The discovery of DuP 753, a potent, orally active nonpeptide angiotensin II receptor antagonist.
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Angiotensin II↗
Biomedical subjects
W A Price
Publications and source records attributed to W A Price.
Subculturing of a polychlorinated biphenyl-dechlorinating anaerobic enrichment on solid media.
An anaerobic culture capable of dechlorinating polychlorinated biphenyls was subcultured under strict anaerobic conditions on solid media containing sterilized river sediment. The dechlorination activity was transferred as a bacterial colony on a solid medium three times. After two transfers on solid medium, the culture was no longer methanogenic but still dechlorinated a mixture of tri- and tetrachlorobiphenyls. This demonstrates that anaerobic bacteria are responsible for the polychlorinated biphenyl dechlorination and can be grown without polychlorinated biphenyl on solid media.
Bacteria, Anaerobic↗
Changes in IGF-I and -II, IGF binding protein, and IGF receptor transcript abundance after uterine artery ligation.
Altered IGF activity may be one mechanism involved in the pathogenesis of intrauterine growth retardation (IUGR). We assessed the expression of IGF, IGF binding protein (IGFBP), and IGF receptor transcripts in liver, carcass, and placenta of fetal rats with IUGR resulting from unilateral uterine artery ligation. We found that uterine artery ligation on d 17 of gestation resulted in reduced body weight, liver weight, and placental weight on d 20 in the fetuses from the ligated uterine horn (UA-lig) compared with those from the opposite, nonligated uterine horn (UA-nonlig) and those from dams with no surgery or anesthesia. As assessed by solution hybridization, UA-lig fetuses exhibited significantly higher hepatic IGFBP-1, IGFBP-2, and IGF-II transcript abundance than UA-nonlig controls (increased 110, 50, and 31%, respectively). The only major difference among groups in carcass and placenta mRNA abundance was a 44% decrease in placental IGF-II expression in UA-lig pups compared with pups from dams that had had no surgery or anesthesia. Serum IGFBP, analyzed by ligand blot, showed a 2.4-fold increase in the doublet IGFBP-1/-2 band in UA-lig fetuses. Serum immunoreactive IGFBP-2 was unchanged among the groups, indicating that IGFBP-1 accounted for the increase in doublet intensity. Our results suggest that increased serum IGFBP-1 concentrations may decrease IGF activity in serum and thus inhibit IGF-stimulated cell proliferation or, by crossing the endothelial border, inhibit the activity of locally produced IGF. Decreased IGF-II expression in placenta also may contribute to decreased placental growth and, in turn, to IUGR.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Gene expression of insulin-like growth factors (IGFs), the type 1 IGF receptor, and IGF-binding proteins in dexamethasone-induced fetal growth retardation.
Altered gene expression and/or actions of the insulin-like growth factors (IGFs) have been implicated in the mediation of both pre- and postnatal growth retardation secondary to glucocorticoid excess. To investigate this possibility, we assessed the gene expression of the IGFs, the type I IGF receptor, and IGF-binding proteins (IGFBPs) in 20-day gestation liver and lung of growth-retarded fetuses whose mothers were treated with dexamethasone (DXM; 100 micrograms, ip, daily) on gestation days 15-19 (gestation = 21-22 days). DXM treatment in dams produced fetal growth retardation without decreasing litter size (32% decrease in fetal body weight). Both fetal liver and lung demonstrated decreased wet weight (48% and 47%, respectively) and DNA content (65% and 51%, respectively) compared to control animals. Our results suggest that increased expression of IGFBP-1, and possibly IGFBP-2, is involved in mediating the marked growth retardation. As assessed by solution hybridization assays and Northern blot analysis, there was an 8.5-fold increase in IGFBP-1 mRNA expression in the livers of DXM-treated fetal animals compared to that in sham-injected controls (P less than 0.002). IGFBP-2 mRNA expression was also increased (60%) in fetal liver, whereas IGFBP-3 was decreased (57%). In fetal lung, IGFBP-1 transcript abundance was also higher in DXM-treated fetal animals. Serum concentrations of IGFBP-1, but not those of IGFBP-2, were increased (approximately 4-fold) in the DXM-treated fetuses, as quantified by [125I]IGF-I ligand blotting and IGFBP-2 immunoblotting. Because hypoinsulinemia increases the expression of IGFBP-1 and -2, serum insulin concentrations were measured and found to be decreased in the DXM-treated fetuses (24 microU/ml) compared to control values (72 microU/ml). Analysis of mRNA expression for IGF-I, IGF-II, and the type 1 receptor transcripts did not support a role for decreased IGF or IGF receptor expression in the etiology of DXM-mediated growth retardation. IGF-I was unchanged in both liver and lung, and IGF-II transcripts were increased by 31% in liver and unchanged in lung of DXM-treated fetal animals. Northern analysis of hepatic and lung poly(A) RNA demonstrated no evidence for independent regulation of specific-sized IGF transcripts. Further, type 1 IGF receptor RNA abundance increased 42% in fetal liver and was unchanged in lung. Because IGFBPs may modulate IGF action, these results suggest that increased IGFBP-1, and possibly IGFBP-2, expression may be of importance in the etiology of DXM-induced fetal growth retardation.
