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Article ; Online: Efficacy of BAY 60-2770, a soluble guanylate cyclase activator, for coronary spasm in animal models.

Tawa, Masashi / Nakagawa, Keisuke / Ohkita, Mamoru

The Journal of pharmacology and experimental therapeutics

2024

Abstract: Ischemia with non-obstructive coronary arteries (INOCA), caused by coronary artery spasm, has gained increasing attention owing to the poor quality of life of impacted patients. Therapeutic options to address INOCA remain limited, and developing new ... ...

Abstract	Ischemia with non-obstructive coronary arteries (INOCA), caused by coronary artery spasm, has gained increasing attention owing to the poor quality of life of impacted patients. Therapeutic options to address INOCA remain limited, and developing new therapeutic agents is desirable. Herein, we examined whether soluble guanylate cyclase (sGC) activators could be beneficial in preventing coronary spasms. In organ chamber experiments with isolated canine coronary arteries, prostaglandin F
Language	English
Publishing date	2024-01-23
Publishing country	United States
Document type	Journal Article
ZDB-ID	3106-9
ISSN	1521-0103 ; 0022-3565
ISSN (online)	1521-0103
ISSN	0022-3565
DOI	10.1124/jpet.123.001918
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Article ; Online: Effects of beetroot juice supplementation on vascular functional and structural changes in aged mice.

Tawa, Masashi / Nakagawa, Keisuke / Ohkita, Mamoru

Physiological reports

2023 Volume 11, Issue 12, Page(s) e15755

Abstract: This study investigated whether beetroot juice (BRJ) ingestion ameliorates aging-induced functional and structural changes in vasculature. Aged mice (98-100 weeks old) were supplemented with BRJ (nitrate: 3.5 mmol/L) or drinking water for 4 weeks and ... ...

Abstract	This study investigated whether beetroot juice (BRJ) ingestion ameliorates aging-induced functional and structural changes in vasculature. Aged mice (98-100 weeks old) were supplemented with BRJ (nitrate: 3.5 mmol/L) or drinking water for 4 weeks and compared with young mice (12-15 weeks old). The vasorelaxant response of isolated aortas to acetylcholine was markedly weaker in aged mice than in young mice, but the attenuated relaxation was significantly improved in BRJ-supplemented aged mice. The acetylcholine-induced relaxation was completely abolished by N
MeSH term(s)	Mice ; Animals ; Nitrates ; Acetylcholine ; Antioxidants ; Dietary Supplements ; Vascular Diseases
Chemical Substances	Nitrates ; Acetylcholine (N9YNS0M02X) ; Antioxidants
Language	English
Publishing date	2023-06-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2724325-4
ISSN	2051-817X ; 2051-817X
ISSN (online)	2051-817X
ISSN	2051-817X
DOI	10.14814/phy2.15755
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Article ; Online: Acute Kynurenine Exposure of Rat Thoracic Aorta Induces Vascular Dysfunction via Superoxide Anion Production.

Nakagawa, Keisuke / Kobayashi, Fumika / Kamei, Yoshiki / Tawa, Masashi / Ohkita, Mamoru

Biological & pharmaceutical bulletin

2022 Volume 45, Issue 4, Page(s) 522–527

Abstract: The accumulation of uremic toxins is known to be one of the causes of cardiovascular disorder related to renal disease. Among the many uremic toxins, we focused on kynurenine (kyn), whose levels have been shown to be positively correlated with vascular ... ...

