Abstract 05: Cyclooxygenase-2 Inhibition As A New Tool To Combat Angiogenesis Inhibitor-induced Hypertension And Renal Toxicity

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Daan C van Dorst ◽  
Katrina M Mirabito Colafella ◽  
Leni van Doorn ◽  
Richard van Veghel ◽  
Ingrid M Garrelds ◽  
...  
Keyword(s):  
Vascular Function ◽  
Renal Toxicity ◽  
Angiogenesis Inhibitor ◽  
Angiogenesis Inhibitors ◽  
High Dose ◽  
Angiogenesis Inhibition ◽  
Dose Aspirin ◽  
Induced Hypertension ◽  
Cox 2 ◽  
Cox 1

Angiogenesis inhibitors are effective anti-cancer agents, but also cause hypertension and renal injury. Earlier, we observed in rats that high-dose aspirin (capable of blocking cyclooxygenase (COX)-1 and -2) prevented these side effects better than low-dose aspirin (blocking COX-1 only). Therefore, we hypothesized that selective COX-2 inhibition would prevent toxicity during angiogenesis inhibition, and that this toxicity involves a reduced ratio of vasodilator/constrictor COX-derived prostanoids, i.e., prostacyclin (PGI 2 ) and thromboxane (TXA 2 ). Male WKY rats received vehicle, angiogenesis inhibition (sunitinib (SU), 14 mg/kg/day) alone or combined with COX-2 inhibition (celecoxib, 10mg/kg/day), a PGI 2 analogue (iloprost 100 μg/kg/day), or a dual TXA 2 synthase/receptor antagonist (picotamide, 2.5 mg/kg/day) for 8 days (n=7-8/group). Mean arterial pressure (MAP) was measured via radiotelemetry, vascular function was assessed via wire myography, and biochemical measurements were performed by ELISA. SU induced a rapid increase in MAP (16±2 vs. 3±1 mmHg after vehicle on day 6, P<0.001), which was blunted by celecoxib (10±2 mmHg on day 6, P=0.06 versus SU), temporarily attenuated by iloprost (on treatment days 1-2) and unaffected by picotamide. Wire myography demonstrated a trend towards increased vasoconstrictor response to endothelin-1 in iliac arteries after SU, which was prevented by celecoxib (P<0.001). SU increased albuminuria (0.6±0.1 vs. 0.3±0.1 mg/24h after vehicle; P<0.001), and this was prevented by celecoxib only (0.4±0.1 mg/24h, P=0.01 vs. SU). SU increased the PGI 2 /TXA 2 ratio in both plasma (2.7±1.2 vs. 0.6±0.2 after vehicle, P=0.05) and urine (22±2.2 vs. 0.9±0.2 after vehicle, P<0.001). In conclusion, selective COX-2 inhibition combats angiogenesis inhibitor-induced hypertension and renal toxicity. SU paradoxically increases the PGI 2 /TXA 2 ratio, particularly in the kidney. Although this upregulation might initially be protective, it could eventually contribute to renal toxicity, most likely because PGI 2 exerts deleterious effects in excessive concentrations. Targeting excessive renal PGI 2 production might be another promising strategy to prevent renal toxicity during angiogenesis inhibition.

Abstract 453: Angiogenesis Inhibition-Induced Hypertension and Nephrotoxicity: Not All Antihypertensives are the Same

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Stephanie Lankhorst ◽  
Mariëtte H Kappers ◽  
Joep H Van Esch ◽  
Frank M Smedts ◽  
Stefan Sleijfer ◽  
...  
Keyword(s):  
Ace Inhibitor ◽  
Ace Inhibition ◽  
Cell Swelling ◽  
Histological Evaluation ◽  
High Dose ◽  
Angiogenesis Inhibition ◽  
Vegf Inhibitor ◽  
Renal Histology ◽  
Anti Cancer ◽  
Induced Hypertension