Animals↗
Placebo-controlled trial to evaluate zidovudine in treatment of human immunodeficiency virus infection in asymptomatic patients with hemophilia. NHF-ACTG 036 Study Group.
One hundred ninety-three asymptomatic patients with hereditary coagulation disorders and human immunodeficiency virus (HIV) infection were studied in a controlled trial of zidovudine (ZDV) versus a placebo (with an average of 9.7 months on study). Pretreatment characteristics were well balanced between the placebo and drug-treated groups, including CD4 distributions, types of clotting disorders, transaminase abnormalities, and use of various hemostatic agents. At the time of analysis, 161 patients either were still receiving treatment or had previously reached an endpoint of disease progression while receiving treatment. Twenty-five patients withdrew voluntarily. The toxic effects noted included granulocytopenia and anemia, especially in older patients, and subjective symptoms of asthenia, malaise, and nausea, consistent with the known consequences of treatment with 300 mg ZDV five times daily. There was a trend toward more diagnoses of acquired immunodeficiency syndrome (AIDS), advanced or early AIDS-related complex (ARC), single ARC symptoms, or death in placebo recipients as compared with those receiving ZDV (22 v 13). Because older patients with hemophilia have more rapid disease progression, the same efficacy analysis was performed in the 89 patients aged more than 30 years who were receiving treatment. In this subgroup, there was a similar trend (11 v 6). With regard to the most advanced problems of the infection among the older patients, there were five patients who were newly diagnosed with AIDS or died in the placebo group versus none in the ZDV group (P = .02) among the older patients. The pretreatment distribution of CD4 counts for the placebo and ZDV groups were similar, but patients aged more than 30 years had significantly (P less than .049) fewer CD4 cells than patients aged less than 30 years. A beneficial ZDV effect is also supported by a trend toward higher CD4 counts (a 48-cell increase in the ZDV group at 24 weeks as compared with a four-cell increase in the placebo group) and a significant (P = .03) difference in weight gain in the ZDV patients aged more than 30 years (8 pounds) as compared with the older placebo patients (aged more than 30 years) (2 pounds) at week 24. The findings in the asymptomatic hemophilic patients aged more than 30 years support a useful effect of ZDV, which is similar to observations in the larger study of its use in asymptomatic, nonhemophilic patients.
AIDS-Related Complex↗
DuP 532: a second generation of nonpeptide angiotensin II receptor antagonists.
DuP 532 is a novel nonpeptide angiotensin II (AII) receptor antagonist under development for the treatment of hypertension. DuP 532 is a more potent antihypertensive agent in renal hypertensive rats (ED30 = 0.042 mg/kg, i.v.) and displays a similar or longer duration of action than the previously described AII antagonist, DuP 753. DuP 532, in contrast to DuP 753, is a noncompetitive antagonist of AII-induced contractions of rabbit aortic strips (KB = 1.1 x 10(-10) M). However, the inhibition of AII binding by DuP 532 in rat adrenal cortex does not correlate with either the aortic contractile response or with the hypotensive response. Assay conditions were evaluated and the presence or absence of BSA was shown to markedly affect the apparent binding affinity of DuP 532 and other 5-carboxylic acid derivatives. DuP 753 and other compounds were much less affected. The IC50 for DuP 532 was 4.7 x 10(-6) M with and 3 x 10(-9) M without BSA. The IC50s for DuP 753 were 1.7 x 10(-8) M with and 5 x -9 M without BSA. Both compounds with or without BSA did not completely inhibit AII binding which is characteristic of AT1 selectivity. BSA also reduced the effect of DuP 532 on the AII-induced contractions of rat main pulmonary artery preparations and the AII-induced Ca2+ mobilization in rat aortic smooth muscle cells. DuP 532 was very specific for AT1 receptors and did not interfere with receptors associated with neurotensin, prazosin, bradykinin, nitrendipine, or vasopressin. It is concluded that DuP 532 represents a new class of specific, but noncompetitive. AII receptor antagonists whose binding characteristics may provide new insight into AII receptor function.
