Renin Inhibitory Effect of N-Acetyl-Pepstatin

Miyazaki, Mizuo; Okunishi, Hideki; Komori, Tadamitsu; Yamamoto, Kenjiro

doi:10.1254/jjp.28.171

Cited by 13 publications

(3 citation statements)

References 10 publications

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“…Thus, the inhibitory action of Af-acetylpepstatin on renin in the vascular wall may, at least in part, contribute to its antihypertensive action. 7 The mechanism of the hypotensive effects of ACE inhibitors has been explained by their suppression of the circulating RAS. However, accumulating evidence has indicated that the consequent decrease in circulating level of plasma Ang II is probably not the sole mechanism involved.…”

Section: Resultsmentioning

confidence: 99%

Renin inhibitor and converting enzyme inhibitors suppress vascular angiotensin II.

et al. 1989

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The direct effects of a renin inhibitor, W-acetyl-pepstatin and five angiotensin converting enzyme inhibitors, captopril and the active diacid forms of enalapril, ramipril, cilazapril, and CS-622, on the vascular renin-angiotensin system were examined in isolated perfused rat mesenteric arteries. Vascular renin activity and angiotensin II (Ang II) released into the perfusate were determined. Infusion of iV-acetyl-pepstatin (5xl0~8-5xl0~6 M) suppressed vascular renin activity and Ang II release dose dependently. Isoproterenol (10~6 M) induced a 135±30% increase in Ang II release from the basal value. A'-Acetyl-pepstatin (5xiO~6 M) suppressed isoproterenol-induced Ang II release. Infusions of 5xlO~6 M captopril and the diacid forms of enalapril, ramipril, cilazapril, and CS-622 by themselves had little effect on Ang II release, but concomitant infusion of isoproterenol with these angiotensin converting enzyme inhibitors significantly decreased Ang II release (71 ±21%, 51±40%, 8±21%, 69±24%, and 44±29% increase, respectively, from the basal values). These results indicate that iV-acetyl-pepstatin suppresses the vascular renin-angiotensin system. This effect may in part contribute to the hypotensive actions of renin inhibitors. Although angiotensin converting enzyme inhibitors also suppress locally generated Ang II, the mechanism and physiological significance still remain to be clarified. (Hypertension 1989;13:749-753) A ngiotensin II (Ang II), which is a final vasoactive peptide of the renin-angiotensin system (RAS), is known to be important in regulation of blood pressure and in control of water and salt metabolism. Recently, various angiotensin converting enzyme (ACE) inhibitors and renin inhibitors have been developed. The therapeutic goal of ACE inhibitors and renin inhibitors in treatment of high blood pressure is to down-regulate the RAS by reducing Ang II production.Recent biochemical and molecular biological studies have indicated that essential components of the RAS are present in vascular tissue independently of classical circulating RAS. 1 -4 In previous work, we detected a small measurable amount of Ang II in the perfusate from rat mesenteric arteries and found that locally generated Ang II is released by /3-adrenergic receptor activation and may regulate vascular tone directly by inducing contraction of Address for correspondence: Toshio Ogihara, MD, Department of Geriatric Medicine, Osaka University Medical School, 1-1-50, Fukushima-ku, Osaka 553, Japan. vascular smooth muscle or indirectly by augmenting sympathetic nerve activity. 5Several investigations have shown that the hypotensive mechanism of ACE inhibitors and renin inhibitors may be mediated not only through suppression of the circulating RAS but also by suppression of the tissue RAS, including the vascular RAS. However, there is little direct evidence for the interaction between these inhibitors and the vascular RAS. In the present study, we compared the direct acute effects of a renin inhibitor, Nacetyl-pepstatin and five different ACE in...

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Section: Resultsmentioning

confidence: 99%

Renin inhibitor and converting enzyme inhibitors suppress vascular angiotensin II.

et al. 1989

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“…This work was difficult to reproduce, probably because of the insolubility of the peptide, 37 -38 and did not lead to the widespread adoption of pepstatin in physiologic experiments. Improvements in solubility, first by acetylation of pepstatin 39 and then by the substitution of hydrophilic amino acids at the carboxy terminus of the molecule, 40 yielded more convincing results. Although pepstatin derivatives may eventually prove to be adequate in vivo renin inhibitors, their use as investigative agents is limited conceptually by their lack of specificity for renin.…”

Section: Pepstatin and Its Congenersmentioning

confidence: 99%

Is renin a factor in the etiology of essential hypertension?

