Summary
The successful introduction of angiotensin converting enzyme (ACE) inhibitors in the treatment of patients with essential hypertension or heart failure has increased interest in the (patho)physiological role of the renin-angiotensin system (RAS). ACE is not only involved in the formation of angiotensin II from angiotensin I, but also inactivates vasoactive substances such as bradykinin and substance P. Accumulation of these substances during treatment with ACE inhibitors may contribute to both their therapeutic action and certain adverse effects associated with their use, such as cough and angioneurotic oedema.
Renin inhibitors offer an alternative approach to inhibit the RAS. The major advantage of these, still experimental, drugs is their high specificity for the RAS since angiotensinogen is the only known substrate of renin. The currently available renin inhibitors are pseudopeptides that are rapidly taken up by the liver and excreted in the bile. Consequently, these drugs are subjected to a considerable first pass effect which limits their oral bioavailability. Additionally, plasma elimination half-life times are short and the duration of action is limited. Despite these shortcomings, single oral or intravenous administration results in a 80 to 90% inhibition of plasma renin activity and a slight reduction in blood pressure in patients with hypertension. The extent of blood pressure reduction is dependent on the patient’s salt balance.
After 1 week of oral treatment with the renin inhibitor remikiren, the antihypertensive effect was reduced in salt-repleted hypertensive patients. Subsequent intravenous administration of the drug did not further affect blood pressure, indicating that it was not the first pass effect that was limiting the efficacy of remikiren. The reactive increase in immunoreactive renin, alternative routes of angiotensin II formation and counteracting blood pressure regulating mechanisms may also be involved in the limited haemodynamic response to renin inhibitors.
Similar content being viewed by others
References
Campbell DJ. Chapter 23: metabolism of prorenin, renin, angiotenisogen, and angiotensins by tissues. In: Robertson JIS, Nicholls MG, editors. The renin-angiotenins system. London: Gower Medical Publishing, 1993; 1–23
Opsahl JA, Smith KL, Murray RD, et al. Renin and renin inhibition in anephric man. Clin Exp Hypertens 1993; 15: 289–306
Campbell DJ, Kladis A, Duncan AM. Nephrectomy, converting enzyme inhibition, and angiotensin peptides. Hypertension 1993; 22: 513–22
Kurtz A, Scholz H, Della Bruna R. Molecular mechanisms of renin release. J Cardiovasc Pharmacol 1990; 16 Suppl. 4: S1–S7
Stella A, Zanchetti A. Chapter 22: elimination of renin, prorenin, and angiotensins by the kidney: renin in urine. In: Robertson JIS, Nicholls MG, editors. The renin-angiotensin system. London: Gower Medical Publishing, 1993; 1–8
Page IH, McSwain B, Knapp GM, et al. The origin of renin activator. Am J Physiol 1941; 135: 214–22
Schneider EG, Rostorfer HH, Nash FD. Distribution volume and metabolic clearance rate of renin in anesthetized nephrectomized dogs. Am J Physiol 1968; 215: 1115–22
Campbell DJ, Kladis A, Skinner SL, et al. Characterization of angiotensin peptides in plasma of anephric man. J Hypertens 1991; 9: 265–74
Dzau V, Pratt RE. Cardiac, vascular, and intrarenal renin-angiotensin systems in normal physiology and disease. In: Robertson JIS, Nicholls MG, editors. The renin-angiotensin system. London: Gower Medical, 1993; 42: 1–11
Campbell DJ. The site of angiotensin production. J Hypertens 1990; 3: 199–207
