Objectives Aliskiren is a new renin inhibitor of a novel structural class that has recently been shown to be efficacious in hypertensive patients after once-daily oral dosing. We report the results of animal experiments performed in marmosets and rats in order to characterize aliskiren before its recent investigation in humans. Methods The effects of aliskiren were investigated in sodium-depleted marmosets (oral dosing) and in spontaneously hypertensive rats (dosing via subcutaneous osmotic minipumps). Blood pressure (BP) and heart rate were measured by radiotelemetry. Results In sodium-depleted marmosets, single oral doses of aliskiren (1-30 mg/kg) dose-dependently lowered BP. At a dose of 3 mg/kg, peak effects were observed 1 h after dosing (-30 +/- 4 mmHg, n = 6) and the response persisted for more than 12 h. A single oral dose of 3 mg/kg aliskiren was more effective than the same dose of either remikiren or zankiren, two orally active renin inhibitors previously tested in humans. Aliskiren (10 mg/kg) was at least as effective as equal doses of the AT1-receptor blocker valsartan or the angiotensin-converting enzyme inhibitor benazepril. In spontaneously hypertensive rats, aliskiren dose-dependently (10-100 mg/kg per day) decreased BP. Aliskiren also potentiated the antihypertensive effects of low doses of valsartan or benazeprilat (1 or 3 mg/kg per day). Conclusions Aliskiren is an orally effective, long-lasting renin inhibitor that shows antihypertensive efficacy in animals superior to previous renin inhibitors and at least equivalent to angiotensin-converting enzyme inhibitors and AT1-receptor blockers. Aliskiren may therefore represent an effective, novel approach to the treatment of hypertension and related disorders, alone or in combination with other antihypertensive agents.

Aliskiren, a novel, orally effective renin inhibitor, lowers blood pressure in marmosets and spontaneously hypertensive rats.

The renin–angiotensin system (RAS) plays an important role in the development of cardiovascular diseases such as hypertension and heart failure. Inhibitors of renin (EC 3.4.99.19) block the RAS at its first and rate-limiting step and may therefore offer major potential benefits in blood pressure control. Despite intensive research, however, previous attempts to develop clinically useful renin inhibitors have failed. This review discusses recent patent applications for the development of two novel classes of non-peptide renin inhibitors: 3-alkoxy-4-aryl-piperidines, such as Ro 66-1132 (Hoffmann-La Roche), and alkanecarboxamides, such as aliskiren (SPP-100; Novartis). Both classes are effective in animal models, while results from studies in humans suggest that aliskiren may represent the first in a new class of orally-effective renin inhibitors. Patents claiming the use of renin inhibitors in combination therapy are also discussed.

Renin inhibitors as novel treatments for cardiovascular disease

Objective To investigate the chronic effects of combined administration of an angiotensin II receptor antagonist (valsartan) and an angiotensin converting enzyme inhibitor (benazeprilat) on blood pressure and heart rate in conscious telemetered spontaneously hypertensive rats. Methods Blood pressure and heart rate were monitored (by radiotelemetry) during 2-week infusions of 0.5–10 mg/kg valsartan per day and 0.5–10 mg/kg benazeprilat per day, alone or in combination, into conscious spontaneously hypertensive rats. Also, responses of blood pressure in conscious spontaneously hypertensive rats to exogenous angiotensin I and II were determined. Results Synergistic antihypertensive effects were observed when valsartan and benazeprilat were coadministered at submaximal monotherapy doses in the range 0.5–1.5 mg/kg per day. For all combination groups, the area over the curve (mmHg × days) for lowering of blood pressure was significantly greater (synergy) than that predicted from the sum of the monotherapy responses. Combination therapy abrogated pressor responses to angiotensin I more effectively than did comparable doses of the monotherapies. Conclusions These results demonstrate that combination therapy aimed at interrupting operation of the renin–angiotensin system simultaneously at multiple sites can prevent the partial escape which occurs during chronic angiotensin converting enzyme inhibitor monotherapy. Furthermore, multiple-site intervention results in a more efficacious antihypertensive response than that achieved with high doses of the individual monotherapies.

