RESUMO
Okur-Chung syndrome is a neurodevelopmental condition attributed to germline CSNK2A1 pathogenic missense variants. We present 8 unreported subjects with the above syndrome, who have recognizable dysmorphism, varying degrees of developmental delay and multisystem involvement. Together with 6 previously reported cases, we present a case series of 7 female and 7 male subjects, highlighting the recognizable facial features of the syndrome (microcephaly, hypertelorism, epicanthic fold, ptosis, arched eyebrows, low set ears, ear fold abnormality, broad nasal bridge and round face) as well as frequently occurring clinical features including neurodevelopmental delay (93%), gastrointestinal (57%), musculoskeletal (57%) and immunological (43%) abnormalities. The variants reported in this study are evolutionary conserved and absent in the normal population. We observed that the CSNK2A1 gene is relatively intolerant to missense genetic changes, and most variants are within the protein kinase domain. All except 1 variant reported in this cohort are spatially located on the binding pocket of the holoenzyme. We further provide key recommendations on the management of Okur-Chung syndrome. To conclude, this is the second case series on Okur-Chung syndrome, and an in-depth review of the phenotypic features and genomic findings of the condition with suggestions on clinical management.
Assuntos
Deficiências do Desenvolvimento/genética , Deficiência Intelectual/genética , Transtornos do Neurodesenvolvimento/genética , Adolescente , Caseína Quinase II/química , Caseína Quinase II/genética , Criança , Pré-Escolar , Deficiências do Desenvolvimento/fisiopatologia , Face/fisiopatologia , Feminino , Genótipo , Humanos , Deficiência Intelectual/fisiopatologia , Masculino , Anormalidades Musculoesqueléticas/genética , Anormalidades Musculoesqueléticas/fisiopatologia , Mutação de Sentido Incorreto/genética , Transtornos do Neurodesenvolvimento/fisiopatologia , Fenótipo , Conformação Proteica , Dobramento de Proteína , Sequenciamento do Exoma/métodosRESUMO
OBJECTIVE: To evaluate psychometric properties of the Chinese version of Dementia Quality of Life Measure - Proxy (C-DEMQoL-Proxy). METHODS: Care home residents aged ≥60 years who were diagnosed with dementia or demonstrated impairment in cognition were recruited from four care facilities in Hong Kong. Caregivers of these participants were also invited to participate. The original DEMQoL-Proxy was translated into Chinese (Cantonese) by a trained translator. The forward-translated version was reviewed by an expert panel of six experienced healthcare professionals. Revisions were made based on comments. The instrument was back-translated to English to check whether further changes were necessary. Demographic data (age, sex, type and severity of dementia, and Mini-Mental State Examination [MMSE] score) were collected from medical records of participants with dementia. Caregivers were interviewed by an occupational therapist or personnel supervised by the occupational therapist using the C-DEMQoL-Proxy and the Chinese version of Quality of Life-Alzheimer's Disease-Proxy (C-QoL-AD-Proxy). Acceptability, reliability, and validity of the C-DEMQoL-Proxy were evaluated using standard psychometric methods. RESULTS: 90 individuals (82.2% women) with dementia aged 72 to 102 years were included. Their diagnosis included Alzheimer's disease (23.3%), vascular dementia (15.6%), mixed and other types of dementias (51.1%), and missing (10%). Severity was mild in 12.2%, moderate in 62.2%, and severe in 25.6%. The mean MMSE score was 12.0 ± 4.9. 20% of the caregivers were family members and the rest were professional carers. The C-DEMQoL-Proxy had good acceptability, with no floor or ceiling effects or missing data. It had good internal consistency (Cronbach alpha = 0.91) and test-retest reliability (intraclass correlation coefficients = 0.83). It was mildly correlated with C-QoL-AD-Proxy (r = 0.29, p < 0.01). Age and sex were not correlated with C-DEMQoL-Proxy scores. C-DEMQoL-Proxy scores were not significantly different between dementia types, severity levels, or between those with higher or lower MMSE scores. CONCLUSION: The C-DEMQoL-Proxy is a valid and reliable instrument to assess health-related quality of life in individuals with dementia.
