 4 mmHg. A dose-dependent diuretic-natriuretic response to ET-1 occurred despite progressive declines in glomerular filtration rate (GFR) and renal blood flow. In the face of a 36% reduction in GFR in response to the highest dose of ET-1, urinary sodium excretion (UNaV) increased threefold from 0.57 +/- 0.11 to 1.6 +/- 0.10 mumol.100 g-1.min-1. Indomethacin (5 mg/kg) decreased basal GFR from 1.2 +/- 0.3 ml.100 g-1.min-1 to 0.8 +/- 0.1 ml.100 g-1.min-1 and potentiated the GFR lowering action of ET-1 associated with reductions in UNaV and urine volume. Cobalt chloride (CoCl2) and dibromododec-11-enoic acid (DBDD), which diminish CYP450-dependent AA metabolism through different mechanisms, were used to identify CYP450 products mediating the renal functional actions of ET-1. DBDD (12.5 micrograms/min) reduced urinary excretion of 20-hydroxyeicosatetraenoic acid from 3.4 +/- 0.9 (control) to 1.1 +/- 0.6 ng/h and abolished the negative effects of ET-1 on GFR while decreasing the diuretic-natriuretic action of ET-1. Similar effects were produced by CoCl2. Clotrimazole, an inhibitor of epoxygenase activity, was without effect on ET-1-induced renal functional changes. Thus the capacity of ET-1 to enhance prostaglandin production was primarily expressed in terms of positive effects on renal hemodynamics. In contrast, CYP450 products promoted sodium excretion despite negative effects on renal hemodynamics.

Anesthesia, General↗
PubMed1998

Angiotensin II induces TNF production by the thick ascending limb: functional implications.

The effects of angiotensin II (ANG II) on tumor necrosis factor-alpha (TNF) production were determined in freshly isolated tubules from the medullary thick ascending limb (MTAL). ANG II (10(-9) M) increased the accumulation of TNF mRNA associated with enhanced production of TNF by approximately five- to sixfold. ANG II also increased prostaglandin E2 (PGE2) production by the MTAL in a dose-dependent manner and exerted biphasic differential effects on 86Rb uptake, depending on the exposure time of the tubules to the peptide and the doses used. Low-dose ANG II (10(-11) M) increased 86Rb uptake by MTAL tubules after a "short-term" (15 min) challenge, whereas uptake was inhibited after a "long-term" (3 h) incubation period. High-dose ANG II (10(-6) M) inhibited MTAL 86Rb uptake, irrespective of incubation time. Uptake of 86Rb was inhibited by approximately 60% in MTAL tubules that were challenged for 3 h with ANG II. The inhibitory action of ANG II was prevented by eliminating the participation of either TNF with antisera to the cytokine or PGE2 by inhibition of cyclooxygenase with indomethacin. We conclude that ANG II regulates TNF production in the MTAL, an interaction that affects 86Rb uptake via an eicosanoid-dependent mechanism in this nephron segment.

Angiotensin II↗
PubMed1998

NO-independent vasodilation to acetylcholine in the rat isolated kidney utilizes a charybdotoxin-sensitive, intermediate-conductance Ca(++)-activated K+ channel.

The role of K+ channels in the nitric oxide-independent renal vasodilator effect of acetylcholine (Ach) was examined to address the hypothesis that the mechanism underlying this response was different from that of bradykinin, because an earlier study indicated the possibility of different mediators. We used the rat isolated, perfused kidney that was constricted with phenylephrine and treated with nitroarginine and indomethacin to inhibit nitric oxide synthase and cyclooxygenase, respectively. The nonspecific K+ channel inhibitors, procaine and tetraethylammonium (TEA), reduced vasodilator responses to Ach and cromakalim, but not those to nitroprusside. Glibenclamide, an inhibitor of ATP-sensitive K+ channels, reduced vasodilator responses to cromakalim but did not affect those to Ach or nitroprusside. Charybdotoxin, an inhibitor of Ca(++)-activated K+ channels, reduced vasodilator responses to Ach without affecting those to cromakalim or nitroprusside. Iberiotoxin and apamin, inhibitors of large- and small-conductance Ca(++)-activated K+ channels, respectively, did not reduce vasodilation induced by Ach, cromakalim or nitroprusside. The inhibitor of cytochrome P450, clotrimazole, reduced the renal vasodilator effects of Ach and bradykinin but not those of nitroprusside or SCA 40, an agonist for Ca(++)-activated K+ channels. These results suggest that in the rat kidney, Ach, like bradykinin, utilizes a charybdotoxin-sensitive Ca(++)-activated K+ channel of intermediate conductance to elicit vasodilation and that this effect may be dependent on cytochrome P450 activity.