Hirsch AT, Talsness CE, Schunkert H, et al. Tissue-specific activation of cardiac angiotensin converting enzyme in experimental heart failure. Circ Res 1991; 69: 475–82
Carretero OA, Scicli AG. Kinins paracrine hormone. Kidney International 1988; 34 Suppl. 26: S52-S59
Lindsey CJ, Bendhack LM, Paiva ACM. Effects of teprotide, captopril and enalaprilat on arterial wall kininase and angiotensin converting enzyme activity. J Hypertens 1987; 5 Suppl. 2: S71-S76
Marks ES, Bing RF, Thurston H, et al. Vasodepressor property of the converting enzyme inhibitor captopril (SQ 14 225): the role of factors other than renin-angiotensin blockade in the rat. Clin Sci 1980; 58: 1–6
Quilley J, Duchin KL, Hudes EM, et al. The antihypertensive effect of captopril in essential hypertension: relationship to prostaglandins and the kallikrein-kinin system. J Hypertens 1987; 5: 121–8
Vallance P, Collier J, Moncada S. Nitric oxide synthesised from L-arginine mediates endothelium dependent dilatation in human veins in vivo. Cardiovasc Res 1989; 23: 1053–7
Mitchell JA, Denucci G, Warner TD, et al. Different patterns of release of endothelium-derived relaxing factor and pro-stacyclin. Br J Pharmacol 1992; 105: 485–9
Radomski MW, Palmer RM, Moncada S. The anti-aggregating properties of vascular endothelium: interactions between pro-stacyclin and nitric oxide. Br J Pharmacol 1987; 92: 639–46
Cooke JP, Rossitch Jr E, Andon NA, et al. Flow activates an endothelial potassium channel to release an endogenous nitrovasodilator. J Clin Invest 1991; 88: 1663–71
The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325: 293–302
The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992; 327: 685–91
Zanchetti A. The clinical role of angiotensin converting enzyme inhibitors in antihypertensive therapy in the 1990s. J Hypertens 1989; 7 Suppl. 5: S37-S40
Hajjali AF, Wong PC. Beta-adrenoceptor blockade in rabbit inhibits the renin-releasing effect of AT(1)-receptor antagonist losartan. J Pharmacol Exp Ther 1993; 267: 1423–7
Kitami Y, Hiwada K, Murakami E, et al. The effect of the renin inhibitor ES-1005 on the expression of the kidney renin gene in sodium-depleted marmosets. J Hypertens 1990; 8: 1143–6
Corvol P, Menard J. Renin inhibition: immunological procedures and renin inhibitor peptides. Kidney Int 1988; 34 Suppl. 26: S73-S79
Burton J, Cody Jr RJ, Herd JA, et al. Specific inhibition of renin by an angiotensin analog: studies in sodium depletion and renin-dependent hypertension. Proc Natl Acad Sci USA 1980; 77: 5476–9
Gross F, Lazar J, Orth H. Inhibition of the renin-angiotensin reaction by pepstatin. Science 1972; 175: 656
Hui KY, Haber E. Chapter 85: renin inhibitors. In: Robertson JIS, Nicholls MG, editors. The renin-angiotensin system. London: Gower Medical, 1993; 1–14
Zusman RM, Burton J, Christensen D, et al. Hemodynamic effects of a competitive renin inhibitory peptide in humans: evidence for multiple mechanisms of action. Trans Assoc Am Physicians 1983; 96: 365–74
Webb DJ, Manhem PJ, Ball SG, et al. A study of the renin inhibitor H142 in man. J Hypertens 1985; 3: 653–8
van den Meiracker AH, Admiraal PJJ, Man in’t Veld AJ, et al. Prolonged blood pressure reduction by orally active renin inhibitor Ro 42-5892 in essential hypertension. BMJ 1990; 301: 205–10
Glassman HN, Kleinen HD, Boger RS, et al. Clinical pharmacology of enalkiren, a novel dipeptide renin inhibitor. J Cardiovasc Pharmacol 1990; 16 Suppl. 4: S76–S813
Kokubu T, Hiwada K, Murakami E, et al. ES-8891, an orally active inhibitor of human renin. Hypertension 1990; 15: 909–13
