It is well known that the major pharmacologic actions of angiotensin II, such as contraction of vascular smooth muscle, aldosterone release from the adrenal gland, and cell proliferation and hypertrophy of cardiovascular tissues, are mediated by the AT1 subtype (1,2). Therefore angiotensin II-receptor antagonists with selectivity for the AT1 subtype are considered to be useful for the treatment of patients with hypertension accompanying cardiac hypertrophy and vascular thickening. Since the discovery of losartan, the first drug developed and marketed as an AT1-receptor antagonist (3-5), a growing number of angiotensin-receptor antagonists have been introduced. Numerous studies reported that losartan is an orally active competitive angiotensin II-receptor antagonist with selectivity for AT1 subtype in animals (6,7) and humans (8,9). Losartan and its metabolite EXP3174 were reported to antagonize angiotensin II in different ways, showing surmountable and insurmountable antagonism, respectively (5,10).
SK-1080 (KR-31080; 2-butyl-5-methyl-6-(1-oxopyridin-2-yl)-3-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-3H-imidazo[4,5-b] pyridine), synthesized at the Korea Research Institute of Chemical Technology (KRICT, Taejon, Korea), belongs to a novel class of nonpeptide angiotensin II-receptor antagonists with a high affinity for AT1 receptors. SK-1080 was shown to act by itself but not via its metabolites (data not shown) to exert a potent insurmountable antagonism against contractile and pressor responses to angiotensin II in the isolated aorta and pithed rats (10a). On the other hand, SK-1080 interacted with human recombinant AT1 receptor in a competitive manner, as with losartan rats (unpublished data). In our study, we examined the pharmacologic profile of SK-1080 in conscious normotensive (angiotensin II challenged), conscious renally (RHRs) and spontaneously (SHRs) hypertensive rats, and conscious furosemide-treated dogs.
Effects in conscious angiotensin II-challenged normotensive rats
This study conformed with the Guide for the Care and Use of Laboratory Animals, published by the U.S. National Institutes of Health. Male Sprague-Dawley rats (300-350 g, KRICT) were used in this study, and the arterial blood pressure was measured as previously described (11). Under ketamine anesthesia (125 mg/kg, i.p.), the polyethylene (PE-50) catheter connected to PE-10 catheter filled with heparinized saline solution (20 IU/ml) was inserted into the femoral artery and vein for recording arterial blood pressure and intravenous drug administration, respectively. The free end of catheters closed with a metal plug was passed through a subcutaneous tunnel to be exposed and fixed at the dorsal skin of the neck. The animals were allowed 1 day to recover and stabilize in individual cages. On the day of the experiment, rats were kept moving free in individual cages in a quiet room, and the arterial catheter was connected to a Isotec pressure transducer (Healthdyne, Marietta, GA, U.S.A.) coupled to a Graphtec Linearcorder (model 3310; Graphtec Corp., Tokyo, Japan). Arterial blood pressure was continuously recorded during the whole experiment. After the arterial blood pressure and heart rate (HR) were stabilized, angiotensin II (0.1 μg/kg/250 μl) was intravenously administered twice at 20-min intervals to establish a reproducible control angiotensin II pressure response. After each injection, the catheter was flushed with 0.2 ml saline. Each rat was then treated with a single oral dose of SK-1080 (0.3, 1, 3 mg/kg), losartan (0.1, 0.3, 1, 3 mg/kg), or vehicle (5% Tween 80, 2 ml/kg). After oral administration of test compound, angiotensin II was subsequently injected at 30-min intervals for 2 h and then at 1-h intervals for the next 6 h. Angiotensin II challenges also were repeated 24 h after oral administration. Results were expressed as percentage inhibition from control responses. The ID50 values of compounds, doses that inhibited the maximal angiotensin II-induced pressor response by 50%, were determined by linear regression of log dose-response data.
Antihypertensive effects in conscious RHRs and SHRs
Male SHRs (12-14 weeks, Charles River, Yokohama, Japan) and RHRs were used. For preparing RHRs, the left renal artery of Sprague-Dawley rats (300-350 g, KRICT) was completely ligated under ketamine (125 mg/kg, i.p.) anesthesia (12,13). They were fed normal diet and water ad libitum for 1 week in plastic cages in rooms maintained on 12-h light/dark cycles. To measure the arterial blood pressure from RHRs and SHRs, the animals were prepared as described earlier and kept moving free in individual cages in a quiet room on the day of the experiment. Then the arterial catheter was connected to a pressure transducer (CDX-III; Modular Instruments, Malvern, PA, U.S.A.) coupled to a physiograph (Modular 8000 Signal processor, Modular Instruments), and HR was derived from the blood pressure pulse, both parameters being analyzed and stored by Biowindow program (Modular Instruments). Arterial blood pressure and HR were monitored for 6 h after single intravenous administration of SK-1080 (0.03, 0.06, 0.1, and 0.3 mg/kg) and single oral administration of SK-1080 (3, 6, 10 mg/kg) and losartan (3 and 10 mg/kg) in RHRs, and single oral administration of SK-1080 (10 and 30 mg/kg) in SHRs. In RHRs, arterial blood pressure and HR also were measured 24 h after oral administration. Results were expressed as percentage change from control mean arterial pressure (MAP) and HR, respectively. The ED20 values of compounds, doses that decreased the maximal MAP by 20%, were obtained from linear regression of log dose-response data.