Abstract	The accumulation of uremic toxins is known to be one of the causes of cardiovascular disorder related to renal disease. Among the many uremic toxins, we focused on kynurenine (kyn), whose levels have been shown to be positively correlated with vascular endothelial dysfunction markers, and directly evaluated the influence of kyn on the rat thoracic aorta. Exposure of the endothelium-intact aorta to kyn markedly attenuated the acetylcholine (ACh)-induced relaxation and significantly increased superoxide anion (O
MeSH term(s)	Animals ; Aorta, Thoracic ; Endothelium, Vascular ; Kynurenine/pharmacology ; Rats ; Superoxides ; Vasodilation
Chemical Substances	Superoxides (11062-77-4) ; Kynurenine (343-65-7)
Language	English
Publishing date	2022-04-01
Publishing country	Japan
Document type	Journal Article
ZDB-ID	1150271-x
ISSN	1347-5215 ; 0918-6158
ISSN (online)	1347-5215
ISSN	0918-6158
DOI	10.1248/bpb.b21-01079
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Article ; Online: Soluble Guanylate Cyclase-Mediated Relaxation in Aortas from Rats with Renovascular Hypertension.

Tawa, Masashi / Shimosato, Takashi / Nakagawa, Keisuke / Okamura, Tomio / Ohkita, Mamoru

Pharmacology

2021 Volume 107, Issue 3-4, Page(s) 235–240

Abstract: Soluble guanylate cyclase (sGC) plays an important role in nitric oxide (NO)-mediated regulation of vascular tone; however, NO bioavailability is often reduced in diseased blood vessels. Accumulating evidence suggests that a shift of sGC from the NO- ... ...

Abstract	Soluble guanylate cyclase (sGC) plays an important role in nitric oxide (NO)-mediated regulation of vascular tone; however, NO bioavailability is often reduced in diseased blood vessels. Accumulating evidence suggests that a shift of sGC from the NO-sensitive form to the NO-insensitive form could be an underlying cause contributing to this reduction. Herein, we investigated the impact of renovascular hypertension on NO-sensitive and NO-insensitive sGC-mediated relaxation in rat aortas. Renovascular hypertension was induced by partially clipping the left renal artery (2-kidneys, 1-clip; 2K1C) for 10 weeks. Systolic, diastolic, and mean arterial pressures were significantly increased in the 2K1C group when compared with the sham group. In addition, plasma thiobarbituric acid reactive substances and aortic superoxide generation were significantly enhanced in the 2K1C group when compared with those in the sham group. The vasorelaxant response of isolated aortas to the sGC stimulator BAY 41-2272 (NO-sensitive sGC agonist) was comparable between the sham and 2K1C groups. Likewise, the sGC activator BAY 60-2770 (NO-insensitive sGC agonist)-induced relaxation did not differ between the sham and 2K1C groups. In addition, the cGMP mimetic 8-Br-cGMP (protein kinase G agonist) induced similar relaxation in both groups. Furthermore, there were no differences in BAY 41-2272-stimulated and BAY 60-2770-stimulated cGMP generation between the groups. These findings suggest that the balance between NO-sensitive and NO-insensitive forms of sGC is maintained during renovascular hypertension. Therefore, sGC might not be responsible for the reduced NO bioavailability observed during renovascular hypertension.
MeSH term(s)	Animals ; Aorta ; Cyclic GMP ; Guanylate Cyclase ; Hypertension, Renovascular ; Nitric Oxide ; Rats ; Soluble Guanylyl Cyclase
Chemical Substances	Nitric Oxide (31C4KY9ESH) ; Guanylate Cyclase (EC 4.6.1.2) ; Soluble Guanylyl Cyclase (EC 4.6.1.2) ; Cyclic GMP (H2D2X058MU)
Language	English
Publishing date	2021-12-20
Publishing country	Switzerland
Document type	News
ZDB-ID	206671-3
ISSN	1423-0313 ; 0031-7012
ISSN (online)	1423-0313
ISSN	0031-7012
DOI	10.1159/000520655
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Article ; Online: Preventive effects of nitrate-rich beetroot juice supplementation on monocrotaline-induced pulmonary hypertension in rats.

Tawa, Masashi / Nagata, Rikako / Sumi, Yuiko / Nakagawa, Keisuke / Sawano, Tatsuya / Ohkita, Mamoru / Matsumura, Yasuo

PloS one

2021 Volume 16, Issue 4, Page(s) e0249816

Abstract: Beetroot (Beta vulgaris L.) has a high level of nitrate; therefore, its dietary intake could increase nitric oxide (NO) level in the body, possibly preventing the development of pulmonary hypertension (PH). In this study, we examined the effects of ... ...