Acetylcholine↗
PubMed1998

A method for the determination of 5,6-EET using the lactone as an intermediate in the formation of the diol.

The 5,6 epoxyeicosatrienoic acid (5,6-EET) exhibits a range of biological activities but the functional significance of this labile eicosanoid is unknown due, in part, to difficulties of quantitation in biological samples. We have developed a sensitive and specific method to measure 5,6-EET utilizing its selective capacity to form a lactone. The initial conversion of 5,6-EET and 5,6-dihydroxyeicosatrienoic acid (5,6-DHT) to 5,6-delta-lactone is followed by selective purification using reverse phase high performance liquid chromatography (HPLC), reconversion to 5,6-DHT and quantitation by gas chromatography-mass spectrometry (GCMS). In oxygenated Krebs' buffer, 5,6-EET degrades to 5,6-delta-lactone and 5,6-DHT with a t1/2 approximately 8 min. In the presence of camphorsulfonic acid, 5,6-EET and 5,6-DHT convert to a single HPLC peak (lambda = 205) comigrating with 5,6-delta-lactone. Incubation of 5,6-delta-lactone with triethylamine resulted in a single HPLC peak with the retention time of 5,6-DHT. In the perfusate from the isolated kidney, release of 5,6-EET (20 +/- 5 pg/ml), measured indirectly via conversion to 5,6-DHT, was approx. 6-fold less than that reported for prostaglandin E2 (PGE2) and 20-HETE. The coronary perfusate concentration of 5,6 EET was 9 +/- 2 pg/ml. 5,6-EET recovered from renal and coronary perfusates was increased 2-fold to 45.5 +/- 5.5 pg/ml and 21.6 +/- 6.3 pg/ml, respectively, by arachidonic acid.

8,11,14-Eicosatrienoic Acid↗
PubMed1998

Renal functional effects of endothelins: dependency on cytochrome P450-derived arachidonate metabolites.

The renal tubular and hemodynamic effects of endothelin-1 (ET-1) were studied in the rat in terms of the participation of cytochrome P450 monooxygenases (CYP450)-derived arachidonic acid (AA) metabolites. The availability of specific mechanism-based inhibitors of CYP450-dependent AA metabolism has greatly facilitated studies designed to link AA metabolites generated by CYP450 to renal function. Eicosanoid products synthesized by cyclooxygenase (COX) and CYP450 can account for the renal functional effects of ET-1. Inhibition of COX decreased glomerular filtration rate (GFR) and potentiated the depression of GFR elicited by ET-1. In contrast, inhibition of CY-P450-dependent AA metabolism enhanced GFR and blunted ET-1 induced increase in renal vascular resistance, yet reduced the diuretic response to ET-1. Thus, CYP450-dependent AA products depress GFR and renal blood flow, while promoting sodium excretion. The effects of ET-1 on renal function correspond to those of 20-HETE, the predominant renal CYP450-derived AA metabolite.

Animals↗
PubMed1997

Hyperpolarizing factors.

There is now overwhelming evidence for factors, other than nitric oxide (NO), that 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 epoxides, 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 be important regulators of vascular tone; alterations in this system can be demonstrated in hypertension and diabetes, conditions associated with altered endothelium-dependent vasodilator responsiveness.

Animals↗