Synergistic effects of combined converting enzyme inhibition and angiotensin II antagonism on blood pressure in conscious telemetered spontaneously hypertensive rats.

Background. Remikiren is an orally active renin inhibitor with established antihypertensive efficacy. As a single dose it induces renal vasodilatation, suggesting specific renal actions. Data on the renal effects of continued treatment by renin inhibition are not available, either in subjects with normal, or in subjects with impaired renal function. Methods. The effect of 8 days of treatment with remikiren 600 mg o.i.d. on blood pressure, renal haemodynamics, and proteinuria was studied in 14 hypertensive patients with normal or impaired renal function. The study was conducted on an ambulatory in-hospital basis and was designed in a single-blind, longitudinal order. Results. Remikiren induced a significant peak fall in mean arterial pressure of 11.2 +/- 0.8%, with corresponding trough values of -6 +/- 0.8%. This fall was somewhat more pronounced in the patients with renal function impairment (-13.3 vs -9.6%; P <0.01). Glomerular filtration rate remained stable, whereas effective renal plasma flow increased from 301 +/- 35 to 330 +/- 36 ml/min/1.73 m(2) (P <0.05). Filtration fraction and renal vascular resistance fell by 10 +/- 2% and 15 +/- 2% respectively (both P <0.01). Remikiren induced a cumulated sodium loss of -82 +/- 22 mmol and a positive potassium balance of 49 +/- 9 mmol (both P <0.01). During remikiren, proteinuria fell by 27% (range -18 to -38%; P <0.01) in the patients with overt proteinuria at onset (n = 6). In the remainder of the patients albuminuria fell by 20% (range -1 to -61%, P <0.05). No side-effects were observed. Conclusions. Continued treatment with remikiren induced a sustained fall in blood pressure, renal vasodilatation, negative sodium balance, and a reduction in glomerular protein leakage. These data are consistent with a renoprotective potential of renin inhibition.

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Renal and systemic effects of continued treatment with renin inhibitor remikiren in hypertensive patients with normal and impaired renal function

Effects of doxazosin on serum lipids: a review of the clinical data and molecular basis for altered lipid metabolism.

The effects of coadministration of a renin inhibitor, CP-80,794, and an angiotensin converting enzyme inhibitor, captopril, on blood pressure of sodium-depleted guinea pigs was studied. Dose-response curves for CP-80,794 (0.3-3.0 mg/kg i.v.) and captopril (0.03-1.0 mg/kg i.v.) were obtained either alone or in the presence of a submaximal dose of the other inhibitor. The hypotensive response calculated for each compound individually was subtracted from the combined dose response. The results showed that statistically significant synergy with captopril and CP-80,794 occurred when the area rather than the peak drop or duration of change in blood pressure was measured. The degree of the synergy indicated that to achieve the same reduction in blood pressure, the dose of each drug, below the high end of its response range, could be decreased approximately sixfold when administered in combination. It was determined that the plasma pharmacokinetics of CP-80,794 were not altered during coadministration, as plasma concentrations of CP-80,794 were similar in the presence and absence of 0.1 mg/kg i.v. of captopril. These results indicate that by inhibiting sequential enzymes in the renin-angiotensin system, synergistic effects can be produced. The relative safety of each inhibitor could be improved by large reductions in dose when used concurrently.

Synergistic effect on reduction in blood pressure with coadministration of the renin inhibitor, CP-80,794, and the angiotensin converting enzyme inhibitor, captopril.

