H-77: a potent new renin inhibitor. In vitro and in vivo studies.

Szelke, M.; Leckie, Brenda J.; Tree, M; Brown, Anthony R.; Grant, J. K.; Hallett, Allan; Hughes, M; Jones, D.; Lever, A. F.

doi:10.1161/01.hyp.4.3_pt_2.59

Cited by 8 publications

(9 citation statements)

References 5 publications

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“…Kallikrein, a serine protease, known to convert inactive prorenin into active renin (Sealey et al, 1980;Carretero & Beierwaltes, 1984), produced a marked and concentration-dependent shift to the left of the response curve to angiotensinogen, suggesting the existence of an inactive, but activatable form of renin in the vascular wall of porcine intrarenal arteries. This was supported by the observation that the renin inhibitor H-77 (Szelke et al, 1982), tended to attenuate contractile responses to angiotensinogen in the presence of kallikrein, i.e., after activation of tissue renin, but not in the absence of the reninactivator. However, though blockade of angiotensin converting enzyme with enalaprilic acid effectively attenuated responses to angiotensin I, the same treatment produced no substantial inhibition of the angiotensinogen effects.…”

Section: Discussionmentioning

confidence: 78%

Pharmacological evidence for the existence of a local renin‐angiotensin system in porcine interlobar renal arteries

Müller‐Schweinitzer

Olea-Baza

1990

British J Pharmacology

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1 Changes in tension in response to cumulative additons of angiotensins (i.e., angiotensinogen, angiotensin I and angiotensin II), bradykinin and acetylcholine were monitored isometrically on ring preparations from porcine interlobar renal arteries. 2 Angiotensins consistently elicited contractile responses, whereas both bradykinin and acetylcholine produced relaxation of the arterial rings when active tone was induced by prostaglandin F2a.3 Contractile responses to angiotensin II could be completely blocked by the combined action of the cyclo-oxygenase inhibitor, indomethacin (1 ,IM) and the lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA, 10pM). 4 Relaxant responses to bradykinin were unchanged during blockade of thromboxane A2 synthesis by dazoxiben (30juM) and proved to be largely resistant to blockade by indomethacin (1 gM) and the prostaglandin 12 (prostacyclin) synthesis inhibitor, tranylcypromine (40pM). 5 The angiotensin receptor blocker, saralasin (10 and 100 nM) antagonized responses to angiotensinogen, angiotensin I and angiotensin II effectively and with similar potency. Enalaprilic acid, the active metabolite of the converting enzyme inhibitor enalapril (300nM), attenuated responses to angiotensin I but failed to inhibit those to angiotensinogen up to 1 pm. The serine protease kallikrein (0.001 to 1 u ml 1) produced a dose-dependent shift to the left of the concentration-response curve for angiotensinogen. 6 It is suggested that the porcine interlobar renal artery possesses a local renin-angiotensin system with activatable angiotensin II forming enzyme(s) within the vessel wall.

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Section: Discussionmentioning

confidence: 78%

Pharmacological evidence for the existence of a local renin‐angiotensin system in porcine interlobar renal arteries

Müller‐Schweinitzer

Olea-Baza

1990

British J Pharmacology

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“…Similarly, H-77 and SCRIP lower blood pressure during intravenous infusion in sodium-depleted dogs and blood pressure recovers within minutes after stopping the infusion. 9 ' l0 The structural feature of CGP 29 287 that appears to be responsible for its increased half-life in vivo is the protection groups at both terminals. CGP 29 291, a renin inhibitor with the same structure as CGP 29 287 but without protection groups, has a much shorter duration of action.…”

Section: Effects In Untreated and Nephrectomized Marmosetsmentioning

confidence: 99%

“…They lower blood pressure during intravenous infusion, and blood pressure recovers within minutes after stopping an infusion. 9 " 12 The present study characterizes the in vitro and in vivo properties of CGP 29 287 (Figure 1), a potent and specific renin inhibitor with a prolonged duration of action. CGP 29 287 is an analogue of the amino acid sequence around the cleavage site of human angiotensinogen.…”