Abstract	Beetroot (Beta vulgaris L.) has a high level of nitrate; therefore, its dietary intake could increase nitric oxide (NO) level in the body, possibly preventing the development of pulmonary hypertension (PH). In this study, we examined the effects of beetroot juice (BJ) supplementation on PH and the contribution of nitrate to such effects using a rat model of monocrotaline (MCT, 60 mg/kg s.c.)-induced PH. Rats were injected subcutaneously with saline or 60 mg/kg MCT and were sacrificed 28 days after the injection. In some rats injected with MCT, BJ was supplemented from the day of MCT injection to the day of sacrifice. First, MCT-induced right ventricular systolic pressure elevation, pulmonary arterial medial thickening and muscularization, and right ventricular hypertrophy were suppressed by supplementation with low-dose BJ (nitrate: 1.3 mmol/L) but not high-dose BJ (nitrate: 4.3 mmol/L). Of the plasma nitrite, nitrate, and their sum (NOx) levels, only the nitrate levels were found to be increased by the high-dose BJ supplementation. Second, in order to clarify the possible involvement of nitrate in the preventive effects of BJ on PH symptoms, the effects of nitrate-rich BJ (nitrate: 0.9 mmol/L) supplementation were compared with those of the nitrate-depleted BJ. While the former exerted preventive effects on PH symptoms, such effects were not observed in rats supplemented with nitrate-depleted BJ. Neither supplementation with nitrate-rich nor nitrate-depleted BJ affected plasma nitrite, nitrate, and NOx levels. These findings suggest that a suitable amount of BJ ingestion, which does not affect systemic NO levels, can prevent the development of PH in a nitrate-dependent manner. Therefore, BJ could be highly useful as a therapy in patients with PH.
MeSH term(s)	Animals ; Beta vulgaris/chemistry ; Blood Pressure ; Dietary Supplements ; Fruit and Vegetable Juices ; Hypertension, Pulmonary/etiology ; Hypertension, Pulmonary/prevention & control ; Male ; Monocrotaline/toxicity ; Nitrates/analysis ; Rats ; Rats, Sprague-Dawley
Chemical Substances	Nitrates ; Monocrotaline (73077K8HYV)
Language	English
Publishing date	2021-04-08
Publishing country	United States
Document type	Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0249816
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Article ; Online: Vascular Endothelial Dysfunction in the Thoracic Aorta of Rats with Ischemic Acute Kidney Injury: Contribution of Indoxyl Sulfate.

Nakagawa, Keisuke / Tanaka, Ryosuke / Donouchi, Masahide / Kanda, Masaya / Kamada, Saaya / Kobuchi, Shuhei / Tawa, Masashi / Matsumura, Yasuo / Ohkita, Mamoru

Oxidative medicine and cellular longevity

2022 Volume 2022, Page(s) 7547269

Abstract: Chronic kidney disease (CKD) and cardiovascular disease are known to be linked, and the involvement of indoxyl sulfate (IS), a type of uremic toxin, has been suggested as one of the causes. It is known that IS induces vascular dysfunction through ... ...

