scholarly journals Renal 20-hydroxyeicosatetraenoic acid synthesis during pregnancy

2002 ◽  
Vol 282 (2) ◽  
pp. R383-R389 ◽  
Author(s):  
Mong-Heng Wang ◽  
Barbara A. Zand ◽  
Alberto Nasjletti ◽  
Michal Laniado-Schwartzman
Keyword(s):  
Blood Pressure ◽  
Arachidonic Acid ◽  
Cytochrome P450 ◽  
Acid Synthesis ◽  
Regulatory Mechanisms ◽  
Thick Ascending Limb ◽  
Hydroxyeicosatetraenoic Acid ◽  
Hydroxylase Activity ◽  
Site Specific ◽  
Medullary Thick Ascending Limb

We examined whether renal 20-hydroxyeicosatetraenoic acid (20-HETE) synthesis is altered during gestation. Renal microsomal arachidonic acid ω-hydroxylase activity increased by 50 and 48% in rats on days 12 and 19 of gestation, respectively. Renal microvessel 20-HETE synthesis increased by 50 and 82% in rats on days 6 and 12 of gestation, respectively, and returned to control levels at day 19 of gestation. In contrast, 20-HETE synthesis in isolated medullary thick ascending limb was unchanged from control levels on days 6and 12 of gestation, but it increased twofold on day 19 of gestation. This increase on day 19 of gestation was associated with a twofold increase in urinary 20-HETE excretion, and it coincided with a 23-mmHg fall in blood pressure. Moreover, change in the rate of 20-HETE synthesis in microvessels was consistent with the level of expression of cytochrome P450 (CYP)4A proteins. Administration of the CYP4A inhibitor 1-aminobenzotriazole (ABT) for 2 days on day 12 of pregnancy or for 5 days starting on day 15 of pregnancy caused a transient but significant reduction in systolic blood pressure. ABT treatment also decreased urinary sodium, urinary 20-HETE, and renal and microvessel 20-HETE synthesis. This study, to our knowledge, is the first to demonstrate that 20-HETE synthesis in the kidney is altered in time- and site-specific manners during pregnancy. The localized pattern of changes suggests that there are distinct regulatory mechanisms for 20-HETE synthesis in the kidney during pregnancy.

Different mechanisms of renal Na-K-ATPase regulation by protein kinases in proximal and distal nephron

1993 ◽  
Vol 265 (3) ◽  
pp. F399-F405 ◽  
Author(s):  
T. Satoh ◽  
H. T. Cohen ◽  
A. I. Katz
Keyword(s):  
Arachidonic Acid ◽  
Protein Kinase ◽  
Collecting Duct ◽  
Common Mechanism ◽  
Thick Ascending Limb ◽  
Cortical Collecting Duct ◽  
Distal Nephron ◽  
Inhibitory Peptide ◽  
Medullary Thick Ascending Limb ◽  
Pump Activity

We recently reported a novel intracellular mechanism of Na-K-adenosinetriphosphatase (Na-K-ATPase) regulation in the cortical collecting duct (CCD) by agents that increase cell adenosine 3',5'-cyclic monophosphate (cAMP), which involves stimulation of protein kinase A (PKA) and phospholipase A2 (PLA2). We now determined whether this mechanism also operates in other nephron segments. In the medullary thick ascending limb (MTAL) dopamine, the DA1 agonist fenoldopam, forskolin, or dibutyryl-cAMP inhibited Na-K-ATPase activity, similar to results in CCD. In both segments this effect was blocked by 20-residue inhibitory peptide (IP20), a peptide inhibitor of PKA, but not by staurosporine, a protein kinase C (PKC) inhibitor. PKC activators phorbol 12-myristate 13-acetate, phorbol 12,13-dibutyrate, and 1,2-myristate 13-acetate, phorbol 12,13-dibutyrate, and 1,2-dioctanoylglycerol had no effect on Na-K pump activity in either CCD or MTAL. In contrast, all three PKC activators inhibited pump activity in the proximal convoluted tubule (PCT), an effect reproduced only by dopamine or by parathyroid hormone [PTH-(1-34)]. In PCT the pump inhibition by dopamine or PTH-(1-34) was abolished by staurosporine but not by IP20. The PLA2 inhibitor mepacrine prevented the effect of all agents, and arachidonic acid produced a dose-dependent pump inhibition in each of the three segments studied. We conclude that intracellular mechanisms of Na-K-ATPase regulation differ along the nephron, as they involve activation of PKA in CCD and MTAL and of PKC in PCT. These two pathways probably share a common mechanism in stimulating PLA2, arachidonic acid release, and production of eicosanoids in both the proximal and distal nephron.

