Ebelactone B, an inhibitor of urinary carboxypeptidase Y-like kininase, prevents the development of deoxycorticosterone acetate-salt hypertension in rats

Murakami, Masataka; Ikeda, Yasuhiro; Kuribayashi, Yoshikazu; Mizogami, Susumu; Katori, Makoto; Aoyagi, Takaaki

doi:10.1016/0014-2999(95)00320-k

Cited by 20 publications

(27 citation statements)

References 30 publications

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“…Administration of ebelactone B to anesthetized rats caused diuresis and natriuresis in parallel with increased secretion of urinary kinin. This diuresis and natriuresis due to ebelactone B are blocked by the BK antagonist Hoe 140 (211). In DOCA-salt hypertension rats (185), subcutaneous infusion of lisinopril with a mini-osmotic pump for one week from 8 weeks of age does not reduce the systemic blood pressure, since renin has been suppressed in this model.…”

Section: Genetic Backgroundmentioning

confidence: 96%

“…The urinary so dium excretion of normal BN-Ki rats was increased and urine volume tended to be increased in the BN-Ki rats. Mutant kininogen-deficient BN-Ka rats rapidly developed hypertension on the same treatment, and their systemic blood pressure leveled off 2 weeks after the onset of the treatment (at 9 weeks of age), but neither ebelactone B nor lisinopril had any effect, since no kinin was generated in the urine (211). Poststatin, which is isolated from the fermentation broth of Streptomyces viridochromogens MH534-30F3, inhibits all kininase activity in rat urine (108).…”

Section: Genetic Backgroundmentioning

confidence: 99%

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Pivotal Role of Renal Kallikrein-Kinin System in the Development of Hypertension and Approaches to New Drugs Based on This Relationship

Katori

Murakami

1996

Japanese Journal of Pharmacology

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ABSTRACT-Renal kallikrein is one of the tissue kallikreins, and the distal nephron is fully equipped as an element of the kallikrein-kinin system. Although a low excretion of urinary kallikrein has been reported in essential hypertension, the results from studies on patients with hypertension are not consistent. Congeni tally hypertensive animals also excrete lowered levels of urinary kallikrein, but the effects of this are yet unknown. Extensive genetic and environmental studies on large Utah pedigrees suggest that the causes of hypertension are closely related to the combination of low kallikrein excretion and the potassium intake. Mutant kininogen-deficient Brown Norway-Katholiek rats, which cannot generate kinin in the urine, are very sensitive to salt loading and to sodium retention by aldosterone released by a non-pressor dose of angiotensin II, which results in hypertension. The major function of renal kallikrein-kinin system is to excrete sodium and water when excess sodium is present in the body. Failure of this function causes accumulation of sodium in the cerebrospinal fluid and erythrocytes, and probably in the vascular smooth muscle, which become sensitive to vasoconstrictors. We hypothesize that impaired function of the renal kallikrein-kinin system may play a pivotal role in the early development of hypertension. Inhibitors of kinin degradation in renal tubules and agents, which accelerate the secretion of urinary kallikrein from the con necting tubules and increase the generation of urinary kinin, may be novel drugs against hypertension.

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Section: Genetic Backgroundmentioning

confidence: 96%

Section: Genetic Backgroundmentioning

confidence: 99%

Pivotal Role of Renal Kallikrein-Kinin System in the Development of Hypertension and Approaches to New Drugs Based on This Relationship

Katori

Murakami

1996

Japanese Journal of Pharmacology

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“…We found two urinary kininase inhibitors, ebelactone B [41] and poststatin [42]. Ebelactone B was originally isolated from the culture medium of Actinomysetes as an esterase inhibitor [43].…”

Section: What Is the Renal Kallikrein-kinin System (Renal Kks)? Ismentioning

confidence: 99%

“…Ebelactone B exerts its inhibitory action on CPY in urine [41,48] and poststatin inhibits both CPY and NEP in urine [42]. Intra-duodenal administration of ebelactone B (3 mg/kg) to anesthetized rats caused marked diuresis (by 110%) and natriuresis (by 110%), in parallel with the increase in urinary kinin levels (by 110%).…”

Section: What Is the Renal Kallikrein-kinin System (Renal Kks)? Ismentioning

confidence: 99%

A Novel Category of Anti-Hypertensive Drugs for Treating Salt-Sensitive Hypertension on the Basis of a New Development Concept