Adrenal Glands↗
Nonpeptide angiotensin II receptor antagonists: the discovery of a series of N-(biphenylylmethyl)imidazoles as potent, orally active antihypertensives.
A new series of nonpeptide angiotensin II (AII) receptor antagonists has been prepared. These N-(biphenylyl-methyl)imidazoles, e.g. 2-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-chloro-5- (hydroxymethyl)imidazole, differ from the previously reported N-(benzamidobenzyl)imidazoles and related compounds in that they produce a potent antihypertensive effect upon oral administration; the earlier series generally were active only when administered intravenously. It has been found that the acidic group at the 2'-position of the biphenyl is essential. Only ortho-substituted acids possess both high affinity for the AII receptor and good oral antihypertensive potency. The carboxylic acid group has been replaced with a variety of acidic isosteres, and the tetrazole ring has been found to be the most effective. The tetrazole derivative, DuP 753, is currently in development for the treatment of hypertension.
Administration, Oral↗
The discovery of a new class of highly specific nonpeptide angiotensin II receptor antagonists.
Since angiotensin II (AII) is the effector molecule of the renin angiotensin system, the most direct approach to interfere with this system would be to antagonize AII at the level of its receptor. AII receptor antagonists would represent an ideal species, for regardless of how and where AII is produced, its function could be specifically turned off. However, the AII receptor antagonists currently available have been limited to AII-like peptides and their usefulness as therapeutics and pharmacologic tools has been hampered by their lack of oral bioavailability, metabolic instability, and partial agonistic activity. A detailed pharmacologic characterization of some simple N-benzylimidazoles, originally described by Takeda Chemical Industries (Osaka, Japan), identified this class of compound as very weak but selective AII receptor antagonists with a competitive mode of action. Encouraged by the quality of these lead compounds, we embarked on a synthetic program aimed at designing more potent and orally effective antagonists, while preserving their selectivity for the AII receptor. Our efforts have culminated in the discovery of DuP 753, 2-n-butyl-4-chloro-5-hydroxymethyl-1-[2'-(1H-tetrazol-5-yl)biph eny l-4-yl) methyl]imidazole, potassium salt, a potent, nonpeptide AII receptor antagonist.
Angiotensin Receptor Antagonists↗
In vitro pharmacology of DuP 753.
DuP 753, 2-n-butyl-4-chloro-5-hydroxymethyl-1-[2'-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl]imidazole, potassium salt, was characterized in vitro with respect to its affinity and specificity for functional antagonism of angiotensin II (AII) receptors. In rat adrenal cortical microsomes and cultured aortic smooth muscle cells DuP 753 inhibited the specific binding of [125I]AII in a concentration-dependent manner yielding IC50 values of 1.7 and 2.0 x 10(-8) mol/L, respectively. In contrast, DuP 753 had no appreciable affinity for other receptor systems as well as for Ca2+ channels. Functional antagonism was demonstrated by its blockade of AII-induced 45Ca2+ efflux in rat smooth muscle cells. The AII-induced contraction of rabbit aortic strips was competitively antagonized by DuP 753 resulting in a pA2 value of 8.48. Responses induced by other agonists, such as norepinephrine and KCl, were not altered. No partial agonistic effect was noted in any of the in vitro assays. In addition, DuP 753 (10(-5) mol/L) had no effect on rabbit lung converting enzyme or rat/human renin activity. These data demonstrate that DuP 753 is a highly potent and specific AII receptor antagonist. DuP 753 represents a useful experimental tool for dissecting the role of the renin-angiotensin system.
Adrenal Cortex↗
In vivo pharmacology of DuP 753.