Inhibition of renal arachidonic acid ω-hydroxylase activity with ABT reduces blood pressure in the SHR

1998 ◽  
Vol 275 (2) ◽  
pp. R426-R438 ◽  
Author(s):  
Ping Su ◽  
K. Maya Kaushal ◽  
Deanna L. Kroetz
Keyword(s):  
Blood Pressure ◽  
Arachidonic Acid ◽  
Acid Metabolism ◽  
Arachidonic Acid Metabolism ◽  
Sprague Dawley ◽  
Hydroxylase Activity ◽  
Outer Medulla ◽  
Spontaneously Hypertensive ◽  
Protein Levels ◽  
Intraperitoneal Dose

The mechanism-based cytochrome P-450 (CYP) inhibitor 1-aminobenzotriazole (ABT) was characterized as an inhibitor of renal arachidonic acid metabolism and administered to spontaneously hypertensive rats (SHRs) to determine the effect of reduced eicosanoid production on mean arterial pressure (MAP). A single intraperitoneal dose of ABT to Sprague-Dawley rats caused a dose-dependent loss of renal CYP content, arachidonic acid metabolism, and CYP4A protein. In the cortex and outer medulla, ABT showed a high degree of selectivity for the CYP4A enzymes, reflected by the potent inhibition of 19- and 20-hydroxyeicosatetraenoic acid (19- and 20-HETE) formation. A 50 mg/kg dose of ABT reduced cortical 20-HETE formation to 16.1 ± 0.82% of control and outer medullary 20-HETE formation to 23.8 ± 0.45% of control. In contrast, there was no inhibition of renal epoxygenase activity at this dose. Renal CYP content, arachidonic acid ω- and (ω-1)-hydroxylase activity, and CYP4A protein levels gradually return to control levels by 72 h after a single dose of ABT. Cortical 20-HETE formation recovered from 17.9 ± 3.15% of control at 6 h to 84.8 ± 4.67% of control at 72 h after ABT administration. A single injection of ABT to 7-wk-old SHRs caused an acute reduction in MAP, which remained suppressed for at least 12 h. The effect was maximal within 4 h and averaged 17–23 mmHg during the 4- to 12-h period after administration. 20-HETE formation was inhibited 85% in the cortex and 70–80% in the outer medulla during the period when MAP was reduced. A structurally related ABT analog 1-hydroxybenzotriazole had no effect on blood pressure or renal arachidonic acid metabolism. These results identify ABT as a selective inhibitor of renal CYP4A activity and provide further support for a role for 20-HETE in the regulation of blood pressure.

Enzymatic Activity and Expression of Cytochrome P450 LAω within Intrasplenically Transplanted Fetal Hepatocytes in Spontaneously Hypertensive Rats

1997 ◽  
Vol 6 (5) ◽  
pp. 531-534 ◽  
Author(s):  
Kazuya Kato ◽  
Junji Kato ◽  
W. John B. Hodgson ◽  
Nader G. Abraham ◽  
Kazuhiko Onodera ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Cytochrome P450 ◽  
Enzymatic Activity ◽  
Microscopic Examination ◽  
Spontaneously Hypertensive Rats ◽  
Hypertensive Rats ◽  
Hydroxylase Activity ◽  
Spontaneously Hypertensive ◽  
Fetal Hepatocytes ◽  
Red Pulp

We examined the expression and enzymatic activity of the cytochrome P450 LAω within transplanted hepatocytes. Fetal hepatocytes were harvested at day 20 of gestation from spontaneously hypertensive rats (SHRs) and transplanted into recipient adult SHR spleens. Microscopic examination of the recipient spleens 4 and 10 wk after transplantation revealed masses of hepatocytes with cordlike structures in the red pulp. Immunochemical studies detected cytochrome (cyto) P450 LAω in the fetal hepatocytes before transplantation without prior induction. Although the cyto P450 LAω was not detected by the second week after transplantation, by the 6th and 10th wk after transplantation, it was. Cyto P450-arachidonic acid ω/4oM-1 hydroxylase activity (formation of 20- and 19-hydroxyeico-satetraenoic acid) was detected at 10 wk after transplantation, but not 2 or 6 wk after transplantation. These results demonstrated that fetal hepatocytes can be transplanted successfully into recipient spleens and then grow in the spleens, as in the case of the adult hepatocyte response.

scholarly journals Effect of arachidonic acid on activity of the apical K+ channel in the thick ascending limb of the rat kidney.