Angiogenesis inhibition with the VEGF inhibitor sunitinib is an established anti-cancer therapy inducing hypertension and nephrotoxicity. Here we compared the effects of the endothelin antagonist (ET-R) macitentan (30 mg/kg/day, p.o; n=8), the calcium channel blocker (CCB) amlodipine (3 mg/kg/day, p.o; n=9), or the ACE-inhibitor captopril (3 or 12 mg/kg/day, s.c.; n=9) vs. no treatment (n=14) in sunitinib (26.7 mg/kg/day, p.o)-exposed hypertensive WKY rats. Treatment lasted 8 days; mean arterial pressure (MAP) was monitored telemetrically. At the end of the treatment period, 24-hour urine samples for protein and endothelin-1 (ET-1) measurements, and blood samples and kidneys for histological evaluation were collected. With sunitinib, MAP increased from 94.7±0.9 mmHg to 125.8±1.5 mmHg (Δ31.1±0.9 mmHg, p<0.001). Co-administration of macitentan (Δ12.3±1.5 mmHg, p<0.001) or amlodipine (Δ11.4±1.7 mmHg, p<0.001) attenuated the sunitinib-induced MAP rise, whereas low and high captopril doses did not (Δ28.1±2.0 and Δ27.2±1.1 mmHg). With sunitinib, serum creatinine increased from 8.0±2.7 to 29.9±4.6 μmol/l (p<0.01) and proteinuria from 7.5±1.3 to 33.3±4.8 mg/day, p<0.05. Although no agent could prevent the sunitinib-induced rise in creatinine, the induced proteinuria was attenuated by 62% (p<0.01) with macitentan and by 88% with low and 114% (p<0.001) with high dose of captopril, while proteinuria increased by 56% (p=NS) with amlodipine. With sunitinib, urinary ET-1 increased from 3.3±0.5 to 4.8±1.0 pg/day (p<0.05). Macitentan and captopril abolished this increase. Renal histology revealed extensive glomerular ischemia and endothelial cell swelling. Concomitant with the decrease in proteinuria, glomerular intra-epithelial protein deposition decreased with macitentan and captopril. In conclusion, ET-R antagonism and CCB effectively reduced the sunitinib-induced hypertension, whereas ACE-inhibition did not. Both ET-R antagonism and ACE inhibition diminished the sunitinib-induced proteinuria. Since ET-R antagonists are not yet available as anti-hypertensive agents, CCBs are preferred in angiogenesis inhibition-induced hypertension, while adding an ACE-inhibitor might be considered when proteinuria is also present.

Abstract 528: Dose- And Salt-dependency Of Angiogenesis Inhibition-induced Blood Pressure Rise And Renal Toxicity

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Stephanie Lankhorst ◽  
Mariëtte H Kappers ◽  
Stefan Sleijfer ◽  
A H Danser ◽  
Anton H van den Meiracker
Keyword(s):  
Low Dose ◽  
Renal Toxicity ◽  
Pressure Rise ◽  
High Salt ◽  
High Dose ◽  
Low Doses ◽  
High Salt Diet ◽  
Salt Diet ◽  
Angiogenesis Inhibition ◽  
Cystatine C