Nussberger J, Delabays A, de Gasparo M, et al. Hemodynamic and biochemical consequences of renin inhibition by infusion ofCGP38560A in normal volunteers. Hypertension 1989; 13: 948–53
Denolle T, Luo P, Guyene TT, et al. Acute effects of a pseudotetrapeptide as renin inhibitor on blood pressure and renin-angiotensin system of sodium-repleted and sodium-depleted hypertensive patients. Arzneimittelforschung 1993; 43: 255–9
Zusman RM, Hui KY, Nussberger J, et al. R-PEP-27, a potent renin inhibitor, decreases plasma angiotensin II and blood pressure in normal volunteers. Am J Hypertens 1994; 7: 295–301
Ogihara T, Nagano M, Higaki J, et al. Antihypertensive efficacy of FK906, a novel human renin inhibitor. Clin Ther 1993; 15: 539–48
Kleinbloessem CH, Weber C, Fahrner E, et al. Hemodynamics, biochemical effects, and pharmacokinetics of the renin inhibitor remikiren in healthy human subjects. Clin Pharmacol Ther 1993; 53: 585–92
Gupta SK, Granneman GR, Boger RS, et al. Simultaneous modeling of the pharmacokinetic and pharmacodynamic properties of enalkiren (Abbott-64662, a new renin inhibitor), I: Single dose study. Drug Metab Dispos Biol Fate Chem 1992; 20: 821–5
Gupta SK, Granneman GR, Packer M, et al. Simultaneous modeling of the pharmacokinetic and pharmacodynamic properties of enalkiren (Abbott-64662, a renin inhibitor), II: a dose-ranging study in patients with congestive heart failure. J Cardiovasc Pharmacol 1993; 21: 834–40
Kleinen HD, Rosenberg SH, Baker WR, et al. Discovery of a peptide-based renin inhibitor with oral bioavailability and efficacy. Science 1992; 257: 1940–3
Weber C, Birnbock H, Leube J, et al. Multiple dose pharmacokinetics and concentration effect relationship of the orally active renin inhibitor remikiren (Ro 42-5892) in hypertensive patients. Br J Clin Pharmacol 1993; 36: 547–54
Weber C, Roos B, Birnboeck H, et al. Effect of food on the oral bioavailability of the renin inhibitor remikiren (Ro 42-5892) [abstract]. Br J Clin Pharmacol 1993; 36: 177P-8P
de Gasparo M, Cumin F, Nussberger J, et al. Pharmacological investigations of a new renin inhibitor in normal sodium-unrestricted volunteers. Br J Clin Pharmacol 1989; 27: 587–96
Cumin F, Schnell C, Richert P, et al. Pharmacokinetics and tissue distribution of the renin inhibitor N-(2-(R)-benzyl-3-tert-buty l-sulfonyl-propionyl)-His-ChacVal-n-butylamine in marmosets. Drug Metab Dispos Biol Fate Chem 1990; 18: 831–5
Corvol P, Chauveau D, Jeunemaitre X, et al. Human renin inhibitor peptides. Hypertension 1990; 16: 1–11
Clozel JP, Fischli W. Comparative effects of three different potent renin inhibitors in primates. Hypertension 1993; 22: 9–17
Wood JM, Criscione L, de Gasparo M, et al. CGP 38 560: orally active, low molecular weight renin inhibitor with high potency and specificity. J Cardiovasc Pharmacol 1989; 14: 221–6
Clozel JP, Fischli W. Discovery of remikiren as the first orally active renin inhibitor. Arzneimittelforschung 1993; 43: 260–2
Ziegler K, Seeberger A. Hepatocellular uptake of peptides, I: Carrier-mediated uptake of hydrophilic linear peptides with renin inhibitory activity into isolated rat liver cells. Biochem Pharmacol 1993; 45: 909–16
Seeberger A, Ziegler K. Hepatocellular uptake of peptides, II: Interactions between hydrophilic linear renin-inhibiting peptides and transport systems for endogenous substrates in liver cells. Biochem Pharmacol 1993; 45: 917–25
Kleinert HD, Stein HH, Boyd S, et al. Discovery of a well-absorbed, efficacious renin inhibitor, A-74273. Hypertension 1992; 20: 768–75