Katori

Murakami

2010

Pharmaceuticals

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Terrestrial animals must conserve water and NaCl to survive dry environments. The kidney reabsorbs 95% of the sodium filtered from the glomeruli before sodium reaches the distal connecting tubules. Excess sodium intake requires the renal kallikrein-kinin system for additional excretion. Renal kallikrein is secreted from the distal connecting tubule cells of the kidney, and its substrates, low molecular kininogen, from the principal cells of the cortical collecting ducts (CD). Formed kinins inhibit reabsorption of NaCl through bradykinin (BK)-B2 receptors, localized along the CD. Degradation pathway of BK by kinin-destroying enzymes in urine differs completely from that in plasma, so that ACE inhibitors are ineffective. Urinary BK is destroyed mainly by a carboxypeptidase-Y-like exopeptidase (CPY) and partly by a neutral endopeptidase (NEP). Inhibitors of CPY and NEP, ebelactone B and poststatin, respectively, were found. Renal kallikrein secretion is accelerated by potassium and ATP-sensitive potassium (KATP) channel blockers, such as PNU-37883A. Ebelactone B prevents DOCA-salt hypertension in rats. Only high salt intake causes hypertension in animals deficient in BK-B2 receptors, tissue kallikrein, or kininogen. Hypertensive patients, and spontaneously hypertensive rats, excrete less kallikrein than normal subjects, irrespective of races, and become salt-sensitive. Ebelactone B, poststatin, and KATP channel blockers could become novel antihypertensive drugs by increase in urinary kinin levels. Roles of kinin in cardiovascular diseases were discussed.

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“…In this context, it may be important to note that while okadaic acid specifically inhibits the CML of PP2Ac by binding to its the C-terminal region, and thus preventing its methylation, the specificity of ebelactone to inhibit PP2Ac methylesterase, however, remains to verified. Ebelactone has also been shown to modulate other enzymes including prenyl cysteine methyl esterases [30], cathepsin A [31], urinary kinases [32], carboxypeptidaseY-like kininases [33], and lipases [34,35]. Future studies will need to develop specific inhibitors for PP2Ac demethylases which can be employed to further decipher roles for these signaling steps in physiological insulin secretion.…”

Section: Methylation Of C-terminal Leucine Of the Catalytic Subunit Omentioning

confidence: 99%

Bridging the gap between protein carboxyl methylation and phospholipid methylation to understand glucose-stimulated insulin secretion from the pancreatic β cell

Kowluru

2008

Biochemical Pharmacology

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Recent findings have implicated post-translational modifications at C-terminal cysteines [e.g., methylation] of specific proteins [e.g., G-proteins] in glucose-stimulated insulin secretion [GSIS]. Furthermore, methylation at the C-terminal leucine of the catalytic subunit of protein phosphatase 2A [PP2Ac] has also been shown to be relevant for GSIS. In addition to these two classes of protein methyl transferases, a novel class of glucose-activated phospholipid methyl transferases have also been identified in the β cell. These enzymes catalyze three successive methylations of phosphatidylethanolamine to yield phosphatidylcholine. The "newly-formed" phosphatidylcholine is felt to induce alterations in the membrane fluidity, which might favor vesicular fusion with the plasma membrane for the exocytosis of insulin. The objectives of this commentary are to: (i) review the existing evidence on the regulation, by glucose and other insulin secretagogues, of posttranslational carboxylmethylation [CML] of specific proteins in the β cell; (ii) discuss the experimental evidence, which implicates regulation, by glucose and other insulin secretagogues, of phosphatidylethanolamine methylation in the islet β cell; [iii] propose a model for potential crosstalk between the protein and lipid methylation pathways in the regulation of GSIS and (iv) highlight potential avenues for future research, including the development of specific pharmacological inhibitors to further decipher regulatory roles for these methylation reactions in islet β cell function.

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Ebelactone B, an inhibitor of urinary carboxypeptidase Y-like kininase, prevents the development of deoxycorticosterone acetate-salt hypertension in rats

Cited by 20 publications

References 30 publications

Pivotal Role of Renal Kallikrein-Kinin System in the Development of Hypertension and Approaches to New Drugs Based on This Relationship

Pivotal Role of Renal Kallikrein-Kinin System in the Development of Hypertension and Approaches to New Drugs Based on This Relationship

A Novel Category of Anti-Hypertensive Drugs for Treating Salt-Sensitive Hypertension on the Basis of a New Development Concept

Bridging the gap between protein carboxyl methylation and phospholipid methylation to understand glucose-stimulated insulin secretion from the pancreatic β cell

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