Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.23.15 (renin)
 35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensin II (ANG II) is the primary mediator of the renin-angiotensin system, which has an important functional role in cardiovascular homeostasis. The angiotensin receptor and its functional correlates have been redefined by the cloning of angiotensin receptors and the discovery and widespread study of specific nonpeptide ANG II-receptor antagonists losartan (AT1 selective) and PD123177 (AT2 selective). With these antagonists, it has been possible to extend the concept of ANG II-receptor heterogeneity to virtually every tissue and species. The losartan-sensitive sites have been shown to mediate all of the major ANG II-induced biologic effects, including vasoconstriction, aldosterone and catecholamine release, and central, ANG II-induced drinking behavior. The function of the AT2 site is not fully understood, but it may be involved in neuronal ion channel modulation and in fibroblast collagen metabolism. The presence of AT2 sites in fetal tissues and in discrete locations in the brain has encouraged continued research. Losartan, which represents the first of a new class of therapeutic agents, is currently undergoing clinical trials. A growing number of other AT1-selective ANG II-receptor antagonists are under development, including L-158,809, SKF 108566, and GR117285. Rat AT1-receptor subtypes have been cloned and sequenced (AT1A and AT1B). Human ANG II receptors have also been cloned and shown to have high affinity for losartan. A number of atypical angiotensin-binding sites have been identified from mycoplasma, amphibians, and mouse neuroblastoma, which are not sensitive to either losartan or PD123177.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Angiotensin II receptors and functional correlates. 129 Jun 17

Angiotensin II is the principal effector molecule of the renin-angiotensin system. Its effects are mediated by cell surface proteins termed AT receptors. On the basis of radioligand binding studies, these have been pharmacologically subdivided into two classes, termed AT1 receptors and AT2 binding sites (Chiu AT, et al, Biochem Biophys Res Commun 1989;165:196-203). AT1 receptors appear to mediate the major cardiovascular effects of angiotensin II, whereas no known physiological properties appear to be coupled to AT2 binding sites (Wong PC, et al, J Pharmacol Exp Ther 1990;255:584-592). To gain further insight into the function of AT1 receptors we have isolated rat cDNA's and genes encoding two distinct but highly similar isoforms of AT1 receptors, termed AT1a and AT1b receptors. Two cDNA's encoding the vascular AT1a receptor were isolated by an expression cloning strategy from a cDNA library prepared from vascular smooth muscle cells. The properties of the clones isolated by this approach are consistent with known pharmacological, biochemical signaling, and tissue distribution properties of AT1 receptors. Using this cDNA as a probe, a second isoform of rat AT1 receptor was isolated from a genomic library. This receptor, termed the AT1b receptor, is 95% identical in amino acid sequence and is pharmacologically indistinguishable from the AT1a receptor. However, the tissue-specific expression pattern of the AT1b gene differs significantly from that for the AT1a receptor.
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PMID:Molecular cloning of AT1 angiotensin receptors. 129 Jun 18

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.
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PMID:Angiotensin II receptor subtypes. 152 67

Membrane angiotensin II receptors were measured in trophoblastic tissues using a 2-step procedure. The first step consisted of the relative measurement performed at a fixed 125I[Sar1 Ile8]AII concentration of 0.15 nM in order to determine which tissues had a sufficient number of binding sites for studying the competition curves. The second consisted of determining the maximal binding (Bmax) and the dissociation constant (Kd) for [Sar1 Ile8] AII and the receptor subtypes in these tissues. The relative binding measurement revealed a significant number of occupied sites in rabbit fetal placenta and chorion (159 +/- 17 and 51 +/- 10 fmol/mg proteins) and in guinea pig chorion (132 +/- 12). The mean values of the other trophoblastic tissues were 3-10-fold lower in the 2 species. The competition curves obtained from tissues with high angiotensin II binding receptors showed the predominance of the AT2 subtype in rabbit fetal placenta (AT1/AT2 = 25/75) and of the AT1 receptor in guinea pig chorion (97/3) and in rabbit chorion (90/10). The [SAR1 Ile8] AII affinity (Kd) obtained from Scatchard plot analysis was 1.2 +/- 0.2 nM (n = 5) in fetal placenta and 1.2 (n = 1) in rabbit chorion and 0.5 +/- 0.1 (n = 3) in guinea pig chorion. In these tissues, the respective Bmax values were 1,281 +/- 115 (n = 5), 263 (n = 1) and 1,188 +/- 134 fmol/mg proteins (n = 3). These findings indicate that rabbit fetal placenta and chorion and guinea pig chorion are the most important sites of action for the renin-angiotensin system present in trophoblastic tissues.
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PMID:[Identification of angiotensin II receptor and determination of its subtypes in rabbit and guinea pig fetal tissue]. 157 5