A review of the in vivo pharmacology of DuP 753 (2-n-butyl-4-chloro-5-hydroxymethyl-1-[2'-(1H-tetrazol-5-yl)biphen yl-4- yl)methyl]imidazole, potassium salt) is presented. In the pithed rat, DuP 753 exerted a selective and competitive inhibition of the pressor response to angiotensin II (AII). In conscious normotensive rats, DuP 753 inhibited the AII-induced aldosterone secretion and drinking response. DuP 753 lowered blood pressure in conscious normotensive rats pretreated with furosemide but not in untreated normotensive rats. Unlike saralasin, DuP 753 given intravenously did not cause pressor response. In conscious renal hypertensive rats (RHRs), a high renin model, DuP 753 decreased blood pressure with an intravenous ED30 of 0.78 mg/kg and an oral ED30 of 0.59 mg/kg. The antihypertensive efficacy of DuP 753 in RHRs was similar to that of captopril. In DOCA hypertensive rats, a low renin model, DuP 753 did not lower blood pressure. In conscious 18- to 21-week-old spontaneously hypertensive rats (SHRs), DuP 753 given orally or intravenously reduced blood pressure dose-dependently and did not alter heart rate at these doses. The acute antihypertensive efficacy of DuP 753 was greater than that of captopril in SHRs. In contrast, DuP 753 and captopril given orally at 10 mg/kg/day for 15 days in SHRs caused a similar decrease in blood pressure. Bilateral nephrectomy but not inhibition of prostaglandin synthesis abolished the antihypertensive effect of DuP 753 in SHRs. Our study, therefore, indicates that DuP 753 is an orally active, nonpeptide, selective, and competitive AII receptor antagonist lacking agonism. It appears that there is a relationship between basal renin level and the acute antihypertensive effect of DuP 753 in rats. Further, our results suggest that the renin-angiotensin system plays a significant role in the control of blood pressure in conscious SHRs.
Angiotensin II↗
Angiotensin II receptor antagonists. From discovery to antihypertensive drugs.
Some simple N-benzylimidazoles, originally described by Takeda Chemical Industries (Osaka, Japan), were characterized to be very weak but selective nonpeptide angiotensin II (Ang II) receptor antagonists with a competitive mode of action. Chemical modifications of these led to EXP6155 and EXP6803, which showed approximately 10- and 100-fold higher affinity, respectively, but were orally ineffective. Oral activity was obtained for the biphenyl carboxylic acid derivatives EXP7711 and especially EXP9654. A further advance in the design of nonpeptide Ang II receptor antagonists was provided by DuP 753, an analogue of EXP7711 in which the carboxylic acid function is replaced by its tetrazol-5-yl equivalent. DuP 753 (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)bi phe nyl-4- yl)methyl]imidazole, potassium salt) displaces radiolabeled Ang II from its specific binding sites in various tissues, affording IC50 values of approximately 20 nM. DuP 753 competitively antagonizes Ang II-induced responses in various in vitro and in vivo preparations but does not influence those to KCl, norepinephrine, vasopressin, and others, nor does it affect converting enzyme and renin. In high renin animal models of elevated arterial blood pressure, intravenous and oral administrations of DuP 753 produce a sustained decrease in pressure without influencing heart rate. Marked antihypertensive effects are observed in spontaneously hypertensive rats, but no efficacy is noticed in deoxycorticosterone acetate hypertensive animals. DuP 753 showed no agonistic properties in any of the above test systems and has been chosen to undergo clinical trials for the treatment of hypertension. In rats, the 5-carboxylic acid (EXP3174) represents a major metabolite of DuP 753.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin II↗
The discovery of potent nonpeptide angiotensin II receptor antagonists: a new class of potent antihypertensives.
A new class of potent antihypertensives has been discovered that exert their effect through blockade of the angiotensin II (AII) receptor. Most AII antagonists reported so far are peptide mimics of the endogenous vasoconstrictor octapeptide angiotensin II. The compounds of this paper are nonpeptides and therefore constitute a new class of potent AII receptor antagonists. Based on the overlap of a conformation of AII with literature lead 3, a hypothesis was developed suggesting the need for an additional acidic functionality to increase the lead's potency. The substitution of an additional carboxylic acid resulted in a 10-fold increase in binding affinity observed for diacid 4. The binding affinities for subsequent compounds were eventually increased 1000-fold over that of the literature leads through a systematic SAR study. Thus the AII receptor binding affinity [IC50 (microM)] of 15 microM for literature lead 1, for example, was increased to 0.018 and 0.012 microM for compounds 33 and 53. A structure-affinity relationship has been found requiring the presence of four key elements for good activity: (1) an additional phenyl ring at the N-benzyl para position of the benzylimidazole nucleus, (2) an acidic functionality at the ortho position of the terminal aromatic ring, (3) a lipophilic side chain at the imidazole 2-position of three to five carbon atoms in length, and (4) a group at the imidazole 5-position capable of hydrogen bonding. The synthesis as well as the pharmacological activity of the compounds in this new series of AII receptor antagonists are presented.