1995 ◽  
Vol 106 (4) ◽  
pp. 727-743 ◽  
Author(s):  
W Wang ◽  
M Lu
Keyword(s):  
Arachidonic Acid ◽  
Cytochrome P450 ◽  
Metabolic Pathway ◽  
Rat Kidney ◽  
Specific Inhibitor ◽  
Inhibitory Effect ◽  
K Channel ◽  
Thick Ascending Limb ◽  
Channel Activity ◽  
Inside Out

We have used patch-clamp techniques to study the effects of arachidonic acid (AA) on the activity of the 70-pS K+ channel, the predominant type of the two apical K+ channels operating under physiological conditions in the thick ascending limb (TAL) of the rat kidney. Addition of 5-10 microM AA blocked the activity of the 70-pS K+ channel in both cell-attached and inside-out patches. The inhibitory effect of AA was specific, because application of 10 microM linoleic acid, oleic acid, or palmitic acid failed to mimic the effect of AA. The effect of AA could not be blocked by pretreatment of the TAL tubules with either 5 microM indomethacin (inhibitor of cyclooxygenase) or 4 microM cinnamyl-3,4-dihydroxy-alpha-cyanocinnamate (CDC) (inhibitor of lipooxygenase). In contrast, addition of 5 microM 17-octadecynoic acid (17-ODYA), an inhibitor of P450 monooxygenases, abolised the effect of AA on the channel activity, indicating that the effect was mediated by cytochrome P450 metabolites of AA. Addition of 10 nM 20-hydroxyeicosatetraenoic acid (20-HETE), the main metabolite of the cytochrome P450 metabolic pathway in the medullary TAL, mimicked the inhibitory effect of 10 microM AA. However, addition of 100 nM 19-HETE or 17-HETE had no significant effects and 100 nM 20-carboxy AA (20-COOH) reduced the channel activity by only 20%, indicating that the inhibitory effect of 20-HETE was specific and responsible for the action of AA. Inhibition of the P450 metabolic pathway by either 5 microM 17-ODYA or 12, 12-dibromododec-11-enoic acid (DBDD) dramatically increased the channel activity by 280% in cell-attached patches. The stimulatory effect of 17-ODYA or DBDD was not observed in inside-out patches. The results strongly indicate that 20-HETE is a specific inhibitor for the 70-pS K+ channel and may play an important role in the regulation of the K+ channel activity in the TAL.

scholarly journals Arachidonic acid epoxygenase and 12(S)-lipoxygenase: evidence of their concerted involvement in ductus arteriosus constriction to oxygen

2011 ◽  
Vol 89 (5) ◽  
pp. 329-334 ◽  
Author(s):  
Barbara Baragatti ◽  
Flavio Coceani
Keyword(s):  
Arachidonic Acid ◽  
Cytochrome P450 ◽  
Ductus Arteriosus ◽  
Tonic Contraction ◽  
Hydroxyeicosatetraenoic Acid ◽  
Lipoxygenase Inhibitors ◽  
Endothelin 1 ◽  
12 Lipoxygenase

Oxygen promotes closure of the ductus arteriosus at birth. We have previously presented a scheme for oxygen action with a cytochrome P450 (CYP450) hemoprotein and endothelin-1 (ET-1) being, respectively, sensor and effector, and a hypothetical monooxygenase product serving as a coupling link. We have also found in the vessel arachidonic acid (AA) 12(S)-lipoxygenase (12-lipoxygenase) undergoing upregulation at birth. Here, we examined the feasibility of a sensor-to-effector messenger originating from AA monooxygenase and 12-lipoxygenase pathways. The epoxygenase inhibitor, N-methylsulfonyl-6-(2-)hexanamide, suppressed the tonic contraction of ductus to oxygen. A similar effect was obtained with 12-lipoxygenase inhibitors baicalein and PD 146176. By contrast, none of the inhibitors modified the endothelin-1 contraction. Furthermore, an AA ω-hydroxylation product, 20-hydroxyeicosatetraenoic acid (20-HETE), reportedly responsible for oxygen contraction in the systemic microvasculature, had no such effect on the ductus. We conclude that AA epoxygenase and 12-lipoxygenase jointly produce a hitherto uncharacterized compound acting as oxygen messenger in the ductus.

Sign in / Sign up

Export Citation Format

Share Document