Abstract	Chronic kidney disease (CKD) and cardiovascular disease are known to be linked, and the involvement of indoxyl sulfate (IS), a type of uremic toxin, has been suggested as one of the causes. It is known that IS induces vascular dysfunction through overproduction of reactive oxygen species (ROS). On the other hand, the involvement of IS in the vascular dysfunction associated with acute kidney injury (AKI) is not fully understood. Therefore, we investigated this issue using the thoracic aorta of rats with ischemic AKI. Ischemic AKI was induced by occlusion of the left renal artery and vein for 45 min, followed by reperfusion 2 weeks after contralateral nephrectomy. One day after reperfusion, there was marked deterioration in renal function evidenced by an increase in plasma creatinine. Furthermore, blood IS levels increased markedly due to worsening renal function. Seven days and 28 days after reperfusion, blood IS levels decreased with the improvement in renal function. Of note, acetylcholine-induced vasorelaxation deteriorated over time after reperfusion, contradicting the recovery of renal function. In addition, 28 days after reperfusion, we observed a significant increase in ROS production in the vascular tissue. Next, we administered AST-120, a spherical adsorbent charcoal, after reperfusion to assess whether the vascular endothelial dysfunction associated with the ischemic AKI was due to a temporary increase in blood IS levels. AST-120 reduced the temporary increase in blood IS levels after reperfusion without influencing renal function, but did not restore the impaired vascular reactivity. Thus, in ischemic AKI, we confirmed that the vascular endothelial function of the thoracic aorta is impaired even after the recovery of kidney injury, probably with excessive ROS production. IS, which increases from ischemia to early after reperfusion, may not be a major contributor to the vascular dysfunction associated with ischemic AKI.
MeSH term(s)	Acute Kidney Injury/blood ; Acute Kidney Injury/complications ; Animals ; Aorta, Thoracic/metabolism ; Carbon/administration & dosage ; Disease Models, Animal ; Disease Progression ; Endothelial Cells/metabolism ; Endothelium, Vascular/metabolism ; Indican/blood ; Ischemia/blood ; Ischemia/complications ; Male ; Nitric Oxide/metabolism ; Oxides/administration & dosage ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Recovery of Function/drug effects ; Renal Insufficiency, Chronic/metabolism ; Reperfusion Injury/blood ; Reperfusion Injury/complications ; Signal Transduction/drug effects
Chemical Substances	Oxides ; Reactive Oxygen Species ; Nitric Oxide (31C4KY9ESH) ; Carbon (7440-44-0) ; AST 120 (90597-58-3) ; Indican (N187WK1Y1J)
Language	English
Publishing date	2022-02-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	2455981-7
ISSN	1942-0994 ; 1942-0994
ISSN (online)	1942-0994
ISSN	1942-0994
DOI	10.1155/2022/7547269
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Article ; Online: Preventive effects of nitrate-rich beetroot juice supplementation on monocrotaline-induced pulmonary hypertension in rats.

Masashi Tawa / Rikako Nagata / Yuiko Sumi / Keisuke Nakagawa / Tatsuya Sawano / Mamoru Ohkita / Yasuo Matsumura

PLoS ONE, Vol 16, Iss 4, p e

2021 Volume 0249816

Abstract	Beetroot (Beta vulgaris L.) has a high level of nitrate; therefore, its dietary intake could increase nitric oxide (NO) level in the body, possibly preventing the development of pulmonary hypertension (PH). In this study, we examined the effects of beetroot juice (BJ) supplementation on PH and the contribution of nitrate to such effects using a rat model of monocrotaline (MCT, 60 mg/kg s.c.)-induced PH. Rats were injected subcutaneously with saline or 60 mg/kg MCT and were sacrificed 28 days after the injection. In some rats injected with MCT, BJ was supplemented from the day of MCT injection to the day of sacrifice. First, MCT-induced right ventricular systolic pressure elevation, pulmonary arterial medial thickening and muscularization, and right ventricular hypertrophy were suppressed by supplementation with low-dose BJ (nitrate: 1.3 mmol/L) but not high-dose BJ (nitrate: 4.3 mmol/L). Of the plasma nitrite, nitrate, and their sum (NOx) levels, only the nitrate levels were found to be increased by the high-dose BJ supplementation. Second, in order to clarify the possible involvement of nitrate in the preventive effects of BJ on PH symptoms, the effects of nitrate-rich BJ (nitrate: 0.9 mmol/L) supplementation were compared with those of the nitrate-depleted BJ. While the former exerted preventive effects on PH symptoms, such effects were not observed in rats supplemented with nitrate-depleted BJ. Neither supplementation with nitrate-rich nor nitrate-depleted BJ affected plasma nitrite, nitrate, and NOx levels. These findings suggest that a suitable amount of BJ ingestion, which does not affect systemic NO levels, can prevent the development of PH in a nitrate-dependent manner. Therefore, BJ could be highly useful as a therapy in patients with PH.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2021-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article ; Online: Indoxyl sulfate induces ROS production via the aryl hydrocarbon receptor-NADPH oxidase pathway and inactivates NO in vascular tissues.

