An Orally Active Inhibitor of Human Renin, ES‐8891

Kokubu, Tatsuo; Hiwada, Kunio; Murakami, Eiki; Muneta, Shinjiro; Kitami, Yutaka; Oizumi, Kiyoshi; Takahagi, Hidekuni; Koike, Hiroyuki

doi:10.1111/j.1527-3466.1991.tb00543.x

Cited by 12 publications

(5 citation statements)

References 33 publications

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“…The same intracellular events occur during Ang II-induced constriction of other vascular smooth muscle cells. 22 Therefore, regulation of the renin-angiotensin system is such that decreased renin secretion accompanies Ang II-induced vasoconstriction and increased renin secretion accompanies vasodilation induced by 25 induce an increase in the plasma level of active renin, and the goal of our study was to investigate whether the fall in the plasma Ang II level entirely explained this rise in the plasma renin level.…”

Section: Discussionmentioning

confidence: 99%

Renin release regulation during acute renin inhibition in normal volunteers.

et al. 1991

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Blockade of the renin-angiotensin system by an angiotensin converting enzyme (ACE) inhibitor or an angiotensin II (Ang II) antagonist is accompanied by a reactive rise in renin release. This rise is generally attributed to interruption of the short feedback loop between Ang II and renin release. Similarly, after the administration of a renin inhibitor, the plasma concentrations of active and total renin are increased and plasma renin activity is suppressed. The aim of the present study was to investigate if a fall in the plasma Ang II level is the unique determinant of the rise in the active renin (AR) level that follows renin Inhibition. Six normal male volunteers participated in three successive 240-minute experiments at weekly intervals according to a single-blind randomized Latin square design. For experiment 1, Ang II was infused at 2 ng/kg/min from 0 to 60 minutes and at 4 ng/kg/min from 60 to 120 minutes. For experiment 2, 0.3 mg/kg of the new potent renin inhibitor Ro 42-5892 was injected at 30 minutes followed by infusion at 0.1 mg/kg/hr from 30 to 240 minutes. For experiment 3, Ang II and Ro 42-5892 were administered simultaneously at the same doses as described above. The mean±SEM Ang II concentration increased from 10.2±1.6 to 33.7±11.2 pg/ml after infusion of exogenous peptide. It decreased from 9.5±0.9 to 1.4±03 pg/ml after the injection of Ro 42-5892 and increased from 15.6±2.9 to 37.1 ±11.8 pg/ml after the simultaneous infusion of both compounds. At 120 minutes, Ang II infusion decreased the AR level from 30±5 to 12±4 pg/ml and Ro 42-5892 increased it from 28±4 to 209 ±40 pg/ml. After the combined infusion of Ang II and Ro 48-5892, the AR level rose by only 42% (from 22±4 to 38±5 pg/ml) and was still threefold higher than during the infusion of Ang II only. It is concluded that the exogenous infusion of an excess of Ang II minimizes but does not completely suppress the renin stimulation secondary to the administration of renin inhibitor. Although the fall in the plasma Ang II level appears to be a major stimulus of renin release, our results suggest that Ro 42-5892 may also have a direct intrarenal effect, possibly at the level of the juxtaglomerular cells, where renin and Ang II have been codetected and are locally produced.

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Section: Discussionmentioning

confidence: 99%

Renin release regulation during acute renin inhibition in normal volunteers.

et al. 1991

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“…These reduced angiotensin levels, lowered BP and had few significant adverse effects (23)(24)(25)(26)(27); however, low potency, poor bioavailability and short duration of action after oral administration prevented their practical use in hypertension (28). Aliskiren is the first in a new class of orally effective, nonpeptide, renin inhibitors for the treatment of hypertension (29,30).…”

Section: Introductionmentioning

confidence: 99%

Aliskiren, a Novel Oral Renin Inhibitor, Provides Dose-Dependent Efficacy and Placebo-Like Tolerability in Japanese Patients with Hypertension

Kushiro

Itakura²,

Abo³

et al. 2006

Hypertens Res

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“…39 The oral bioavailability of ES-8891 (240 mg) and FK 906 (400 mg) are very low, and plasma C max of 42.4 + 7.6 ng/mL and 167 ng/mL, respectively, are achieved. 42 …”

Section: Other Renin Inhibitorsmentioning

confidence: 97%

Direct Renin Inhibitors as Antihypertensive Agents

Israili

Velasco²,

Bermúdez³

2010

American Journal of Therapeutics

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Hypertension, a serious disease affecting almost a billion people (25% of adults) worldwide, is a major modifiable risk factor for cardiovascular (CV) and renal disease. Despite numerous advances in the pharmacologic treatment of high blood pressure (BP) and availability of several antihypertensive drugs to treat hypertension, a significant proportion of treated hypertensive patients still have uncontrolled high BP, and thus, face serious morbidity and mortality. Furthermore, it is not sufficient to aim for optimum BP control, but to treat all CV risk factors, protect end-organ damage, prevent progression of disease, and prevent long-range adverse effects of the drugs. Therefore, new therapeutic modalities have to be developed to achieve the above objectives. Some years ago, investigators identified renin inhibition as the preferred pharmacologic approach to blockade of the renin-angiotensin system. Renin is a monospecific enzyme that catalyzes the rate-limiting step in the synthesis of angiotensin II. Amplified enzymatic activity and additional physiologic effects occur when renin and prorenin bind to the (pro)renin receptor. Until very recently, development of clinically effective renin inhibitors remained elusive but molecular modeling was used to develop aliskiren and other renin inhibitors that produce sustained suppression of plasma renin activity after oral administration with a dose-dependent BP. Additional studies will ultimately determine the place of renin inhibition in the treatment of hypertension and related CV disorders.

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An Orally Active Inhibitor of Human Renin, ES‐8891

Cited by 12 publications

References 33 publications

Renin release regulation during acute renin inhibition in normal volunteers.

Renin release regulation during acute renin inhibition in normal volunteers.

Aliskiren, a Novel Oral Renin Inhibitor, Provides Dose-Dependent Efficacy and Placebo-Like Tolerability in Japanese Patients with Hypertension

Direct Renin Inhibitors as Antihypertensive Agents

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