Effects of repeated oral dosing in SHRs
The effects of repeated administration of SK-1080 on blood pressure and HR were studied in male SHRs (16 weeks, Charles River). SKP-450 (10 and 30 mg/kg) was administered orally once a day (at 9:00-10:00 a.m.) for 21 days, and discontinued thereafter. On days 1, 4, 7, 14, 21, 22, 23, and 24, the measurements of systolic blood pressure (SBP) and HR were made by the tail-cuff method (Multichannel 8000; TSE, Kronberg, Germany) before and 2 h after the administration of SK-1080. To measure the SBP, rats were prewarmed at 37°C for 5-10 min in a restraining cage in a warming box. Results were expressed as percentage change from control MAP and HR measured on day 1 before drug administration.
Antihypertensive effects in furosemide-treated dogs
Male beagle dogs (8-12 kg, Samyook Experimental Animal Co., Suwon, Korea) were anesthetized by intravenous injection of sodium pentobarbital (30 mg/kg) into the left cephalic vein. Under aseptic conditions, the left femoral artery was cannulated with a special long-term catheter device filled with heparin (1,000 IU/ml). The catheter was exteriorized through a subcutaneous tunnel at the back of neck. Two days after catheter implantation, animals were trained to stand in a sling (Daejong Co., Seoul, Korea) for continuous measurement of arterial blood pressure via a Grass P23XL pressure transducer (Grass Instruments, Quincy, MA, U.S.A.) followed by continuous recording on a Gould 2000 physiograph (Gould Inc., Cleveland, OH, U.S.A.). HR was derived from the arterial pressure pulse by ECG/Biotacho amplifier module of the Gould 2000 physiograph. To increase their plasma renin activity, animals were treated with furosemide at 10 mg/kg twice, 18 (given i.m.) and 2 h (given i.v.) before the experiment, as previously described by Wong et al. (14). Food and water were withdrawn from these dogs after the first dose of furosemide. Arterial blood pressure and HR were monitored for 8 h after single intravenous administration (0.1, 0.3, and 1 mg/kg) of SK-1080, and single oral administration of SK-1080 (0.3, 1, 3 mg/kg) and losartan (3, 10, 30 mg/kg). Results were expressed as percentage change from control MAP and HR, respectively. The ED20 values of compounds, doses that decreased the maximal MAP by 20%, were calculated by applying linear regression analysis to log dose-response data.
SK-1080 and losartan were synthesized at the Bio-Organic Science Division, KRICT, and were dissolved in 0.05N KOH in saline and suspended in Tween 80 for intravenous and oral administration, respectively. Ketamine hydrochloride was purchased from Yuhan Co. (Seoul, Korea), and angiotensin II acetate from Sigma Chemical Co. (St. Louis, MO, U.S.A.). All chemicals were prepared just before use.
All values are expressed as mean ± SEM. Data were analyzed by one-way analysis of variance (ANOVA) followed by the Dunnett's test for multiple comparisons (Sigma Stat; Jandel Co., San Rafael, CA, U.S.A.). In all comparisons, the difference was considered to be statistically significant at p < 0.05.
Effects in conscious angiotensin II-challenged normotensive rats
In conscious normotensive rats, angiotensin II (0.1 μg/kg, i.v.) increased diastolic arterial pressure by 45 ± 4 mm Hg; the pressor response was not attenuated during the 24-h observation period in the vehicle-treated group. Basal arterial blood pressure and HR were not changed by SK-1080 and losartan at any oral doses tested. SK-1080 (0.3, 1, and 3 mg/kg, p.o.) inhibited the angiotensin II-induced pressor response in a dose-dependent manner with a rapid onset of action (Fig. 1), the first peak effect (Emax) being reached 30 min after the administration of higher doses, unlike losartan. The inhibitory effect was more increased at all doses except 3 mg/kg, 24 h after administration. When orally administered, losartan (0.1, 0.3, 1, and 3 mg/kg, p.o.) also dose-dependently inhibited the angiotensin II-induced pressor response with the peak response observed between 6 and 8 h after the dose; the peak inhibitory effect remained unchanged at 24 h after the dose at all doses used except the highest dose. The ID50 values for SK-1080 and 0losartan were 1.12 ± 0.36 mg/kg and 0.47 ± 0.15 mg/kg, respectively.