Nakagawa, Keisuke / Itoya, Mayuko / Takemoto, Nao / Matsuura, Yuika / Tawa, Masashi / Matsumura, Yasuo / Ohkita, Mamoru

Life sciences

2020 Volume 265, Page(s) 118807

Abstract: Aims: The uremic toxin indoxyl sulfate (IS) was reported to be the cause of cardiovascular disease associated with chronic kidney disease. Therefore, we evaluated the direct influences of IS on vascular function, focusing on the superoxide anion (O: ... ...

Abstract	Aims: The uremic toxin indoxyl sulfate (IS) was reported to be the cause of cardiovascular disease associated with chronic kidney disease. Therefore, we evaluated the direct influences of IS on vascular function, focusing on the superoxide anion (O Main methods: Isolated rat thoracic aortas with and without vascular endothelium were incubated with IS for 4 h in a physiological solution. In some experiments, several inhibitors were treated 30 min before the addition of IS. O Key findings: 1) Experiments using endothelium-intact vascular rings: IS significantly increased O Significance: This study suggested that IS causes O
MeSH term(s)	Acetylcholine/pharmacology ; Animals ; Aorta, Thoracic/metabolism ; Basic Helix-Loop-Helix Transcription Factors/metabolism ; Endothelium, Vascular/metabolism ; Indican/metabolism ; Male ; NADPH Oxidases/metabolism ; Nitric Oxide/metabolism ; Nitroprusside/pharmacology ; Rats ; Rats, Sprague-Dawley ; Reactive Oxygen Species/metabolism ; Receptors, Aryl Hydrocarbon/metabolism ; Superoxides/metabolism ; Vasodilator Agents/pharmacology
Chemical Substances	Ahr protein, rat ; Basic Helix-Loop-Helix Transcription Factors ; Reactive Oxygen Species ; Receptors, Aryl Hydrocarbon ; Vasodilator Agents ; Superoxides (11062-77-4) ; Nitroprusside (169D1260KM) ; Nitric Oxide (31C4KY9ESH) ; NADPH Oxidases (EC 1.6.3.-) ; Indican (N187WK1Y1J) ; Acetylcholine (N9YNS0M02X)
Language	English
Publishing date	2020-11-21
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/j.lfs.2020.118807
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Article: Indoxyl sulfate induces ROS production via the aryl hydrocarbon receptor-NADPH oxidase pathway and inactivates NO in vascular tissues

Nakagawa, Keisuke / Itoya, Mayuko / Takemoto, Nao / Matsuura, Yuika / Tawa, Masashi / Matsumura, Yasuo / Ohkita, Mamoru

Life sciences. 2021 Jan. 15, v. 265

2021

Abstract: The uremic toxin indoxyl sulfate (IS) was reported to be the cause of cardiovascular disease associated with chronic kidney disease. Therefore, we evaluated the direct influences of IS on vascular function, focusing on the superoxide anion (O₂⁻) and ... ...