Angiogenesis inhibition with the VEGF inhibitor sunitinib is an established anti-cancer therapy, inducing hypertension and nephrotoxicity. We explored the dose- and salt-dependency of these side effects. In male WKY rats, mean arterial pressure (MAP) was monitored telemetrically during oral treatment with a high (27.5 mg/kg.day, n=14), an intermediate (14 mg/kg.day, n=6) and low dose (7 mg/kg.day, n=6) of sunitinib or vehicle (n=8) after normal salt diet for 2 weeks. The low dose-model was also combined with a high salt diet (8% NaCl and saline water). Eight days after administration rats were sacrificed and blood and 24h urine samples collected for biochemical measurements. With the high dose of sunitinib, MAP increased from 94.7±0.9 mmHg to 125.8±1.5 mmHg (Δ31.1±0.9 mmHg, p<0.001). The intermediate and low doses induced MAP rises of 24.3±2.7 mmHg (p<0.001) and 13.4±3.3 mmHg (p<0.001), respectively. The low dose of sunitinib with high salt, induced a MAP rise of 43.5±2.2 mmHg (p<0.001 compared to normal salt). With the high dose, circulating ET-1 increased from 0.6±0.1 pg/ml to 1.6±0.2 pg/ml (p<0.01) and serum cystatine-C from 4.5±0.1 mg/L to 6.6±0.3 mg/L (p<0.001). Comparable increases in circulating ET-1 were seen with the intermediate and low doses, whereas serum cystatine-C did increase with the intermediate dose (to 6.3±0.1 mg/L, p0.05). Serum cystatine-C levels with low and high salt were identical. With the high dose of sunitinib, proteinuria increased from 7.5±1.3 to 33.3±4.8 mg/day (p<0.05). The rise in proteinuria was attenuated with the intermediate (16.2±2.1 mg/day, p<0.01) and low dose (19.9±3.3 mg/day, p<0.01), but increased to 40.4±30.1 mg/day (p>0.05) with high salt. Angiogenesis inhibition-induced hypertension and nephrotoxicity are dose-dependent with a lower threshold for the rise in BP than for renal toxicity. The BP rise observed with the low dose of sunitinib observed in normotensive rats is comparable to the sunitinib-induced BP rise observed in patients and clearly is salt-sensitive. Since cystatine-C levels during normal and high salt diet were comparable, the BP rise during high salt seems independent of renal dysfunction.

The Cardiovascular Pharmacology of COX-2 Inhibition

Hematology ◽  
2005 ◽  
Vol 2005 (1) ◽  
pp. 445-451 ◽  
Author(s):  
Susanne Fries ◽  
Tilo Grosser
Keyword(s):  
Blood Pressure ◽  
Vascular Function ◽  
Cardiovascular Pharmacology ◽  
Pressure Control ◽  
Baseline Risk ◽  
Controlled Clinical Trials ◽  
Arterial Blood ◽  
Inflammatory Drugs ◽  
Cox 2 ◽  
Cox 1

Abstract Selective inhibitors of cyclooxygenase (COX)-2, the coxibs, were developed to inhibit inflammatory prostaglandins derived from COX-2, while sparing gastroprotective prostaglandins primarily formed by COX-1. However, COX-2-derived prostaglandins mediate not only pain and inflammation but also affect vascular function, the regulation of hemostasis/ thrombosis, and blood pressure control. All coxibs depress COX-2-dependent prostacyclin (PGI2) biosynthesis without effective suppression of platelet COX-1-derived thromboxane (Tx) A2, unlike aspirin or traditional nonsteroidal anti-inflammatory drugs, which inhibit both COX-1 and COX-2. The actions of PGI2 oppose mediators, which stimulate platelets, elevate blood pressure, and accelerate atherogenesis, including TxA2. Indeed, structurally distinct inhibitors of COX-2 have increased the likelihood of hypertension, myocardial infarction and stroke in controlled clinical trials. The detection of these events in patients is related to the duration of exposure and to their baseline risk of cardiovascular disease. Thus, coxibs should be withheld from patients with preexisting cardiovascular risk factors, and exposed patients at low cardiovascular baseline risk should be monitored for changes in their risk factor profile, such as increases in arterial blood pressure.

scholarly journals Ethyl Acetate Fraction of Lannea microcarpa Engl. and K. Krause (Anacardiaceae) Trunk Barks Corrects Angiotensin II-Induced Hypertension and Endothelial Dysfunction in Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-13
Author(s):  
Mathieu Nitiéma ◽  
Raffaella Soleti ◽  
Camille Koffi ◽  
Lazare Belemnaba ◽  
Patricia Mallegol ◽  
...  
Keyword(s):  
Ethyl Acetate ◽  
Vascular Function ◽  
Ex Vivo ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Ethyl Acetate Fraction ◽  
Bark Extract ◽  
Phytochemical Analysis ◽  
Ang Ii ◽  
Induced Hypertension ◽  
Cox 2

