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(Hypertension. 1995;26:95-100.)
© 1995 American Heart Association, Inc.
Articles |
Effects of SC-56525, a Potent, Orally Active Renin Inhibitor, in Salt-Depleted and Renal Hypertensive Dogs
From GD Searle & Co, Skokie, Ill, and St Louis, Mo.
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Abstract |
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Abstract SC-56525 is a nanomolar inhibitor of plasma renin activity in human, cynomolgus monkey, dog, guinea pig, Yucatan micropig, and rabbit but is less active in rat. The oral bioavailability of SC-56525 in conscious dogs at doses of 5 mg/kg IV and 30 mg/kg PO was 66.1±16.4%. Oral dosing with SC-56525 at 3, 10, and 30 mg/kg in salt-depleted dogs induced a dose-dependent reduction in mean arterial pressure and inhibition of plasma renin activity with no significant effect on heart rate. In two-kidney, one clip renal hypertensive dogs, SC-56525 given orally at 10, 30, and 60 mg/kg daily for 4 days lowered blood pressure significantly. In conscious dogs monitored in their home cages via radiotelemetry, no significant changes in heart rate occurred in response to large drops in blood pressure in both renal hypertensive and salt-depleted dogs with the renin inhibitor SC-56525. SC-56525 is a nanomolar, orally active inhibitor of renin and effectively lowers blood pressure in both salt-depleted and renal hypertensive dogs.
Key Words: renin • sodium, dietary • hypertension, renovascular • dogs • renin-angiotensin system
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Introduction |
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Inhibition of the renin-angiotensin system with converting enzyme inhibitors is an established method of treating essential hypertension and congestive heart failure.1 2 The antihypertensive mechanism ultimately underlying converting enzyme inhibition is presumably prevention of the production of angiotensin II (Ang II).3 The conversion of angiotensinogen to Ang I by the enzyme renin is the rate-limiting step in Ang II production and is the only known function of renin, whereas angiotensin-converting enzyme (ACE) is known to act on a number of other biologically active peptides.4 Specifically, it has been proposed that the side effects that limit the clinical usefulness of the ACE inhibitors (cough and angioedema) are most likely due to the nonselective nature of ACE inhibition.5 Thus, inhibition of renin may lead to highly specific antihypertensive agents with an improved side effect profile compared with converting enzyme inhibitors.6
We have discovered a highly potent, selective, metabolically stable, and orally available inhibitor of renin (SC-56525) with high potency against dog renin compared with structurally similar inhibitors.7 This unique molecule enabled us to test the hypothesis that chronic renin inhibition would be efficacious in a renin-dependent model of hypertension, the two-kidney, one clip (2K1C) renal hypertensive dog.8 Although other researchers have shown that acute administration of an angiotensin type 1 receptor antagonist (SK&F 108566) and an ACE inhibitor (enalapril) lowers blood pressure (BP) when administered to renal hypertensive dogs,9 chronic dosing in this model has not been reported with any inhibitors of the renin-angiotensin system. Our results indicate that chronic renin inhibition with SC-56525 is highly effective in lowering BP in renal hypertensive dogs.
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Methods |
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In Vitro Pharmacology
Plasma Renin Inhibition Assay
The plasma renin inhibition assay was carried out in human, cynomolgus monkey, dog, guinea pig, Yucatan micropig, rabbit, and rat plasma. SC-56525 was synthesized according to methods described in detail elsewhere.10 Human plasma was collected from an ACE inhibitor user to provide plasma with elevated plasma renin activity (PRA). Cynomolgus monkey, dog, Yucatan pig, and guinea pig were treated with 5 mg/kg IV furosemide (Goldline Laboratories) 30 minutes before blood collection to boost basal PRA. Guinea pigs were anesthetized with isoflurane (Anaquest Inc) during blood collection. Rat plasma was collected from rats anesthetized with pentobarbital (Anpro Pharmaceutical). In a final volume of 0.1 mL, 12 mmol/L EDTA (Sigma Chemical Co), 1.6 mmol/L phenylmethylsulfonyl fluoride (Calbiochem), 4 mmol/L 8-hydroxyquinoline (Aldrich Chemical Co), 0.9 mg/mL bovine serum albumin (Sigma), 0.012 mg/mL neomycin sulfate (Sigma), 81 µL plasma, and 90 mmol/L Tris-acetate buffer (Sigma), pH 7.4, were incubated in the presence and absence of various concentrations of SC-56525 for 2 hours at 37°C. The reaction was terminated by placing the reaction mixture tubes in an ice bath. The amount of Ang I produced was determined by Ang I radioimmunoassay (DuPont-NEN). IC50 values were determined by logit-log analysis.