Abstract	The uremic toxin indoxyl sulfate (IS) was reported to be the cause of cardiovascular disease associated with chronic kidney disease. Therefore, we evaluated the direct influences of IS on vascular function, focusing on the superoxide anion (O₂⁻) and nitric oxide (NO)/soluble guanylate cyclase (sGC) pathways.Isolated rat thoracic aortas with and without vascular endothelium were incubated with IS for 4 h in a physiological solution. In some experiments, several inhibitors were treated 30 min before the addition of IS. O₂⁻ production was measured by the chemiluminescence method, and the vascular reactivity to different vasorelaxants was examined using organ chamber technique.1) Experiments using endothelium-intact vascular rings: IS significantly increased O₂⁻ production. The increase was suppressed by addition of the NADPH oxidase inhibitor apocynin, the antioxidant ascorbic acid and the aryl hydrocarbon receptor (AhR) inhibitor CH223191. Furthermore, IS attenuated the acetylcholine (ACh)-induced vasorelaxantion, which was suppressed by addition of the above drugs. 2) Experiments using endothelium-denuded vascular rings: IS significantly increased O₂⁻ production and also attenuated sodium nitroprusside (SNP)-induced vasorelaxation. These influences of IS were normalized only by ascorbic acid addition. On the other hand, IS did not affect the vasorelaxation by the sGC stimulator BAY 41-2272.This study suggested that IS causes O₂⁻ production in vascular tissues, thereby attenuating ACh- and SNP-induced vasorelaxation, probably through NO inactivation. Furthermore, it is reasonable to consider that IS-promoted O₂⁻ production in the presence of vascular endothelium is through binding to AhR and the activation of NADPH oxidase.
Keywords	NAD(P)H oxidase (H2O2-forming) ; acetylcholine ; aryl hydrocarbon receptors ; ascorbic acid ; cardiovascular diseases ; chemiluminescence ; endothelium ; guanylate cyclase ; kidney diseases ; nitric oxide ; nitroprusside ; rats ; sulfates ; superoxide anion ; toxins ; vasodilation ; vasodilator agents
Language	English
Dates of publication	2021-0115
Publishing place	Elsevier Inc.
Document type	Article
Note	NAL-light
ZDB-ID	3378-9
ISSN	1879-0631 ; 0024-3205
ISSN (online)	1879-0631
ISSN	0024-3205
DOI	10.1016/j.lfs.2020.118807
Database	NAL-Catalogue (AGRICOLA)

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Article: α-Lipoic acid exerts a primary prevention for the cardiac dysfunction in aortocaval fistula-created rat hearts.

Kurumazuka, Daisuke / Kitada, Kento / Tanaka, Ryosuke / Mori, Tatsuhiko / Ohkita, Mamoru / Takaoka, Masanori / Matsumura, Yasuo

Heliyon

2019 Volume 5, Issue 8, Page(s) e02371

Abstract: Aim: α-Lipoic acid exerts a powerful antioxidant effect by acting as a free radical scavenger and inducing endogenous antioxidants such as vitamin E and glutathione. In the present study, we examined the effects of α-lipoic acid on cardiac dysfunction ... ...

Abstract	Aim: α-Lipoic acid exerts a powerful antioxidant effect by acting as a free radical scavenger and inducing endogenous antioxidants such as vitamin E and glutathione. In the present study, we examined the effects of α-lipoic acid on cardiac dysfunction in rat hearts with aortocaval fistulae. Main methods: Aortocaval fistulae were created between the abdominal aorta and inferior vena cava in male rats. Hemodynamic parameters were measured 14 days after surgery using an intravascular pressure transducer, and then these hearts were harvested for tissue weight measurement, pathological evaluation, and mRNA isolation. Results: In vehicle-treated rats, left ventricular end-diastolic pressure and left ventricular weight significantly increased at 14 days after fistula creation. Fistula-creation resulted in expression of 4-hydroxy-2-nonenal, NADPH oxidase subunit p67 Conclusions: Treatment with α-lipoic acid can prevent cardiac hyperplasia and dysfunction, probably by inhibiting superoxide production and enhancing BNP mRNA expression in an early phase after fistula creation.
Language	English
Publishing date	2019-08-28
Publishing country	England
Document type	Journal Article
ZDB-ID	2835763-2
ISSN	2405-8440
ISSN	2405-8440
DOI	10.1016/j.heliyon.2019.e02371
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