Effects of renin inhibition in the conscious primate Macaca fascicularis.

Hui, Kwan Y.; Knight, Delvin R.; Nussberger, Jürg; Hartley, L H; Vatner, Stephen F.; Haber, Edgar

doi:10.1161/01.hyp.14.5.480

Cited by 6 publications

(3 citation statements)

References 27 publications

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“…Each ICX value is the average of at least three experiments. We observed a similar effect in our primate study of a potent human renin inhibitor (30). 200 See footnote to Table 2 In vivo canine study The in vitro inhibition assays showed that compounds 9 and 15 were the most potent canine plasma renin inhibitors, with Ic50 values of 0.96 and 1.7 nM, respectively, when assayed at neutral pH.…”

Section: Ac Pafsupporting

confidence: 63%

“…Thesc results suggest that during sodium deficiency PRA is directly responsible for the support of MAP and that angiotensin I1 makes an important contribution to the maintenance of arterial pressure (30,37). Thesc results suggest that during sodium deficiency PRA is directly responsible for the support of MAP and that angiotensin I1 makes an important contribution to the maintenance of arterial pressure (30,37).…”

Section: Ac Pafmentioning

confidence: 95%

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Design of potent substrate‐analogue inhibitors of canine renin

Hui

Siragy

Haber

1992

International Journal of Peptide and Protein Research

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Through a systematic study of structure-activity relationships, we designed potent renin inhibitors for use in dog models. In assays against dog plasma renin at neutral pH, we found that, as in previous studies of rat renin inhibitors, the structure at the P2 position appears to be important for potency. The substitution of Val for His at this position increases potency by one order of magnitude. At the P3 position, potency appears to depend on a hydrophobic side chain that does not necessarily have to be aromatic. Our results also support the approach of optimizing potency in a renin inhibitor by introducing a moiety that promotes aqueous solubility (an amino group) at the C-terminus of the substrate analogue. In the design of potent dog plasma renin inhibitors, the influence of the transition-state residue 4(S)-amino-3(S)-hydroxy-5-cyclohexylpentanoic acid (ACHPA) -commonly used as a substitute for the scissile-bond dipeptide to boost potencyis not obvious, and appears to be sequence dependent. The canine renin inhibitor Ac-paF-Pro-Phe-Val-statine-Leu-Phe-paF-NH2 (compound 15; ICso of 1.7 nM against dog plasma renin at pH 7.4; statine, 4(S)-amino-3(S)hydroxy-6-methylheptanoic acid; paF, para-aminophenylalanine) had a potent hypotensive effect when infused intravenously into conscious, sodium-depleted, norrnotensive dogs. Also, compound 15 concurrently inhibited plasma renin activity and had a profound diuretic effect.

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Section: Ac Pafsupporting

confidence: 63%

Section: Ac Pafmentioning

confidence: 95%

Design of potent substrate‐analogue inhibitors of canine renin

Hui

Siragy

Haber

1992

International Journal of Peptide and Protein Research

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“…The primate (i.e., cynomolgus monkey) represents an important animal model for the in vivo testing of human renin inhibitors, largely because of the similarity between primate and human renin (Cumin et al 1987;Hui et al 1989;Panek et al 1991;Jauch 1997). Given the logistics of handling larger primates, their limited access, and the amounts of compound required for in vivo testing, emphasis has been put on finding easily accessible smaller animal models for biological evaluation of human renin inhibitors.…”

Section: Introductionmentioning

confidence: 99%

The human renin infused rat: use as an in vivo model for the biological evaluation of human renin inhibitors

Bolger¹,

Vigeant²,

Liard³

et al. 1999

Can. J. Physiol. Pharmacol.

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The human renin infused rat model (HRIRM) was used as an in vivo small-animal model for evaluating the efficacy of a collection of inhibitors of human renin. The intravenous infusion of recombinant human renin (2.4 microg x kg(-1) x min(-1)) in the ganglion-blocked, nephrectomized rat produced a mean blood pressor response of 47+/-3 mm Hg (1 mm Hg = 133.3 Pa), which was reduced by captopril, enalkiren, and losartan in a dose-dependent manner following oral administration, with ED50 values of 0.3+/-0.1, 2.5+/-0.9, and 5.2+/-1.6 mg/kg, respectively. A series of peptidomimetic P2-P3 butanediamide renin inhibitors inhibited purified recombinant human renin in vitro in a concentration-dependent manner, with IC50 values ranging from 0.4 to 20 nM at pH 6.0, with a higher range of IC50 values (0.8-80 nM) observed at pH 7.4. Following i.v. administration of renin inhibitors, the pressor response to infused human renin in the HRIRM was inhibited in a dose-dependent manner, with ED50 values ranging from 4 to 600 microg/kg. The in vivo inhibition of human renin following i.v. administration in the rat correlated significantly better with the in vitro inhibition of human renin at pH 7.4 (r = 0.8) compared with pH 6.0 (r = 0.5). Oral administration of renin inhibitors also resulted in a dose-dependent inhibition of the pressor response to infused human renin, with ED50 values ranging from 0.4 to 6.0 mg/kg and the identification of six renin inhibitors with an oral potency of <1 mg/kg. The ED50 of renin inhibitors for inhibition of angiotensin I formation in vivo was highly correlated (r = 0.9) with the ED50 for inhibition of the pressor response. These results demonstrate the high potency, dose dependence, and availability following oral administration of the butanediamide series of renin inhibitors.

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Renin Inhibitors

Nussberger¹

2005

Hypertension

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Effects of renin inhibition in the conscious primate Macaca fascicularis.

Cited by 6 publications

References 27 publications

Design of potent substrate‐analogue inhibitors of canine renin

Design of potent substrate‐analogue inhibitors of canine renin

The human renin infused rat: use as an in vivo model for the biological evaluation of human renin inhibitors

Renin Inhibitors

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