Protease Specificity
Cathepsin D inhibition was assessed with the method of Agarwal
and Rich.11 Briefly, 50 µL of 2 µmol/L bovine spleen
cathepsin D (Sigma) or human cathepsin D (Calbiochem) was preincubated
with 0.9 mL of 10 mmol/L formate (American Scientific Products) buffer,
pH 3.5, and 10 µL of various concentrations of SC-56525 in dimethyl
sulfoxide (Baxter Healthcare Co) for 5 minutes at 37°C. The reaction
was initiated by the addition of 40 µL of 2 mmol/L substrate
(Phe-Ala-Ala-p-nitro-Phe-Phe-Val-Leu 4-pyridylmethyl ester, Sigma), and
the reaction rate was measured spectrophotometrically at 310 nm for 4
minutes at 37°C with a spectrophotometer (UD 70, Beckman
Instruments).
Pepsin inhibition was assessed with the method of Agarwal and Rich11 with minor modifications. Briefly, 50 µL of 0.1 µmol/L porcine gastric mucosa pepsin (Sigma) was incubated with 0.93 mL of 10 mmol/L formate buffer, pH 3.5, and 10 µL of various concentrations of SC-56525 in dimethyl sulfoxide for 5 minutes at 21°C. The reaction was initiated by the addition of 10 µL of 10 nmol/L substrate (Leu-Ser-p-nitro-Phe-Nle-Ala-Leu methyl ester, Sigma),12 and the reaction rate was determined spectrophotometrically at 310 nm for 4 minutes at 21°C.
In Vivo Pharmacology
Bioavailability and Pharmacokinetics
Oral bioavailability was calculated from plasma concentrations
of SC-56525 measured after oral (30 mg/kg) and intravenous (5 mg/kg)
administration in fasted animals. SC-56525 was dissolved in
polyethylene glycol 400 (PEG 400, Aldrich Chemical Co) acidified with 4
µL of 1 mol/L citric acid per milligram of SC-56525 to a final pH of
3 to 4 for oral dosing and in saline acidified with citric acid for
intravenous dosing. Studies in conscious normotensive dogs were carried
out with a crossover design. Blood was sampled at various time points,
and plasma concentrations of SC-56525 were determined by a
high-performance liquid chromatography/mass spectrometry (HPLC-MS)
method. Briefly, plasma samples were treated with 0.05N NaOH and
extracted onto a 100-mg Bond Elut C18 SPE column (Varian) previously
activated with methanol and water. The column was washed with water,
and analytes were eluted with 1% formic acid in water. The eluant was
evaporated off under nitrogen. The dried extract was solubilized in
water/acetonitrile (3:1, by volume), filtered through a 0.2-µm
membrane, and injected into the HPLC-MS system. Liquid chromatographic
separation was performed with a 2-cm pKb-100 cartridge (Supelco) with a
mobile phase of water/acetonitrile/pyridine/formic acid
(645:350:2.5:2.5, by volume) at a flow rate of 1 mL/min. SC-56525
produced spectra with a base peak of m/z 647 responding to
the MH+ ion and a minor fragment ion
[(MH-H2O)+] at m/z 629.
Quantitation was performed by selected ion monitoring of the
m/z 647 ion and the corresponding MH+ ion of the
internal standard (m/z 636).
Oral bioavailability was calculated by integrating the area under the plasma concentration versus time curves of SC-56525 after oral or intravenous administration. Elimination half-life, distribution volume, and clearance rate were estimated from the plasma concentration of SC-56525 versus time after intravenous administration with the use of standard methods.13
Oral Dose-Response in Conscious Salt-Depleted Dogs
Female beagle dogs (8 to 12 kg; Ridglan Farms, Mt Holeb, Wis, or
Marshall Farms, New Rose, NY) were trained for handling and blood
sampling in their home cages. Two weeks after training was initiated,
the dogs were anesthetized with isoflurane, and a catheter connected to
a radiotelemetry BP transmitter (Mini-Mitter Co) was implanted in the
left femoral artery. The transmitter capsule was anchored
subcutaneously to the abdominal wall, and the incision was closed. The
right femoral artery was cannulated as described above for blood
sampling. Training of the dogs continued for 1 week after surgery, at
which time they were salt depleted by administration of a low salt diet
(Canine H/D diet, Hill's Pet Products) and furosemide treatment
(Lasix, 5 mg/kg IM on days 1, 3, and 5 after initiation of the low salt
diet).