Traditional remedies prepared from Lannea microcarpa leaves, barks, roots, and fruits are used to treat many diseases including hypertension. This study investigated whether oral administration of the ethyl acetate fraction of Lannea microcarpa trunk barks (LMAE) corrects angiotensin (Ang) II-induced hypertension in mice. Its effects on vascular function were specifically investigated. Experiments explored hemodynamic and echocardiographic parameters in vivo and vascular reactivity to acetylcholine (ACh) and CaCl2ex vivo on isolated aortas. Mice received LMAE for 3 weeks (50 mg/kg/day) by oral gavage. In the last two weeks of treatment, mice were implanted with osmotic minipumps delivering NaCl (0.9%) or Ang II (0.5 mg/kg/day). LMAE completely prevented the increase in systolic and diastolic blood pressure induced by Ang II. Echocardiographic and kidney parameters were not affected by the different conditions. LMAE abrogated Ang II-induced impairment of ACh-induced relaxation without affecting that of sodium nitroprusside. LMAE also completely prevented CaCl2-induced contraction in KCl-exposed aorta ex vivo. The extract alone did not modify superoxide (O2-) and nitric oxide (NO⋅) production in femoral arteries from control mice but significantly limited Ang II-induced O2- production. These effects were associated with reduced expression of inducible isoform of cyclooxygenase- (COX-) 2 and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase isoform NOX-2 in aortas. Finally, phytochemical analysis showed that LMAE contains sterols, triterpenes, coumarins, and anthraquinone. These results showed that LMAE prevents Ang II-induced hypertension and vascular dysfunction through a reduction of oxidative stress linked to COX-2 and NOX-2 pathway and inhibition of calcium entry. This study provides pharmacological basis of the empirical use of Lannea microcarpa trunk bark extract against hypertension.

Abstract P186: Selective ET A Receptor Antagonism versus Dual ET A /ET B Receptor Blockade for Preventing Angiogenesis Inhibitor-induced Hypertension

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Katrina M Mirabito Colafella ◽  
Richard van Veghel ◽  
Renè de Vries ◽  
Jorie Versmissen ◽  
Anton H van den Meiracker ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Pressor Response ◽  
Angiogenesis Inhibitor ◽  
Angiogenesis Inhibitors ◽  
Receptor Blockade ◽  
Sunitinib Treatment ◽  
Vegf Inhibitor ◽  
Induced Hypertension ◽  
Vehicle Treatment ◽  
Stimulation Of

Angiogenesis inhibitors are a mainstay treatment for cancer. While effective in preventing tumor growth, angiogenesis inhibitors cause off-target effects including cardiovascular toxicity and renal injury, most likely via endothelin-1 (ET-1) upregulation. ET-1 via stimulation of the ET A receptor causes pro-hypertensive effects whereas stimulation of the ET B receptor can elicit both pro- or anti-hypertensive effects. In the present study, we hypothesized that selective ET A receptor blockade versus dual ET A /ET B blockade provides better cardiovascular protection from angiogenesis inhibitor-induced hypertension. Male WKY rats were treated with vehicle, sunitinib (VEGF inhibitor; 14 mg/kg/day) alone or in combination with macitentan (ET A/B receptor antagonist; 30 mg/kg/day) or sitaxentan (ET A receptor antagonist; 30 or 100 mg/kg/day) for 8 days. Mean arterial pressure (MAP) was measured via radiotelemetry at baseline and days 1-6 of treatment. Vasoreactivity to acetylcholine (ACh) and ET-1 was assessed in iliac vessels. Compared to vehicle treatment, sunitinib treatment caused a rapid and sustained increase in MAP (1±1 versus 23±2 mmHg on day 6 of treatment, respectively, P<0.001). Co-treatment with macitentan blunted the pressor response to sunitinib, such that on day 6 of treatment the increase in MAP was 7±4 mmHg (P<0.01 versus sunitinib-treated). Similar results were observed for co-treatment with 30 mg/kg/day of sitaxentan. Conversely, co-treatment with 100 mg/kg/day sitaxentan, which has been shown to induce a depressor response in normotensive Wistar rats, completely abolished sunitinib-induced hypertension, with MAP actually decreasing before returning to near baseline level (-1±1 mmHg on day 6 of treatment, P<0.001 versus sunitinib-treated). Compared to vehicle treatment, ET B receptor stimulation yielded a constrictor response after 8 days of sunitinib treatment, while the response to ACh was unaltered. Both macitentan and sitaxentan reversed the constrictor ET B receptor response. Our results support a key role for the ET-1 system in the development of sunitinib-induced hypertension and suggest that selective ET A receptor blockade is sufficient to block this effect.