Assuntos
Demência , Qualidade de Vida , Inquéritos e Questionários , Idoso , Idoso de 80 Anos ou mais , Feminino , Hong Kong , Humanos , Masculino , Procurador , Psicometria , Reprodutibilidade dos Testes , Instituições Residenciais , TraduçõesRESUMO
Substantial progress has been made recently in the development of nonpeptide angiotensin II receptor antagonists, a goal that has long remained an unmet challenge. Pieter Timmermans and colleagues review the pharmacology and the course of events that led to the identification of the lead compound and clinical candidate DuP753. Nonpeptide angiotensin II receptor antagonists represent novel therapeutic agents and are the preferred probes for exploring the (patho)physiological role(s) of angiotensin II. In addition, these compounds have provided evidence for the existence of different binding sites/receptors for angiotensin II.
Assuntos
Antagonistas de Receptores de Angiotensina , Sistema Renina-Angiotensina/fisiologia , Animais , Sítios de Ligação , Humanos , Imidazóis/farmacologia , Losartan , Relação Estrutura-Atividade , Tetrazóis/farmacologiaRESUMO
Recently discovered nonpeptide angiotensin II receptor antagonists represent a new class of potential drugs for the treatment of hypertension and congestive heart failure. Further, these antagonists have been successfully used as selective research tools for physiologic studies of angiotensin H and defining angiotensin II receptor subtypes.
RESUMO
EXP6155 (2-n-butyl-1-[4-carboxybenzyl]-4-chloroimidazole-5-acetic acid) and EXP6803 (methyl 2-n-butyl-1-[4-(2-carboxybenzamido)benzyl]-4-chloroimidazole -5-acetate, sodium salt) are shown to be novel, nonpeptide, antihypertensive, specific angiotensin II receptor antagonists. In rabbit aorta, they competitively inhibited the contractile response to angiotensin II with pA2 values of 6.54 and 7.20 and did not alter the response to norepinephrine or KCl. In guinea pig ileum, both agents blocked the responses to angiotensin I and II and did not alter the responses to bradykinin and acetylcholine. A similar specific angiotensin II antagonism was shown in vivo in the spinal pithed rat model. In renal artery-ligated rats, a high renin hypertensive model, EXP6155 and EXP6803 given intravenously, decreased blood pressure with ED30 of 10 and 11 mg/kg, respectively. Both compounds did not alter blood pressure when given orally at 100 mg/kg. Unlike saralasin, EXP6155 and EXP6803 given intravenously did not cause a transient increase in blood pressure in the renal artery-ligated and normotensive rats. Our results indicate that EXP6155 and EXP6803 are selective angiotensin II receptor antagonists and antihypertensive agents. Since neither compound had partial agonist activities or bradykinin potentiation effects, unlike the existing peptide angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, respectively, they may represent preferred probes for studying the physiological roles of angiotensin II.
Assuntos
Antagonistas de Receptores de Angiotensina , Imidazóis/farmacologia , Animais , Aorta/efeitos dos fármacos , Pressão Sanguínea/efeitos dos fármacos , Captopril/farmacologia , Relação Dose-Resposta a Droga , Cobaias , Íleo/efeitos dos fármacos , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Coelhos , Ratos , Saralasina/farmacologiaRESUMO
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.
Assuntos
Angiotensina II/antagonistas & inibidores , Anti-Hipertensivos/farmacologia , Azóis/farmacologia , Imidazóis/farmacologia , Tetrazóis/farmacologia , Administração Oral , Animais , Captopril/farmacologia , Furosemida/farmacologia , Injeções Intravenosas , Losartan , Masculino , Ratos , Ratos Endogâmicos SHR , Ratos Endogâmicos WKYRESUMO
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.