Haber¹,

Zusman²,

Burton³

et al. 1983

Hypertension

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The widespread clinical study of converting-enzyme inhibitors has shown that they are effective antihypertensive drugs even in patients who may manifest either normal or decreased plasma renin activity. This suggests either that renin in a site other than plasma may play a contributory role in essential hypertension or that the hypotensive effect is caused by increased concentrations of kinins and prostaglandins, both demonstrated consequences of converting-enzyme inhibitor administration. Specific renin inhibitors appropriate for studies in humans would aid in the resolution of this question. Four classes of compounds have been demonstrated to be renin inhibitors of high potency: specific antibody, general peptide inhibitors of acid proteases, analogs of angiotensinogens, and peptides that are related to the amino-terminal sequence of prorenin. With the purification of renin, specific polyclonal or monoclonal antibodies have become available. The former have already been used extensively in physiologic studies in intact animals. Pepstatin is an inhibitor of many acid proteases. Its in vivo application has been retarded by its relative insolubility, but recent chemical modifications, particularly the addition of charged amino acids at the carboxy terminus, have rendered it more useful. The minimal substrate for renin is an octapeptide segment of the protein substrate: His-Pro- Phe-His-Leu-Leu-Val-Tyr. Variants of this sequence have resulted in competitive inhibitors that are useful in vivo. Recently, remarkably active inhibitors have been synthesized by reducing the peptide bond that is cleaved by renin, producing what may be a transition state inhibitor. Several of these peptides have been shown to be effective as in vivo inhibitors of the hypertensive effect of the enzyme. The development of inhibitors based on prorenin sequences is awaited with interest. Substrate analog inhibitors have now been studied in dogs and monkeys, and, most recently, preliminary studies have been reported in humans. A hypotensive response has been demonstrated in sodium-replete, normal human subjects as well as in a low-renin hypertensive subject. The mechanism of this unexpected finding needs to be explained. (Hypertension 5 (supp V): V-8-V-15, 1983) KEY WORDS • renin essential hypertension converting enzyme * peptide inhibitors • pepstatinC ARDIOVASCULAR disease remains the principal cause of death in developed countries, and hypertension is one of the major risk factors leading to its development. 1 It is now well accepted that the treatment of hypertension results in reduced cardiovascular mortality and morbidity. 2 " 9 More than 95% of all patients with high blood pressure are classified as having "essential hypertension," a symptom complex without known cause. Thus, treatment, while effective, is directed at a manifestation of one or more disease processes rather than at the cause. When treatment is stopped, hypertension recurs in most instances. This leads to a curious paradox: patients must

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“…Since that time, we have focused our attention on the development of a synthetic renin inhibitor and showed that phosphatidyl and phosphorylethanolamine deriva tives (7,8) and N-acetyl-pepstatin (9) inhibited the renin activity and lowered the blood pressure in hypertensive animals. Unfortunately, the potencies of these compounds were not high enough to inhibit human renin.…”

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confidence: 99%

KRI-1314: An Orally Effective Inhibitor of Human Renin

Etoh

Miyazaki

Shinmoto

et al. 1993

Japanese Journal of Pharmacology

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ABSTRACT-Biochemicaland pharmacological properties of KRI-1314, a newly synthesized, low molecular weight (M.W.: 690) renin inhibitor, were investigated in vitro and in vivo. The novel amino acid norstatine, which is shorter in chain length than the well-known statine, was incorporated into KRI-1314 as a tetrahedral transition-state analogue for the Leu10-Val" scissile peptide in the renin substrate. KRI-1314 more strongly inhibited plasma renins from primates than those from dogs, rabbits, guinea pigs and rats. KRI-1314 competitively inhibited highly-purified human renin with a K; value of 9.9 x 10-10 M. KRI-1314 strongly inhibited the tissue renin-like activities of various organs from Japanese monkeys, with IC50 values on the order of 10-8 M. KRI-1314 was also very stable in various tissue homogenates from Japanese mon keys. Both intravenous (from 0.25 to 3 mg/kg) and oral (10 and 30 mg/kg) administration of KRI-1314 to anesthetized and conscious sodium-depleted Japanese monkeys, respectively, significantly lowered the blood pressure and plasma renin activity without affecting the heart rate. In Japanese monkeys, KRI-1314 was continuously detected in the plasma up to at least 7 hr after oral administration of 10 and 30 mg/kg. These results demonstrate that KRI-1314 is a highly potent, primate-selective and long-lasting oral renin in hibitor with a blood pressure lowering effect.

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Renin Inhibitory Effect of N-Acetyl-Pepstatin

Cited by 13 publications

References 10 publications

Renin inhibitor and converting enzyme inhibitors suppress vascular angiotensin II.

Renin inhibitor and converting enzyme inhibitors suppress vascular angiotensin II.

Is renin a factor in the etiology of essential hypertension?

KRI-1314: An Orally Effective Inhibitor of Human Renin

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