Kararli TT, Needham TE, Griffin M, et al. Oral delivery of a renin inhibitor compound using emulsion formulations. Pharm Res 1992; 9: 888–93
Sheehy AM, Hoover JL, Rush BD, et al. Intrapulmonary delivery of renin inhibitory peptides results in sustained release because of saturable transport. Pharm Res 1993; 10: 1548–51
Doig JK, MacFadyen RJ, Meredith PA, et al. Neurohormonal and blood pressure responses to low-dose infusion of an orally active renin inhibitor, Ro 42-5892, in salt-replete men. J Cardiovasc Pharmacol 1992; 20: 875–80
van den Meiracker AH, Admiraal PJJ, Derkx FHM, et al. Comparison of blood pressure and angiotensin responses to the renin inhibitor Ro 42-5892 and the angiotensin converting enzyme inhibitor enalapril in essential hypertension. J Hypertens 1993; 11: 831–8
Rongen GA, Lenders JWM, Kleinbloesem CH, et al. Efficacy and tolerability of the renin inhibitor Ro 42-5892 in patients with hypertension. Clin Pharmacol Ther 1993; 54: 567–77
Kobrin I, Viskoper RJ, Laszt A, et al. Effects of an orally active renin inhibitor, Ro 42-5892, in patients with essential hypertension. Am J Hypertens 1993; 6: 349–56
Schalekamp MA, Derkx FH, van den Meiracker AH. Renin inhibitors, angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists: relationships between blood pressure responses and effects on the renin-angiotensin system. J Hypertens 1992; 10 Suppl.: S157–S164
Jeunemaitre X, Menard J, Nussberger J, et al. Plasma angiotensins, renin, and blood pressure during acute renin inhibition by CGP 38 560A in hypertensive patients. Am J Hypertens 1989; 2: 819–27
Menard J, Guyene T, Chatellier G, et al. Renin release regulation during acute renin inhibition in normal volunteers. Hypertension 1991; 18: 257–65
Camenzind E, Nussberger J, Juilerat L, et al. Effect of renin response during renin inhibition: oral Ro 42-5892 in normal humans. J Cardiovasc Pharmacol 1991; 18: 299–307
Ii Y, Murakami E, Hiwada K. Effect of renin inhibitor, ES-8891, on renal renin secretion and storage in the marmoset: comparison with captopril. J Hypertens 1991; 9: 1119–25
Murakami E, Kokubu T, Ii Y, et al. Effects of repeated oral administration of renin inhibitor ES-8891 on the renin-angiotensin system in human subjects. Hypertens Res 1992; 15: 41–4
Delabays A, Nussberger J, Porchet M, et al. Hemodynamic and humoral effects of the new renin inhibitor enalkiren in normal humans. Hypertension 1989; 13: 941–7
Weber MA, Neutel JM, Essinger I, et al. Assessment of renin dependency of hypertension with a dipeptide renin inhibitor. Circulation 1990; 81: 1768–74
van den Meiracker AH, Admiraal PJ, Man in’t Veld AJ, et al. Prolonged blood pressure reduction by orally active renin inhibitor RO 42-5892 in essential hypertension. BMJ 1990; 301: 205–10
Boger RS, Glassman HN, Cavanaugh JH, et al. Prolonged duration of blood pressure response to enalkiren, the novel dipeptide renin inhibitor, in essential hypertension. Hypertension 1990; 15: 835–40
Neuberg GW, Kukin ML, Penn J, et al. Hemodynamic effects of renin inhibition by enalkiren in chronic congestive heart failure. Am J Cardiol 1991; 67: 63–6
Morice AH, Lowry R, Brwon MJ, et al. ACE and the cough reflex. Lancet 1987; ii: 1116–8
Mento PF, Holt WF, Murphy WR, et al. Combined renin and converting enzyme inhibition in rats. Hypertension 1989; 13: 741–8
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Rongen, G.A., Lenders, J.W.M., Smits, P. et al. Clinical Pharmacokinetics and Efficacy of Renin Inhibitors. Clin-Pharmacokinet 29, 6–14 (1995). https://doi.org/10.2165/00003088-199529010-00002
Published:
Issue Date:
DOI: https://doi.org/10.2165/00003088-199529010-00002