Antihypertensive effects in conscious RHRs and SHRs
The effects of the intravenously administered SK-1080 (0.03, 0.06, 0.1, and 0.3 mg/kg) on MAP and HR in conscious RHRs are shown in Fig. 2. The mean predose values of MAP and HR were 173 ± 4 mm Hg and 367 ± 14 beats/min in RHRs. SK-1080 produced an immediate dose-dependent decrease in MAP, with 10 min taken to reach the maximum at all doses used, respectively (ED20 value, 0.06 ± 0.02 mg/kg). The antihypertensive effects of SK-1080 at lower dose returned to baseline within 1 h after the dose. However, at the higher dose of 0.3 mg/kg, its antihypertensive effect assumed a biphasic form and was still significant even at 24 h after the dose. SK-1080 induced a slight reflex tachycardia but without clear dose dependency.
The effects of the orally administered SK-1080 (3, 6, and 10 mg/kg) on MAP and HR in conscious RHRs are shown in Fig. 3A. SK-1080 produced a dose-dependent decrease in MAP with a gradual onset of the effect (10 min), the maximum being reached 4-6 h after the dose depending on the dose used (Emax, 39.2% at 10 mg/kg). The antihypertensive effects of SK-1080 persisted even at 24 h after the dose at all doses, although not significant (ED20 value, 5.06 ± 0.77 mg/kg). Any significant change in HR was not noted during the period of antihypertensive effect. The effects of the orally administered losartan (3 and 10 mg/kg) on MAP and HR in conscious RHRs are shown in Fig. 3B. Losartan produced a dose-dependent decrease in MAP (ED20 value, 3.36 ± 1.02 mg/kg) with a similar pattern of time course to SK-1080 (time to the onset of the effect and the maximum). At 24 h after the dose, the antihypertensive effects of losartan were maintained at a more significant level, but without any significant change in HR.
The effects of the orally administered SK-1080 (10 and 30 mg/kg) on MAP and HR in conscious SHRs are shown in Fig. 4. The mean predose values of MAP and HR were 151 ± 3 mm Hg and 312 ± 8 beats/min in SHRs. SK-1080 produced a similar decrease in MAP at doses tested (Emax, 9.8 ± 1.2% and 11.6 ± 2.4% at 10 and 30 mg/kg, respectively). SK-1080 showed a rapid onset of action (time to the onset and the maximum: 20 min and 30 min-4 h, respectively), and the antihypertensive effects lasted >6 h without any significant change in HR except a temporary weak reflex tachycardia at the onset of the effect.
Effects of the repeated oral dosing in SHRs
The effects of repeated oral treatment with SK-1080 (10 and 30 mg/kg) for 21 consecutive days on SBP and HR in SHRs are shown in Fig. 5. The mean predose values of SBP and HR were 187 ± 3 mm Hg and 363 ± 7 beats/min in SHRs. SK-1080 dose-dependently decreased SBP, and the antihypertensive effect measured 2 h after dosing gradually increased with the repetition of treatment and reached the maximum on day 7 (the decrease in SBP, 4.6 ± 2.0% and 6.1 ± 2.6%; 10.6 ± 1.9% and 10.8 ± 2.0%; 15.0 ± 1.7% and 19.7 ± 3.9% on days 1, 4, and 7 for 10 and 30 mg/kg, respectively). Then the antihypertensive effects were slightly attenuated on day 14 and potentiated again at a significant level on day 21. The antihypertensive effect of SK-1080 recovered gradually to control without rebound phenomena in several days after discontinuation of dosing. SK-1080 did not significantly change HR during the whole experiment.
Antihypertensive effects in furosemide-treated dogs
The effects of the intravenously administered SK-1080 (0.1, 0.3, and 1 mg/kg) on MAP and HR in furosemide-treated dogs are shown in Fig. 6. The mean predose values of MAP and HR were 110 ± 4 mm Hg and 137 ± 6 beats/min in furosemide-treated dogs. SK-1080 produced a dose-dependent decrease in MAP with a rapid onset of action (time to the onset and the maximum, 1 and 5-20 min, respectively), and the antihypertensive effects of SK-1080 (ED20 value, 0.13 ± 0.03 mg/kg) lasted 3 h and >8 h after the dose (p < 0.05) at 0.3 and 1 mg/kg, respectively. SK-1080 did not significantly change HR at all doses tested.