One week after the first furosemide treatment, vehicle or SC-56525 (dissolved in PEG 400 and citric acid) at 3, 10, and 30 mg/kg was given orally in a gelatin capsule. A receiver (Data Sciences Inc) under each dog's cage was used to collect mean arterial pressure (MAP) and heart rate (HR) values every 5 minutes. A 486 computer (Compaq Computer Corp) was used to process the data with DATAQUEST IV 2.0 (Data Sciences Inc). One-hour averages of MAP and HR were calculated from 3 hours before to 24 hours after dosing. However, animal care workers entered the dog holding rooms between 7 to 8 AM to feed the dogs, and this intervention can result in artifactually high HR values; therefore, HR was analyzed only up to 19 hours after dosing.
Blood samples were collected via the femoral artery catheter in EDTA Vacutainers (Becton Dickinson) on the day before salt depletion, a few minutes before dosing, and at 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after dosing. PRA was determined by the method of Sealey and Laragh14 with minor modification. Briefly, 0.2 mL of plasma was incubated with 3 µL of 10% neomycin sulfate (Sigma), 3 µL of 0.5 mol/L 8-hydroxyquinolone (Aldrich Chemical Co), 1 µL of 5% phenylmethylsulfonyl fluoride (Calbiochem), and 20 µL of 0.5 mol/L TES buffer (Sigma), pH 7.4, at 37°C for 90 minutes. Ang I concentrations were determined by radioimmunoassay as described above. PRA was expressed as nanograms Ang I per milliliter of plasma per hour.
Oral Dose-Response in 2K1C Renal Hypertensive Dogs
Female beagle dogs (7 to 12 kg; Ridglan Farms, Mt Holeb,
Wis, or Marshall Farms, New Rose, NY) were implanted with
radiotelemetry transmitter units as described above. One week later,
the dogs were anesthetized with isoflurane, and under sterile
conditions a left flank incision was made and a 3-mm stainless steel
Goldblatt clamp (Keystone Automation Technology) was placed around the
left renal artery. When the clamp was tightened, blood flow was reduced
to 70% to 80% of control as measured by an electromagnetic flowmeter
with a 6- or 8-mm circumference probe (Carolina Medical Electronics).
If the decrease in blood flow was not maintained for at least 15
minutes, the clamp was further tightened until a stable reduction in
flow was obtained. The screw of the clamp was then secured with
cyanoacrylate glue, and the flank incision was closed. After recovery
from anesthesia, dogs were placed in their home cages with a receiver
under the cage for continuous monitoring of BP and HR. Cardiovascular
parameters were monitored every 5 minutes by the telemetry system from
24 hours before renal artery constriction to the end of the experiment.
One-hour averages of MAP and HR were calculated.
Before renal artery constriction, 3 mL of blood was collected for PRA determination as described above. This measurement was repeated 4 days after renal artery constriction. Dogs with MAP values less than 125 mm Hg when measured 5 days after renal artery constriction or dogs with PRA increases of less than twofold compared with preclip levels were excluded from the study. Use of these exclusion criteria eliminated 50% of the dogs undergoing left renal artery constriction.
Six days after renal artery constriction, vehicle (PEG 400) or SC-56525 (10, 30, or 60 mg/kg in PEG 400) was given orally in a gelatin capsule once a day (11 AM to noon) for 4 days. Six-hour averages of MAP and HR were calculated from 24 hours before dosing to 24 hours after the last dose. All procedures were performed in accordance with institutional guidelines for animal experimentation.
Statistical Analysis
All calculations were performed with the SAS statistical
analysis system (SAS Institute). Comparisons between the vehicle-
and drug-treated groups were performed with a repeated-measures ANOVA.
If the time-by-treatment interaction was found to be significant (using
the Huynh-Feldt adjustment of P value), follow-up
comparisons using individual two-sided Dunnett tests at the 5% level
of significance were conducted. For each experiment, different
individual dogs were used in each treatment group, with no crossover of
dogs to different treatments in any study.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In Vitro Activity
Fig 1 shows the structure of SC-56525. This molecule is similar in structure to other peptidomimetic transition-state analogues of angiotensinogen that have renin inhibitory activity,15 except that the imidazole moiety at the P2 position has been replaced with a propargyl group in SC-56525. The inhibitory potency of SC-56525 was tested against endogenous renin in the plasma from various species at pH 7.4. As shown in Table 1, all species tested except the rat showed significant inhibition of plasma renin at nanomolar concentrations of SC-56525. SC-56525 is exceptional in that this molecule possesses nanomolar inhibitory potency against human and dog renin, unlike structurally similar compounds described by other researchers.9 The specificity of SC-56525 for renin compared with other known aspartyl proteases was tested with the use of human recombinant renin, porcine pepsin, bovine, and human cathepsin D (Table 2). SC-56525 was approximately 100-fold and 1000-fold more potent as an inhibitor of renin compared with cathepsin D and pepsin, respectively.