Assuntos
Angiotensina II/efeitos adversos , Azóis/farmacologia , Compostos de Bifenilo/farmacologia , Imidazóis/farmacologia , Receptores de Angiotensina/efeitos dos fármacos , Tetrazóis/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Aorta/metabolismo , Cobaias , Hipertensão Renal/fisiopatologia , Íleo/efeitos dos fármacos , Losartan , Coelhos , RatosRESUMO
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)
Assuntos
Angiotensina II/metabolismo , Anti-Hipertensivos/farmacologia , Compostos de Bifenilo/farmacologia , Imidazóis/farmacologia , Receptores de Angiotensina/efeitos dos fármacos , Tetrazóis/farmacologia , Animais , Compostos de Bifenilo/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Imidazóis/metabolismo , Losartan , Tetrazóis/metabolismoRESUMO
Segments of a cDNA encoding human plasminogen activator inhibitor type 1 (PAI-1) were subcloned into a highly regulated and inducible Escherichia coli expression system. A plasmid encoding the mature form of human endothelial PAI-1 produced a functional recombinant molecule, as indicated by its ability to inhibit tissue plasminogen activator's enzymatic activity. In contrast to PAI-1 isolated from human fibrosarcoma cells, the biological activity of the recombinant PAI-1 was not dependent on pretreatment with denaturing agents. A construct encoding a polypeptide lacking the first 80 amino acids of PAI-1 also produced elevated levels of the truncated recombinant protein. However, this truncated product was functionally inactive, indicating that an intact N terminus is required for activity.
Assuntos
Escherichia coli/genética , Expressão Gênica , Inativadores de Plasminogênio/metabolismo , Sequência de Aminoácidos , Clonagem Molecular , DNA Recombinante/genética , Escherichia coli/metabolismo , Humanos , Dados de Sequência Molecular , Plasmídeos , Inativadores de Plasminogênio/farmacologia , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/farmacologiaRESUMO
Three bradykinin analogues have been synthesized in which the phenylalanine residue(s) at positions 5 and/or 8 have been substituted by isoleucine. All these analogues have weak bradykinin-like activity in isolated rat uterine smooth muscle or in rat blood pressure assay. No antagonistic activity was observed with any of these analogues. The importance of phenylalanine at positions 5 and 8 is discussed.
Assuntos
Bradicinina/análogos & derivados , Sequência de Aminoácidos , Animais , Pressão Sanguínea/efeitos dos fármacos , Bradicinina/antagonistas & inibidores , Bradicinina/síntese química , Bradicinina/farmacologia , Feminino , Cobaias , Técnicas In Vitro , Contração Muscular/efeitos dos fármacos , Ratos , Contração Uterina/efeitos dos fármacosRESUMO
The availability of peptide and non-peptide Ang II receptor antagonists has permitted the study of Ang II receptor heterogeneity. It is now widely recognized that there are at least two distinct Ang II receptor subtypes. AT1 receptors are selective in their recognition of agents such as losartan, DuP 532, L-158,809, SK&F108566, and similar non-peptides. To date, all of the well-known actions of Ang II in mammals are blocked by the AT1 selective antagonists such as losartan and are thus designated as being mediated by the AT1 receptor. Although there have been reports of functional activity mediated through AT2 sites, the pharmacological role for the AT2 receptor has not yet been elucidated. Herein, we report the chemistry and SAR on a novel series of 1,2,3,4-tetrahydrosioquinoline-3-carboxylic acids which have selective affinity for AT2 receptors. The most potent of which (19) has an IC50 of 30 nM for the AT2 receptor in the rat adrenal radioligand binding assay.