The effects of the orally administered SK-1080 (0.3, 1, and 3 mg/kg) on MAP and HR in furosemide-treated dogs are shown in Fig. 7A. SK-1080 produced a dose-dependent decrease in MAP with a gradual onset of the effect (10 min), the maximal effect being reached 1-1.5 h after the dose (Emax, 10.8 ± 1.9%, 25.8 ± 3.4% and 28.5 ± 2.5% at 0.3, 1, and 3 mg/kg, respectively). The antihypertensive effects of SK-1080 (ED20, 0.72 ± 0.13 mg/kg) lasted >8 h after the dose (p < 0.05), and these effects were not accompanied by any significant changes in HR at all doses used. The effects of the orally administered losartan (3, 10, and 30 mg/kg) on MAP and HR in furosemide-treated dogs are shown in Fig. 7B. Losartan produced a dose-dependent decrease in MAP with a gradual onset of action (within 10 min), the maximal effects occurring at 1 h at doses of 3 and 10 mg/kg and at 5 h after the dose at 30 mg/kg (Emax, 10.7 ± 2.5%, 22.9 ± 2.5%, and 28.7 ± 1.2% at 3, 10, and 30 mg/kg, respectively.). The antihypertensive effects of losartan (ED20, 8.13 ± 1.02 mg/kg) persisted at a significant level at 8 h after the dose (p < 0.05), but without any significant change in HR.
The results from this study indicate that SK-1080, a structurally novel nonpeptide AT1-receptor antagonist, is an orally active, potent antihypertensive agent with long-lasting activity in rats and dogs. In this study, the hemodynamic profile and the in vivo potencies of SK-1080 and losartan were compared in several animal models of hypertension in which the activated renin-angiotensin system was known to play an important role in the development and the maintenance of blood pressure. The results from studies with conscious angiotensin II-challenged normotensive rat indicate the antagonistic action at angiotensin II receptor without any agonistic action. SK-1080 exerted a more rapid onset of action and a more rapid arrival at the maximal inhibitory effect compared with losartan. The inhibitory effect of SK-1080 became much stronger 24 h after oral administration at all doses, whereas the peak inhibitory effect of losartan remained unchanged at 24 h after the dose. The findings from the conscious normotensive rat indicate that SK-1080 exerts long-lasting angiotensin II-receptor antagonistic effects with a hemodynamic profile somewhat different from that of losartan, and the differences in hemodynamic profile between two compounds may be due to the difference in metabolic change or oral absorption or both, considering the in vivo generation of the active metabolite EXP3174 after oral administration in this species (10).
In the second series of experiments, the potential of SK-1080 as a novel antihypertensive agent was evaluated in two different rat models of hypertension; two-kidney, one-ligated RHRs, a high-renin model, and the Okamoto strain of SHRs, a widely recognized model of essential hypertension with normal renin levels. In RHRs, orally administered SK-1080 and losartan produced dose-dependent antihypertensive effects with a similar hemodynamic profile (gradual onset of the effect, time to Emax, and long duration of >24 h). However, their antihypertensive potency in RHRs (p.o., ED20) was smaller than their antagonistic potency against pressor response to angiotensin II in normotensive rats (p.o., ID50). The differential potency of SK-1080 and losartan in these two experimental models also was reported for other angiotensin AT1-receptor antagonists such as GR11728915, and it might indicate that the blockade of AT1 receptor by these antagonists contributed less efficiently to their effects in RHRs than in normotensive rats, probably because of more complicated involvement of activated renin-angiotensin system in the maintenance of hypertension in RHRs over a 1-week period. When intravenously administered in RHRs, SK-1080 exerted an extremely greater antihypertensive effect compared with oral administration (ED20, 0.06 and 5.06 mg/kg, respectively). Compared with losartan, intravenously administered SK-1080 was ∼20-fold more potent in antagonizing pressor responses to exogenously administered angiotensin II in pithed rats (i.v. ID50, 0.07 and 1.74 mg/kg, respectively; 10a), although different modes of antagonism must be considered. These greater i.v. potency of SK-1080 over losartan was in line with other in vitro data: >50-fold more potent in blocking the angiotensin II-induced contraction of rat and rabbit aorta, and 12-fold more potent in displacing [125I]-[Sar1, Ile8]-angiotensin II from human recombinant angiotensin AT1 receptor. Despite its greater in vitro and i.v. potency as an angiotensin AT1-receptor antagonist, the oral antihypertensive effects of SK-1080 were not greater than those of losartan in RHRs, indicating relatively poor oral absorption in rats.