Angiotensin II↗
Nonpeptide angiotensin II receptor antagonists: N-[(benzyloxy)benzyl]imidazoles and related compounds as potent antihypertensives.
A series of compounds has been synthesized and demonstrated to be antagonists of the angiotensin II (AII) receptor. These compounds are structurally related to the N-(benzamidobenzyl)imidazoles and extend the scope of this new class of nonpeptide AII antagonists. It has been found that the amide linkage (X = NHCO) in the N-(benzamidobenzyl)imidazoles can be replaced successfully by a variety of groups (X = single bond, O, S, CO, OCH2, CH = CH, NHCONH); linkers of 0-1 atoms in length are most effective. When administered intravenously to awake renal hypertensive rats, these compounds are potent antihypertensives.
Adrenal Cortex↗
Nonpeptide angiotensin II receptor antagonists.
Although the most direct way to interfere with the renin-angiotensin system (RAS) is at the level of the angiotensin II (AII) receptor, the currently available AII receptor antagonists are peptides still retaining significant agonistic properties with the obvious drawbacks of limited stability and lack of oral activity. We have characterized simple N-benzylimidazoles as weak, but selective AII receptor antagonists with a competitive mode of action. Chemical modification of these early leads led to EXP6155 and EXP6803, which show approximately 10- and 100-fold higher affinity. Oral activity was obtained for EXP7711, and in particular for EXP9654. This class of compounds displaces 3H-AII from its specific binding sites in various tissues. They competitively antagonize AII-induced responses in various in vitro and in vivo preparations, but do not influence AII-induced responses to KCl, norepinephrine, and vasopressin, nor do they affect converting enzyme or renin. In high renin models of elevated blood pressure, such as the renal hypertensive rat and sodium-depleted dog, these substances produce a sustained decrease in arterial pressure without changing heart rate after intravenous and oral (EXP7711 and EXP9654) administration. None of these compounds showed agonistic activity in any of the above test systems. In conclusion, the nonpeptide structures described herein are selective and competitive AII receptor antagonists and add another dimension to the arsenal of drugs manipulating the RAS.
Angiotensin II↗
Stable carbon isotope analysis of nucleic acids to trace sources of dissolved substrates used by estuarine bacteria.
The natural abundance of stable carbon isotopes measured in bacterial nucleic acids extracted from estuarine bacterial concentrates was used to trace sources of organic matter for bacteria in aquatic environments. The stable carbon isotope ratios of Pseudomonas aeruginosa and nucleic acids extracted from cultures resembled those of the carbon source on which bacteria were grown. The carbon isotope discrimination between the substrate and total cell carbon from bacterial cultures averaged 2.3% +/- 0.6% (n = 13). Furthermore, the isotope discrimination between the substrate and nucleic acids extracted from bacterial cultures was 2.4% +/- 0.4% (n = 10), not significantly different from the discrimination between bacteria and the substrate. Estuarine water samples were prefiltered through 1-micron-pore-size cartridge filters. Bacterium-sized particles in the filtrates were concentrated with tangential-flow filtration and centrifugation, and nucleic acids were then extracted from these concentrates. Hybridization with 16S rRNA probes showed that approximately 90% of the nucleic acids extracted on two sample dates were of eubacterial origin. Bacteria and nucleic acids from incubation experiments using estuarine water samples enriched with dissolved organic matter from Spartina alterniflora and Cyclotella caspia had stable carbon isotope values similar to those of the substrate sources. In a survey that compared diverse estuarine environments, stable carbon isotopes of bacteria grown in incubation experiments ranged from -31.9 to -20.5%. The range in isotope values of nucleic acids extracted from indigenous bacteria from the same waters was similar, -27.9 to -20.2%. Generally, the lack of isotope discrimination between bacteria and nucleic acids that was noted in the laboratory was observed in the field.(ABSTRACT TRUNCATED AT 250 WORDS)
Bacteria↗
Nonpeptide angiotensin II receptor antagonists: a novel class of antihypertensive agents.