Histamine-dependent prolongation by aldosterone of vasoconstriction in isolated small mesenteric arteries of the mouse

2013 ◽  
Vol 304 (8) ◽  
pp. H1094-H1102 ◽  
Author(s):  
Jeppe Schjerning ◽  
Torben R. Uhrenholt ◽  
Per Svenningsen ◽  
Paul M. Vanhoutte ◽  
Ole Skøtt ◽  
...  
Keyword(s):  
Mast Cells ◽  
Receptor Antagonist ◽  
Vascular Function ◽  
Mesenteric Arteries ◽  
Wild Type ◽  
Rt Pcr ◽  
No Donor ◽  
High K ◽  
Cox 2 ◽  
Cox 1

In arterioles, aldosterone counteracts the rapid dilatation (recovery) following depolarization-induced contraction. The hypothesis was tested that this effect of aldosterone depends on cyclooxygenase (COX)-derived products and/or nitric oxide (NO) synthase (NOS) inhibition. Recovery of the response to high K+ was observed in mesenteric arteries of wild-type and COX-2−/− mice but it was significantly diminished in preparations from endothelial NOS (eNOS)−/− mice. Aldosterone pretreatment inhibited recovery from wild-type and COX-2−/− mice. The NO donor sodium nitroprusside (SNP) restored recovery in arteries from eNOS−/− mice, and this was inhibited by aldosterone. Actinomycin-D abolished the effect of aldosterone, indicating a genomic effect. The effect was blocked by indomethacin and by the COX-1 inhibitor valeryl salicylate but not by NS-398 (10−6 mol/l) or the TP-receptor antagonist S18886 (10−7 mol/l). The effect of aldosterone on recovery in arteries from wild-type mice and the SNP-mediated dilatation in arteries from eNOS−/− mice was inhibited by the histamine H2 receptor antagonist cimetidine. RT-PCR showed expression of mast cell markers in mouse mesenteric arteries. The adventitia displayed granular cells positive for toluidine blue vital stain. Confocal microscopy of live mast cells showed loss of quinacrine fluorescence and swelling after aldosterone treatment, indicating degranulation. RT-PCR showed expression of mineralocorticoid receptors in mesenteric arteries and in isolated mast cells. These findings suggest that aldosterone inhibits recovery by stimulation of histamine release from mast cells along mesenteric arteries. The resulting activation of H2 receptors decreases the sensitivity to NO of vascular smooth muscle cells. Aldosterone may chronically affect vascular function through paracrine release of histamine.

scholarly journals Tubuloglomerular feedback is decreased in COX-1 knockout mice after chronic angiotensin II infusion

2010 ◽  
Vol 298 (4) ◽  
pp. F1059-F1063 ◽  
Author(s):  
Magali Araujo ◽  
William J. Welch
Keyword(s):  
Angiotensin Ii ◽  
Mean Arterial Pressure ◽  
Renal Cortex ◽  
Tubuloglomerular Feedback ◽  
Ang Ii ◽  
Wild Type ◽  
Induced Hypertension ◽  
Genetic Deletion ◽  
Cox 2 ◽  
Cox 1