The antihypertensive effects of SK-1080 were further studied in furosemide-treated conscious dogs, another animal model with high plasma renin level (14), to compare the results with those from rat models of hypertension. In furosemide-treated dogs, the p.o. and i.v. ED20 values of SK-1080 for antihypertensive activity were 0.72 and 0.13 mg/kg, respectively (ED20 ratio 5.5 in dog vs. 84.3 in RHRs), indicating much better oral bioavailability of SK-1080 in dogs than in rats. In our study, SK-1080 was ∼10-fold more potent than losartan in its antihypertensive activity in furosemide-treated dogs, probably because of much better bioavailability in dogs (p.o. ED20, 0.72 and 8.13 mg/kg, respectively). Compared with the results from RHRs, oral antihypertensive effects of SK-1080 were much more potent (ED20, 0.72 and 5.06 mg/kg, respectively) and reached the maximum more quickly (time to Emax, 1-15 and 4-6 h after the dose, respectively) in furosemide-treated dogs. The greater potency and the earlier onset of the maximal effect of SK-1080 in furosemide-treated dog than in rats may indicate species differences in the effects of SK-1080 on the cardiovascular system. It is thought that this species difference is closely related to the better absorption in dogs, considering similar i.v. antihypertensive activities in dogs and RHRs. The comparison of the results from various in vitro and in vivo experiments appeared to indicate the differential absorption of SK-1080 and losartan in rat and dog. The biphasic antihypertensive pattern of SK-1080 after i.v. administration to RHRs could be explained by a more intense compensatory reflex mechanism activated by a more rapid decrease in blood pressure associated with the i.v. route.
The comparison of the maximal antihypertensive effects of SK-1080 administered in a single dose to RHRs and SHRs indicates a greater potency in RHRs. It is thought that the more potent effect of SK-1080 in RHRs is associated with the higher plasma renin activity in RHRs, although the local tissue renin-angiotensin system is known to play an important role in the development and maintenance of blood pressure in SHRs. On repeated oral dosing for 21 days in SHRs, SK-1080 significantly reduced blood pressure without inducing tachycardia and tolerance. The antihypertensive effect was gradually potentiated at weeks 1 and 3 of repeated administration of SK-1080. At least two explanations may be considered regarding this potentiation phenomenon-the slow disposition of SK-1080 and the slow dissociation of SK-1080 from the AT1-receptor sites, for which it has high binding affinity. It is conceivable that the slow disposition of SK-1080 due to its pharmacokinetic characteristics or slow dissociation of SK-1080 molecules from AT1 receptors may lead to accumulation in the body on repeated administration, resulting in potentiation of the action of SK-1080 on target tissues. However, the detailed elucidation of the mechanism of potentiation at weeks 1 and 3 requires further studies such as conventional pharmacokinetic experiments to measure changes in levels of SK-1080 and its metabolites in the blood and target tissue on repeated dosing. The reason for the slight reduction in antihypertensive effect on days 14 and 21 compared with the effect on day 7 is not clear.
Despite the potent antihypertensive activity of SK-1080 in rats and dogs, reflex tachycardia was not observed, unlike that with other types of antihypertensive drugs including β-adrenoceptor blocking agents, calcium channel blockers, and potassium channel activators (16-18). Although the lack of reflex tachycardia in the presence of reduced blood pressure also is observed with blockers of the renin-angiotensin system such as angiotensin-converting enzyme inhibitors and angiotensin II-receptor antagonists (7,19,20), the underlying mechanism is still unclear, except the possibilities of venous dilatation, the enhanced vagal tone, or reduction of the sympathetic baroreceptor response (19).
In summary, the results from this study indicate that orally administered SK-1080 exerted significant long-lasting antihypertensive effects in conscious RHRs with similar potency and pattern of time course to losartan. Interestingly, in furosemide-treated conscious dogs, orally administered SK-1080 was >10-fold more potent than losartan in lowering blood pressure, with a long duration of action at least ≤8 h after the dose. In SHRs, SK-1080 also exerted a significant antihypertensive effect without development of significant tolerance, even with repetitive long-term dosing. All these effects of SK-1080 in various hypertension models were due to its long-acting antagonistic activity against angiotensin AT1 receptor, as shown in angiotensin II-challenged conscious rats. All these pharmacologic profiles of SK-1080 indicate that SK-1080 is a potent, orally active AT1-selective receptor antagonist devoid of angiotensin II agonistic properties. The therapeutic potential of the compound as a novel antihypertensive agent awaits further evaluation in clinical studies.
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