Assuntos
Angiotensina II/metabolismo , Antagonistas de Receptores de Angiotensina , Ácidos Carboxílicos/síntese química , Ácidos Carboxílicos/farmacologia , Isoquinolinas/síntese química , Isoquinolinas/farmacologia , Animais , Sítios de Ligação , Ácidos Carboxílicos/química , Isoquinolinas/química , Ratos , Receptores de Angiotensina/metabolismo , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Angiotensina II/antagonistas & inibidores , Anti-Hipertensivos/síntese química , Imidazóis/síntese química , Receptores de Angiotensina/efeitos dos fármacos , Córtex Suprarrenal/efeitos dos fármacos , Córtex Suprarrenal/metabolismo , Antagonistas de Receptores de Angiotensina , Animais , Ligação Competitiva , Fenômenos Químicos , Química , Imidazóis/farmacologia , Microssomos/efeitos dos fármacos , Microssomos/metabolismo , Ratos , Receptores de Angiotensina/metabolismo , Relação Estrutura-AtividadeRESUMO
The identification of the AT1 and AT2 receptor subtypes has stimulated interest in developing balanced angiotensin II receptor antagonists. A series of 5-(3-amidopropanoyl)imidazoles has been prepared which possess balanced affinity for the AT1 and AT2 receptors. XR510 (1), 1-[[2'-[[(isopentoxycarbonyl)amino]sulfonyl]-3- fluoro(1,1'-biphenyl)-4-yl]methyl]-5-[3-(N-pyridin-3- ylbutanamido)propanoyl]-4-ethyl-2-propyl-1H-imidazole, potassium salt, exhibits subnanomolar affinity for both receptor sites. XR510 is very active in lowering blood pressure in renal hypertensive rats and furosemide-treated dogs following oral administration.
Assuntos
Angiotensina I/metabolismo , Antagonistas de Receptores de Angiotensina , Compostos de Bifenilo/metabolismo , Compostos de Bifenilo/farmacologia , Imidazóis/síntese química , Imidazóis/metabolismo , Imidazóis/farmacologia , Receptores de Angiotensina/metabolismo , Administração Oral , Animais , Ensaio Radioligante , Ratos , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Antagonistas de Receptores de Angiotensina , Anti-Hipertensivos/síntese química , Compostos de Bifenilo/síntese química , Imidazóis/síntese química , Administração Oral , Glândulas Suprarrenais/metabolismo , Animais , Anti-Hipertensivos/uso terapêutico , Compostos de Bifenilo/metabolismo , Compostos de Bifenilo/uso terapêutico , Fenômenos Químicos , Química , Hipertensão/tratamento farmacológico , Imidazóis/metabolismo , Imidazóis/uso terapêutico , Losartan , Masculino , Estrutura Molecular , Ratos , Ratos Endogâmicos , Receptores de Angiotensina/metabolismo , Relação Estrutura-Atividade , Tetrazóis/síntese química , Tetrazóis/uso terapêuticoRESUMO
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.
Assuntos
Angiotensina II/antagonistas & inibidores , Anti-Hipertensivos/síntese química , Imidazóis/síntese química , Receptores de Angiotensina/efeitos dos fármacos , Antagonistas de Receptores de Angiotensina , Animais , Sítios de Ligação , Pressão Sanguínea/efeitos dos fármacos , Fenômenos Químicos , Química , Cristalografia , Imidazóis/metabolismo , Imidazóis/farmacologia , Masculino , Modelos Moleculares , Ratos , Ratos Endogâmicos , Receptores de Angiotensina/metabolismo , Relação Estrutura-AtividadeRESUMO
Three murine monoclonal antibodies to tissue-type plasminogen activator (t-PA) were evaluated for their effects on the binding of iodinated t-PA to cultured human hepatoma cells (Hep G2), and on extending the half-life of t-PA injected into rabbits. Two of the antibodies, AE5 and EG2, significantly inhibited t-PA binding in vitro, and extended the in vivo half-life of t-PA four to five-fold. A third antibody, BA10, which had a much smaller inhibitory effect on t-PA binding, had no influence in extending t-PA's half-life. MOPC-21, a control antibody not directed to t-PA, had no effect on either test. Our results are the first to correlate different compounds' effects on t-PA binding with their ability to retard t-PA clearance in vivo, and provide additional evidence for the importance of a liver cell receptor in the t-PA clearance process.