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confidence: 91%

“…6 This has been achieved by replacing the dipeptide that contains the scissile bond of angiotensinogen with structures that resemble its configuration after activation for cleavage by renin. 78 Potent inhibitors of renin, such as H-77, 9 H-142, 7 and statinecontaining renin inhibitory peptide (SCRIP), 10 have been developed by this approach. However, all of these inhibitors have a very short biological half-life.…”

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confidence: 99%

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Effects of a specific and long-acting renin inhibitor in the marmoset.

Wood¹,

Gulati²,

Forgiarini³

et al. 1985

Hypertension

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SUMMARY Inhibition of renin was induced in conscious marmosets with CGP 29 287, Z-Arg-ArgPro-Phe-His-Sta-Ile-Hls-Lys (Boc)-OMe, a renin inhibitor with a prolonged duration of action. In vitro, CGP 29 287 is a potent inhibitor of primate plasma renin (inhibitory concentration, 50%: human = 1 x 10"'M; marmoset = 5 x 10"'M) and less potent against dog (2 x 10~7M)orrat(3 x 10~5 M) plasma renin. CGP 29 287 is a weak inhibitor of other aspartic proteases such as porcine pepsin or bovine cathepsin D (inhibitory concentration, 50% = 4 x 10~5 M). In furosemide-treated marmosets, CGP 29 287 lowered blood pressure and inhibited plasma renin activity during intravenous infusion and after intravenous bolus injection. The duration of action after intravenous injection was dose dependent and ranged from 1 hour after 0.1 mg/kg to more than 3 hours after 10 mg/kg. High doses of CGP 29 287 (100 mg/kg) were active after oral administration. In all experiments a close relation between inhibition of plasma renin activity and reduction of blood pressure was found. A maximum hypotensive response to CGP 29 287 was associated with complete inhibition of plasma renin activity, and the recovery of blood pressure was accompanied by recovery of plasma renin activity. The hypotensive effects of CGP 29 287 were smaller in untreated than in furosemide-treated marmosets. CGP 29 287 had no influence on blood pressure in marmosets after bilateral nephrectomy or after pretreatment with a converting enzyme inhibitor. CGP 29 287 did not affect the pressor responses to exogenous angiotensin I or angiotensin II. These results indicate that CGP 29 287 is a potent and specific inhibitor of primate renin. In furosemide-treated marmosets CGP 29 287 induced a long-lasting reduction in blood pressure that appears to be entirely due to inhibition of renin. (Hypertension 7: 797-803, 1985) KEY WORDS • renin activity converting enzyme inhibitor furosemide • cathepsin D • pepsin • statine T HE renin-angiotensin system (RAS) plays an important role in blood pressure regulation. This finding has led to considerable interest in compounds that inhibit renin, the enzyme that catalyzes the first step in the formation of the biologically active peptide angiotensin II (ANG II).1 -2 One of the first described inhibitors of renin was pepstatin, a peptide of fungal origin.3 The poor solubility, low potency, and lack of specificity of pepstatin restricted its experimental application in vivo. Subsequently, analogues of the amino acid sequence around the cleavage site of angiotensinogen were shown to inhibit renin. However, these compounds were of limited usefulness for studies in vivo because of their low potency and short biological half-life. Recently, more potent ana-

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“…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).…”

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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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H-77: a potent new renin inhibitor. In vitro and in vivo studies.

Cited by 8 publications

References 5 publications

Pharmacological evidence for the existence of a local renin‐angiotensin system in porcine interlobar renal arteries

Pharmacological evidence for the existence of a local renin‐angiotensin system in porcine interlobar renal arteries

Effects of a specific and long-acting renin inhibitor in the marmoset.

Highly potent and specific inhibitors of human renin.

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