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Bioavailability and Pharmacokinetics of SC-56525 in Dogs
Fig 2 shows plasma concentrations of SC-56525 in
dogs dosed with 30 mg/kg PO and 5 mg/kg IV. Oral bioavailability
estimated with these data was 66.1± 16.4%. The intravenous data shown
in Fig 2 were used to estimate the elimination half-life, distribution
volume, and clearance rate. These values for SC-56525 were 1.3±0.1
hours, 1.8±0.2 L/kg, and 1.0±0.1 L/kg per hour, respectively.
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) and 30 mg/kg PO (
) in
conscious normotensive dogs. Plasma concentrations of SC-56525 were
determined with high-performance liquid chromatography/mass
spectrometry. Symbols represent mean±SEM for seven dogs.
Effect of SC-56525 in Salt-Depleted Dogs
SC-56525 or placebo was given orally to salt-depleted dogs with
implanted radiotelemetry units for continuous recording of MAP and HR.
SC-56525 reduced MAP in a dose-dependent manner when administered at 3,
10, and 30 mg/kg, whereas dogs receiving placebo showed stable MAP over
the 24-hour period of measurement after dosing (Fig 3A).
The duration of MAP lowering at 10 and 30 mg/kg was 7 and 15 hours,
respectively. Despite large decreases in MAP, HR was not significantly
different in dogs receiving SC-56525 compared with placebo-treated dogs
(Fig 3B). Plasma samples taken from the dogs during the experiment were
used for measurement of PRA. PRA values in dogs before salt depletion
averaged 1.37±0.26 ng Ang I/mL plasma per hour (n=28) and after salt
depletion, 21.18±1.47 ng Ang I/mL per hour (n=28), an increase that is
similar to levels reported by others in salt-depleted
animals.7 Pretreatment PRA values were not significantly
different in the four groups of dogs and in dogs receiving placebo; PRA
remained relatively stable during the postdosing period (Fig 4). In contrast, PRA was significantly inhibited in a
dose-dependent manner in dogs receiving SC-56525. One hour after
dosing, PRA was 3.0±0.7, 0.6±0.2, and 0.1±0.1 ng Ang I/mL per hour
in the groups treated with 3, 10, and 30 mg/kg, respectively.
Twenty-four hours after dosing, PRA was still inhibited by 89%, 53%,
and 22% compared with predosing levels (17.5±2.3, 18.1±1.8, and
23.9±3.6 ng Ang I/mL per hour) in the groups treated with 3, 10, and
30 mg/kg, respectively.
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Effect of SC-56525 in 2K1C Renal Hypertensive Dogs
MAP and PRA were measured in dogs before clipping of the left
renal artery to produce hypertension. As shown in Table 3, PRA and MAP in dogs before clipping were not
significantly different among any of the groups. However, 4 days after
left renal artery constriction, PRA was increased significantly in all
groups. Five days after renal artery clipping, MAP was increased
substantially and similarly in all groups. Dogs were dosed with drug on
the sixth day after renal artery constriction at noon. As shown in Fig 5A, in dogs treated with placebo, MAP was relatively
stable over the 4 days of study, although a circadian pattern of lower
MAP at night was apparent. SC-56525 at 10, 30, and 60 mg/kg given once
a day at noon lowered MAP significantly. At the 60 mg/kg dose of
SC-56525, MAP was significantly reduced at all time points compared
with placebo-treated dogs. At 30 mg/kg, MAP was significantly decreased
for at least 12 hours each dose day. At 10 mg/kg, MAP was significantly
reduced at 6 and 12 hours after dosing, except for the third dose day,
when pressure stayed down for only 6 hours after dosing. HR in dogs
treated with SC-56525 was not significantly different from that in dogs
receiving placebo throughout the experiment (Fig 5B).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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SC-56525 has nanomolar potency against renin from all of the species tested except rat. Although a structurally similar analogue, A-72517, reported by Abbott Laboratories7 has similar potency against human renin (1.1 nmol/L) compared with SC-56525 (1.2 nmol/L), SC-56525 is substantially more potent against nonprimate renin (110 nmol/L for A-72517 against dog renin compared with 4.6 nmol/L for SC-56525; 120 nmol/L for A-72517 against rabbit renin compared with 1.62 nmol/L for SC-56525). Interestingly, the two compounds are chemically identical except for the functional group at the P2 position of the molecule, with A-72517 having a thiazole in that position and SC-56525 a propargyl moiety. This modification in SC-56525, which imparts good potency against dog renin, coupled with high oral bioavailability in dog enabled us to examine the role of renin inhibition in both salt-depleted and hypertensive dog models at reasonable doses. These aspects of SC-56525 make data interpretation from such studies more meaningful and directly comparable to ACE inhibitor and Ang II receptor antagonist studies in these models.