Prostaglandins (PGs), produced by two isoforms of cyclooxygenase (COX), COX-1 and COX-2, are important modulators of renal hemodynamics. COX-1 and COX-2 are expressed in the kidney often at distinct sites. Thromboxane (TxA2), PGE2, and prostacyclin (PGI2) are the major PGs in the renal cortex of mice. Acute infusion of the vasoconstrictor ANG II increases COX-2-dependent PGE2 and PGI2. COX-2 is primarily expressed in the macula densa (MD), where several PG synthases are also expressed. We previously showed that MD COX-2 products modulate tubuloglomerular feedback (TGF) in the rat. Genetic deletion of COX-1 enhances COX-2 production of PGs, decreases renal and urinary PGs, and attenuates ANG II-induced hypertension. The present study tested the effects of chronic ANG II infusion on TGF in COX-1 knockout (KO) mice. Basal TGF was similar in COX-1 KO and wild-type (WT) mice. Chronic ANG II infusion increased TGF in WT mice (WT: 9.3 ± 0.7 vs. WT + ANG II: 12.2 ± 1.6 mmHg, P < 0.02). However, chronic ANG II decreased TGF in COX-1 KO mice (KO: 11.4 ± 1.1 vs. KO + ANG II: 8.3 ± 0.6 mmHg, P < 0.01). Pretreatment with the COX-2 inhibitor SC-58,236 in COX-1 KO mice prevented the ANG II-associated reduction in TGF (11.4 ± 1.0 vs. 11.5 ± 0.28 mmHg, not significant). Excretion of 6-keto-PGF2α, the metabolite of PGI2, was increased by ANG II infusion, whereas excretion of TxB2, the stable metabolite of TxA2, was not changed. ANG II infusion increased mean arterial pressure similarly in both WT and KO mice (WT: 93 ± 2 vs. KO: 92 ± 3 mmHg), but not in KO mice pretreated with SC-58,236 (85 ± 2 mmHg). This study shows that COX-1-generated PGs partially mediate ANG II increases in TGF and that COX-2 PGs offset that effect.

Design, Synthesis, Characterization and in silico molecular docking studies and in vivo anti-inflammatory Activity of Pyrazoline clubbed Thiazolinone Derivatives

2020 ◽  
Vol 17 ◽  
Author(s):  
Deepak Kumar Singh ◽  
Mayank Kulshreshtha ◽  
Yogesh Kumar ◽  
Pooja A Chawla ◽  
Akash Ved ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Biological Activities ◽  
Inflammatory Activity ◽  
Standard Drug ◽  
Docking Score ◽  
Chemical Structures ◽  
Cox 2 ◽  
Anti Inflammatory ◽  
Cox 1

Background: The pyrazolines give the reactions of aliphatic derivatives, resembling unsaturated compounds in their behavior towards permanganate and nascent hydrogen. This nucleus has been associated with various biological activities including inflammatory. Thiazolinone is a heterocyclic compound that contains both sulfur and nitrogen atom with a carbonyl group in their structure.Thiazolinone and their derivatives have attracted continuing interest because of their various biological activities, such as anti-inflammatory, antimicrobial, anti-proliferative, antiviral, anticonvulsant etc. The aim of the research was to club pyrazoline nucleus with thiazolinone in order to have significantanti-inflammatory activity. The synthesized compounds were chemically characterized for the establishment of their chemical structures and to evaluate as anti-inflammatory agent. Method: In the present work, eight derivatives of substituted pyrazoline (PT1-PT8) were synthesized by a three step reaction.The compounds were subjected to spectral analysis by Infrared, Mass and Nuclear magnetic resonance spectroscopy and elemental analysis data. All the synthesized were evaluated for their in vivo anti-inflammatory activity. The synthesized derivatives were evaluated for their affinity towards target COX-1 and COX-2, using indomethacin as the reference compound molecular docking visualization through AutoDock Vina. Results: Compounds PT-1, PT-3, PT-4 and PT-8 exhibited significant anti-inflammatory activity at 3rd hour being 50.7%, 54.3%, 52.3% and 57% respectively closer to that of the standard drug indomethacin (61.9%).From selected anti-inflammatory targets, the synthesized derivatives exhibited better interaction with COX-1 and COX-2 receptor, where indomethacin showed docking score of -6.5 kJ/mol, compound PT-1 exhibited highest docking score of -9.1 kJ/mol for COX-1 and compound PT-8 having docking score of 9.4 kJ/mol for COX-2. Conclusion: It was concluded that synthesized derivatives have more interaction with COX-2 receptors in comparison to the COX-1 receptors because the docking score with COX-2 receptors were very good. It is concluded that the synthesized derivatives (PT-1 to PT-8) are potent COX-2 inhibitors.

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