No Evidence for the Existence of a Species-Specific Renin Substrate in Plasma from Normal and Bilaterally Nephrectomized Rats*

Hiwada, Kunio; Tanaka, Hiroko; Murakami, Eiki; Ono, Mototane; Kokubu, Tatsuo

doi:10.1210/endo-105-3-818

Cited by 9 publications

(5 citation statements)

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“…Renin substrate contents in the perfusate were estimated as the amounts of angiotensin I generated after incubation of the supernatant fraction with an excess of rat renin (Hiwada, Tanaka, Murakami, Ono & Kokubu, 1979). The angiotensin I thus formed was measured by radioimmunoassay (Menard & Catt, 1972).…”

Section: Methodsmentioning

confidence: 99%

Effects of Insulin and Glucagon on Production of Renin Substrate by the Isolated Rat Liver

Murakami¹,

Hiwada²,

Kokubu³

1980

Journal of Endocrinology

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An isolated rat liver perfusion system was used to study the effects of insulin and glucagon on renin substrate production. Normal livers synthesized renin substrate at a rate of 28.3 +/- 3.8 (S.E.M.) ng angiotensin I equiv./g liver each h (n = 8). The addition of insulin (more than 0.1 i.u.) to the perfusion significantly enhanced the production of renin substrate which was about twofold higher than normal control values (P less than 0.001). However, glucagon (20 micrograms) did not affect the synthesis of renin substrate. These results indicated that insulin promoted the synthesis of renin substrate by the isolated rat liver.

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Section: Methodsmentioning

confidence: 99%

Effects of Insulin and Glucagon on Production of Renin Substrate by the Isolated Rat Liver

Murakami¹,

Hiwada²,

Kokubu³

1980

Journal of Endocrinology

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“…In groups (l), (2) and (3), plasma renin substrate concentration was measured by radioimmunoassay for ANG I as reported previously (Hiwada, Tanaka, Murakami, Ono & Kokubu, 1979). …”

Section: Methodsmentioning

confidence: 99%

Effects of Prostaglandins on Renin Substrate Production by the Liver

1980

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1. The effects of prostaglandin (PG) E1, PGE2 and PGF2 alpha on plasma renin substrate concentration in rats and renin substrate production by perfused rat liver were investigated. 2. After bilateral nephrectomy, both plasma renin substrate concentration and renin substrate production were remarkably elevated. 3. The increase in plasma renin substrate level and production of renin substrate by the liver after nephrectomy was markedly suppressed by the treatment with PGE1 or PGE2. 4. In contrast PGF2 alpha had no suppressive effect on renin substrate synthesis. 5. These findings suggest that PGE1 and PGE2 might be inhibitory factors in the regulation of renin substrate synthesis.

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“…Monkey, pig, goat, dog, rabbit, and rat renins, which were prepared by the method described previously, 17 were further purified by gel filtration on Ultrogel AcA 44 (LKB, Bromma, Sweden).…”

Section: -9mentioning

confidence: 99%

Highly potent and specific inhibitors of human renin.

Kokubu¹,

Hiwada²,

Murakami³

et al. 1985

Hypertension

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SUMMARY Small peptide analogues representing the C-terminal portion of angiotensin I sequence were designed as inhibitors of human renin. Among synthesized compounds, benzyloxycarbonyl (-"Z")-O-naphthyl)Ala-His-leucinal (ES-188), Z-(l-naphthyl)Ala-His-statine ethyl ester (ES-226), and Z-(l-naphthyl)Ala-His-statine 2-methylbutylamide (ES-254) markedly inhibited human and primate renins (inhibitory concentration, 50% [IC50], near 10~7 M). These peptide analogues inhibited rabbit renin with one or two orders of magnitude less potency. They were very weak inhibitors of renins from pig, goat, dog, and rat. ES-188 had no discernible effect on cathepsin D, pepsin, or human angiotensin-converting enzyme at the concentration of 10" 4 M. ES-226 had little effect on the three enzymes at the concentration of 10"' M; however, ES-254 had a considerable inhibitory effect on cathepsin D(ICJO of 1.4 x 10" 5 M), pepsin (IC^ of 4.2 x 10" 5 M), and human angiotensin-converting enzyme (ICso of 7.1 x 10" 6 M). Our results indicate that 1-naphthylalanine-containing tripeptide analogues are highly potent human renin inhibitors. (Hypertension 7[Suppl I]: 1-8- [1][2][3][4][5][6][7][8][9][10][11] 1985) KEY WORDS • tripeptide analogues • 1-naphthylalanine • statine R ENIN (EC 3.4.23 15) acts on a protein substrate, angiotensinogen, to release the hemo-. dynamically inactive angiotensin I (ANG I). The ANG I subsequently is converted to the potent pressor peptide angiotensin II (ANG II) by angiotensin-converting enzyme (ACE; EC 3.4.15 1). The development of orally active ACE inhibitors 1 ' 2 and the clear demonstration of their efficacy as antihypertensive drugs in patients with remn-dependent hypertension and essential hypertension 3 " 3 have evoked the interest in the development of potent renin inhibitors that are orally active.In 1968 we reported that methyl or ethyl ester of a tetrapeptide (Leu-Leu-Val-Tyr) in the sequence of equine angiotensinogen acted as a competitive inhibitor of rabbit renin.6 But the inhibitor constant was only in the millimolar range. To develop more potent inhibitors of renin, many analogues of a large segment of renin substrate subsequently have been synthesized, 7 " 10 and inhibitory potency has been improved by replacing the peptide bond (-CO-NH-) at the cleavage site of renin with a reduced bond (-CH 2 -NH-).'' These compounds also have shown a high degree of species specificity.12 Boger and colleagues' 3 tried another approach, incorporating statine into peptide analogues of angiotensinogen. Unfortunately, none of these substrate analogues are orally active.In our preliminary report, 14 we synthesized small peptides in the ANG I sequence, with leucinal at the C terminus, and showed that benzyloxycarbonyl(-"Z")-Phe-His-leucinal and its derivatives were potent inhibitors of human renin in vitro. In this study we report in vitro experiments with derivatives of Z-Phe-Hisleucinal and with new small peptide analogues containing statine that are highly potent and species-specific inhibitors of human renin. were...

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No Evidence for the Existence of a Species-Specific Renin Substrate in Plasma from Normal and Bilaterally Nephrectomized Rats*

Cited by 9 publications

References 0 publications

Effects of Insulin and Glucagon on Production of Renin Substrate by the Isolated Rat Liver

Effects of Insulin and Glucagon on Production of Renin Substrate by the Isolated Rat Liver

Effects of Prostaglandins on Renin Substrate Production by the Liver

Highly potent and specific inhibitors of human renin.

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