This invention relates of the use of a certain thiazolidine-2,4-dione, namely, dl-5-[(2-benzyl-3,4-dihydro-2H-benzopyran-6-yl)methyl]thiazolidine-2,4-dione, or a pharmaceutically acceptable cationic salt thereof, for retarding the development of arterial disease in mammals. More specifically, it relates to a method for reducing the serum cholesterol levels in mammals by administering to said mammals dl-5-[(2-benzyl-3,4-dihydro-2H-benzopyran-6-yl)methyl]-thiazolidine-2,4-dione or a pharmaceutically acceptable cationic salt thereof.

dl-5-[(2-benzyl-3,4-dihydro-2H-benzopyran-6-yl)methyl]thiazolidine-2,4-dione as an anti-atherosclerosis agent

Prazosin or doxazosin, selective alpha 1-adrenergic receptor inhibitors used in the treatment of hypertension, are known from clinical studies to lower plasma lipids. When diets and dosing regimens are carefully controlled, both agents produce similar effects on plasma lipids in rats, i.e., decreases in triglycerides and in the non-high density lipoprotein (non-HDL) fraction of cholesterol. In order to conduct these studies, models of rats partially fasting (PF) and eating a high-sucrose diet were developed. The effects of prazosin 2.3 mg/kg/day and doxazosin 20 mg/kg/day on plasma levels of triglycerides, total and HDL cholesterol, free fatty acids (FFA), ketones, and other metabolites were measured in rats in the fed, fasting, or PF states, at various times after a meal, and with a high-cholesterol diet. The pattern of responses leads to the hypothesis that, under conditions of partial or complete fasting, alpha 1-adrenergic receptor inhibition can alter intrahepatic FFA metabolism, causing increased ketogenesis and diminished triglyceride synthesis, possibly through potentiation of beta-adrenergic or related pathways. If these concepts prove to be valid in humans, they suggest that factors such as the rate of very-low-density lipoprotein (VLDL) production or the state of sympathetic nervous activity may influence the changes in lipids induced by these agents.

Effects of alpha 1-inhibition on lipid metabolism in the rat.

Plasma cholesterol levels are markedly reduced when doxazosin, a selective α1-adrenoceptor inhibitor, is administered for several days to C57BR/cdJ mice that have been fed a high cholesterol diet. This system affords a useful model for investigating the mechanism by which selective α1-adrenoceptor inhibitors decrease circulating lipid levels. The results indirectly suggest that hypercholesterolemia induced by dietary cholesterol may involve activation of the sympathetic nervous system. The basis for linkage between circulating cholesterol levels and sympathetic nervous activity, while not yet understood, may involve changes in the balance among cholesterol pathways in the liver, alteration of vasomotor tone and control of the activity of vascular endothelial upases. An additive effect is described for cholestyramine and doxazosin, in which low density lipoprotein cholesterol is decreased by 76% by a combination of maximal doses of the 2 agents.

Effects of doxazosin on diet-induced hypercholesterolemia in C57BR/cdJ mice

Doxazosin, a selective inhibitor of alpha 1-adrenergic receptors, when administered alone or in combination with insulin or glucagon to mature ob/ob mice, consistently lowered levels of triglycerides, cholesterol, glycerol, and lactate and increased levels of beta-hydroxybutyrate and glucose. Doxazosin suppressed the tendency of insulin to elevate triglycerides but had no effect on the hypoglycemic response to insulin. Doxazosin and insulin together (but neither alone) lowered free fatty acids (FFA). Glucagon lowered cholesterol and raised glucose but did not affect triglycerides or beta-hydroxybutyrate. Analysis of variance indicates that a simple additive-effects model cannot explain the interactions between doxazosin and insulin on triglycerides, glucose, and FFA. It is suggested that the alpha 1-adrenergic system may contribute to glycemic control and to ambient hypercholesterolemia, especially in the presence of insulin resistance, as in ob/ob mice, and that the hypolipidemic response to alpha 1-adrenergic inhibition may involve insulin pathways.

Archie C. Swindell

Papers

Synergistic effect on reduction in blood pressure with coadministration of the renin inhibitor, CP-80,794, and the angiotensin converting enzyme inhibitor, captopril.

dl-5-[(2-benzyl-3,4-dihydro-2H-benzopyran-6-yl)methyl]thiazolidine-2,4-dione as an anti-atherosclerosis agent

Effects of alpha 1-inhibition on lipid metabolism in the rat.

Effects of doxazosin on diet-induced hypercholesterolemia in C57BR/cdJ mice

Interactions of doxazosin with insulin or glucagon in the ob/ob mouse.