The most direct approach to block the function of the renin-angiotensin system would be to antagonize angiotensin II (AII) at the level of its receptor. However, the AII receptor antagonists currently available, such as saralasin, are peptides which still retain agonistic activity and lack oral bioavailability. We have identified the N-benzylimidazoles, S-8307 and S-8308, as weak, but selective nonpeptide AII receptor antagonists. These initial leads were subsequently converted into more potent compounds, such as EXP6155, EXP6803 and EXP7711, while maintaining the selectivity. The compounds displace 3H-AII from its specific binding sites in adrenal cortical membranes and smooth muscle cells. They competitively inhibit the vasoconstrictor response to AII in various in vivo and in vitro preparations, but do not influence those to KCl, norepinephrine, and vasopressin. Converting enzyme and renin are not affected by these agents. In renal hypertensive rats and sodium-depleted dogs our compounds cause a sustained decrease in arterial pressure following intravenous and oral (EXP7711) administration, and are devoid of agonistic properties. Taken together, these nonpeptide structures are true competitive AII receptor antagonists and represent a new class of effective antihypertensive agents.
Adrenergic alpha-Antagonists↗
Hypotensive action of DuP 753, an angiotensin II antagonist, in spontaneously hypertensive rats. Nonpeptide angiotensin II receptor antagonists: X.
In conscious 18-21-week-old spontaneously hypertensive rats, DuP 753, a nonpeptide angiotensin II receptor antagonist, given orally at 3 and 10 mg/kg or intravenously at 3, 10, and 30 mg/kg, reduced blood pressure dose dependently. It did not alter heart rate at these doses. At 10 mg/kg i.v., DuP 753 decreased blood pressure significantly for at least 24 hours, suggesting a long duration of the antihypertensive effect. Unlike saralasin, DuP 753 did not cause a transient increase in blood pressure. The acute antihypertensive efficacy of DuP 753 was greater than that of captopril. Our data indicate that, for captopril to reduce blood pressure to a similar extent as that of DuP 753, it would need to be supplemented by a diuretic. DuP 753 did not have an acute diuretic effect. Bilateral nephrectomy, but not inhibition of prostaglandin synthesis, abolished the antihypertensive effect of DuP 753, suggesting that the antihypertensive effect of DuP 753 is dependent on an active renin-angiotensin system. Furthermore, DuP 753 inhibited the pressor response to angiotensin II but not the responses to norepinephrine, vasopressin, and Bay K 8644 (a calcium agonist). As neither DuP 753 nor captopril decreased blood pressure acutely in Wistar-Kyoto normotensive rats, our results suggest that the renin-angiotensin system plays a significant role in the control of blood pressure in spontaneously hypertensive rats.
Administration, Oral↗
Nonpeptide angiotensin II receptor antagonists. Studies with EXP9270 and DuP 753.
A series of nonpeptide angiotensin II (Ang II) receptor antagonists was evaluated in rat adrenal cortical microsomes for their inhibitory effects on the specific binding of [3H]Ang II, in the isolated rabbit aorta bioassay for their functional antagonism of contractile response to Ang II, and in high renin, renal-hypertensive rats for their intravenous antihypertensive effects, expressed as IC50, pA2, and intravenous ED30, respectively. Highly significant linear correlations were found between IC50 and pA2 (r = -0.88), between IC50 and intravenous ED30 (r = 0.79), and between pA2 and intravenous ED30 (r = -0.93). In both in vitro and in vivo functional assays, none of these antagonists exhibited agonistic effects. The orally active nonpeptide Ang II receptor antagonists EXP9270 and DuP 753 (oral ED30 = 3.6 and 0.59 mg/kg, respectively) were selected for further characterization. These antagonists exhibited selective and competitive Ang II antagonism in rabbit aorta and guinea pig ileum. In conscious normotensive rats, DuP 753 abolished the pressor response to saralasin, suggesting that the pressor effect of saralasin is attributed to its Ang II-like activity. In addition, DuP 753 also blocked the Ang II-induced drinking response and aldosterone release in rats. These results suggest that Ang II receptor blockade is the primary mechanism of the antihypertensive effect of these nonpeptide Ang II receptor antagonists. Further, the specificity and lack of partial agonistic effects of these molecules make them potentially useful physiological probes and therapeutic agents.
Angiotensin II↗