In addition to a difference in species specificity, a second difference in activity is apparent when comparing A-72517 with SC-56525. As reported by Rosenberg et al,16 A-72517 is at least 1000-fold more selective for renin compared with other aspartyl proteases, cathepsin D, or pepsin. In contrast, SC-56525 is substantially more potent against pepsin and cathepsin D, although at least a 100-fold selectivity for renin was still achieved. These results suggest that the presence of the propargyl group at P2 in SC-56525 enhances potency against other aspartyl proteases, especially cathepsin D.
In salt-depleted dogs, SC-56525 induced a maximal fall in BP to approximately 60 mm Hg after administration at 30 mg/kg. A clear dissociation between BP responses and PRA inhibition was noted in our study that has been described previously by others.17 18 19 20 This dissociation was clearly evident in the salt-depleted dog, in which a substantial inhibition of PRA was observed with 3 mg/kg SC-56525, but no significant fall in MAP was noted at this dose. At 10 and 30 mg/kg, BP was not significantly lowered until PRA was suppressed by more than 85%. Although somewhat controversial, a possible explanation for this phenomenon is that inhibition of a "tissue" or "extraplasmatic" renin-angiotensin system is involved in the MAP-lowering effect of renin inhibitors and other inhibitors of the renin-angiotensin system. This explanation is supported by the observation that ACE inhibitors are effective at lowering BP in hypertensive animal models and humans when PRA is normal or subnormal.21 22 In addition, when SC-56525 is administered to normotensive, salt-replete dogs at doses comparable to those used in the present study, no significant BP reduction is observed (unpublished observations, 1993). However, an alternative explanation might also be reasonable, such as inhibition of the renin-angiotensin system in the brain.
In previous reports, renin inhibitors have been shown to lower MAP substantially in salt-depleted animals without any significant reflex tachycardia, although in previous work animals were restrained and basal HR values were elevated somewhat by the stress associated with restraint. Our study is the first to measure MAP and HR responses by the radiotelemetry method in salt-depleted dogs freely moving in their home cages. Under these conditions, we observed no increase in HR, even with reductions in MAP down to 60 mm Hg with SC-56525. This lack of reflex tachycardia associated with inhibition of the renin-angiotensin system is believed to be due to the removal of Ang II potentiation of baroreflexes although direct evidence for this is lacking.
Renal artery constriction in the dog results in renin-dependent hypertension, although the renin dependency of the hypertension is transient and often variable.8 23 We chose to test our renin inhibitor in this model from 6 to 10 days after renal artery constriction, a period during which both PRA and MAP are substantially elevated and reasonably stable.24 In the present study, we used a telemetry device to monitor BP and HR continuously at 5-minute intervals throughout the dosing period with the dogs freely moving in their home cages. Observations from the vehicle-treated group indicate that a prominent circadian pattern of BP variation is present in the 2K1C hypertensive dogs that is similar to the profile in hypertensive patients.25 BP was highest in the morning and reached its nadir each night. SC-56525 produced a significant fall in BP in the hypertensive dogs that is most likely due to inhibition of the renin-angiotensin system since we have found that Ang II receptor antagonists produce a similar maximal fall in BP in this model.26
In conclusion, SC-56525 is a potent, orally active inhibitor of renin in the dog. SC-56525 reduces BP in the salt-depleted dog and in renal hypertensive dogs dosed chronically over 4 days. In conscious dogs monitored in their home cages via radiotelemetry, no significant changes in HR occur in response to large drops in BP in both renal hypertensive and salt-depleted dogs with the renin inhibitor SC-56525. SC-56525 is a nanomolar inhibitor of human renin and is therefore likely to be a potent, long-acting antihypertensive in humans although clinical testing of the compound is required to confirm this.
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Acknowledgments |
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We thank Kathryn Houseman for conducting the pepsin and cathepsin D assays and Jim Ottinger for the assay of SC-56525 in plasma. We also thank Devan Mehrotra and Richard Bittman for statistical analyses, and Robert Manning and Richard Gorczynski for their support of this work.
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Footnotes |
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Reprint requests to Ellen G. McMahon, PhD, Cardiovascular Diseases Research, GD Searle & Co, T1G, 800 N Lindbergh Blvd, St Louis, MO 63167.
Received October 10, 1994; first decision November 4, 1994; accepted March 3, 1995.
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