Assuntos
Anticorpos Monoclonais , Ativador de Plasminogênio Tecidual/metabolismo , Células Tumorais Cultivadas/metabolismo , Ligação Competitiva , Carcinoma Hepatocelular/metabolismo , Meia-Vida , Humanos , Neoplasias Hepáticas , Ativador de Plasminogênio Tecidual/imunologia , Ativador de Plasminogênio Tecidual/farmacocinéticaRESUMO
The stimulatory effect of angiotensin II (AT) on the accumulation of inositol phosphates and on aldosterone production is abolished by the AT1 selective receptor antagonist DuP753 while PD123177, an AT2 antagonist, is ineffective. Similarly, a depolarizing effect of AT (inhibition of K+/86Rb efflux) is prevented by DuP753. While mediators derived from phospholipase C activation have a central role in the stimulation of aldosterone production by AT, the effect of AT on K+ permeability is mimicked neither by elevation of cytoplasmic [Ca2+] by ionomycin nor by kinase C activation with phorbol ester. Our results suggest that AT stimulates phospholipase C and the subsequent steroid production by glomerulosa cells through AT1 receptors. In addition some events induced by the activation of AT1 receptors may not be mediated by the activation of phospholipase C.
Assuntos
Aldosterona/biossíntese , Angiotensina II/farmacologia , Potássio/metabolismo , Zona Glomerulosa/efeitos dos fármacos , Animais , Cálcio/metabolismo , Permeabilidade da Membrana Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Canais de Potássio/efeitos dos fármacos , Ratos , Ratos Endogâmicos , Receptores de Angiotensina/efeitos dos fármacosRESUMO
The effect of variations in pH and Ca2+ on angiotensin II (A-II)-induced steroidogenesis was tested on isolated adrenal glomerulosa cell suspensions. The results show that a reduction in pH from 7.4 to 6.5 produces both a shift to the left of the A-II dose-response curve as well as an increase in maximum steroid production. In contrast, removal of Ca2+ from the incubation medium virtually abolished steroidogenesis to A-II (5 X 10(-9)M(, KCl(10mM) and ACTH (250 microU/ml). The Ca2+ antagonist D-600, however, was less effective than simple removal of Ca2+ as 10(-4) M was required to block the steroidogenic response to these same agonists. The results indicate that the response characteristics of this system to A-II resemble most closely those seen with isolated arterial smooth muscle - especially rabbit aortic strips.
Assuntos
Córtex Suprarrenal/metabolismo , Aldosterona/biossíntese , Angiotensina II/farmacologia , Cálcio/farmacologia , Hormônio Adrenocorticotrópico/farmacologia , Animais , Relação Dose-Resposta a Droga , Concentração de Íons de Hidrogênio , Masculino , CoelhosRESUMO
The octapeptide, angiotensin II (Ang II), the biologically active component of the renin-angiotensin system, elicits its multiple actions through the stimulation of specific surface receptors on various target organs. Although the existence of Ang II receptor subtypes has been suspected for some time, definitive evidence for Ang II receptor heterogeneity has been obtained only with the recently introduced nonpeptide Ang II receptor antagonists, exemplified by the prototypic compounds DuP 753 and PD 123177. The sites having high affinity for DuP 753 are designated as site 1 (AT1 receptors) and those having a high affinity for PD 123177 as site 2 (AT2 receptors). Unlike Ang I, Ang II, Ang III, and peptide antagonists, such as saralasin, which all are relatively nonselective ligands for both Ang II receptors, the peptides CGP42112A and p-aminophenylalanine6-Ang II show a marked preference for the AT2 site. The occurrence of the AT1 and AT2 receptor subtypes/binding sites identified so far appears widespread. The presence and proportion of these receptors vary significantly among different tissues/organs of the same species and within the same tissue/organ of different species. Despite the abundance of the AT2 site, its functional correlates remain to be determined. The DuP 753-sensitive site (AT1 receptor) mediates all the major Ang II-induced biological effects, including adrenal aldosterone and catecholamine secretion, release of catecholamines from sympathetic ganglia, central nervous system responses, and vasoconstriction.