DuP 753 (or EXP3174) and PD123177 are nonpeptide angiotensin (AII)-specific ligands, which show high affinities for two AII receptor subtypes, i.e. AT1 and AT2 sites, respectively. In furosemide-treated conscious dogs with high renin, DuP 753 and EXP3714, but not PD123177, were as effective as captopril in lowering blood pressure. Both DuP 753 and EXP3174 exhibited selective vascular antagonism of AII. In conscious dogs with normal renin, DuP 753, but not captopril or EXP3174, caused a dose-dependent but transient decrease in blood pressure. In anesthetized dogs, DuP 753 and captopril caused similar renal vasodilatation and natriuresis. The renal hemodynamic effects of DuP 753 and captopril were more pronounced in dogs with sodium depletion. These results suggest that the AT1 receptor mediates the pressor and renal effects of AII in dogs. The acute transient hypotensive effect of DuP 753 in normal-renin conscious dogs is probably unrelated to AII antagonism.
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PMID:Nonpeptide angiotensin II receptor antagonists. Studies with DuP 753 and EXP3174 in dogs. 174 55

Antagonists of the type 1 (AT1) angiotensin II (Ang II) receptor increase renin secretion and plasma Ang II levels, and the increased Ang II levels may counteract the effects of the antagonist. Moreover, other investigators have suggested that the reactive increase in Ang II levels may increase bradykinin (BK) levels through stimulation of the type 2 Ang II receptor (AT2). We investigated the acute effects of the AT1 receptor antagonist losartan (intraarterial injection of 10 mg/kg every 12 h) in male Sprague Dawley rats by measuring circulating angiotensin and BK peptides at 6, 12, and 24 h. Whereas acute losartan administration increased blood angiotensin levels four- to sixfold, blood BK levels were unchanged. We also investigated the effects of losartan administered for 8 days (10 mg/kg every 12 hours, by intraperitoneal injection) on circulating and tissue levels of angiotensin and BK peptides, and angiotensin-converting enzyme (ACE). Losartan increased plasma renin levels 100-fold; plasma angiotensinogen levels decreased to 24% of control; and plasma aldosterone levels were unchanged. Ang II levels in plasma, adrenal, lung, heart, and aorta were increased 25-, 8-, 3.5-, 2.4-, and 14-fold, respectively, by losartan administration. By contrast, kidney Ang II levels decreased to 71% of control, accompanied by a decrease in kidney levels of BK-(1-7) and BK-(1-9). No other tissue showed a change in BK peptide levels, except for a reduction in blood levels of BK-(1-8) to 43% of control. Plasma ACE increased by 13-50%, but tissue ACE levels were unchanged. These data demonstrate that losartan has tissue-specific effects on endogenous levels of angiotensin and BK peptides and indicate that increased BK levels do not contribute to the actions of losartan. The absence of a reactive increase in endogenous kidney levels of Ang II indicates that this tissue is likely to be the most sensitive to AT1 receptor antagonism.
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PMID:Effects of losartan on angiotensin and bradykinin peptides and angiotensin-converting enzyme. 747 48

Angiotensin II, a potent regulator of blood pressure and of water and electrolyte balance, binds to two different G-protein-coupled receptors. The type-1 receptor (AT1) mediates the vasopressive and aldosterone-secreting effects of angiotensin II, but the function of the type-2 receptor (AT2) is unknown, although it is expressed in both adult and embryonic life. To address this question, we have generated mice lacking the gene encoding the AT2 receptor. Mutant mice develop normally, but have an impaired drinking response to water deprivation as well as a reduction in spontaneous movements. Their baseline blood pressure is normal, but they show an increased vasopressor response to injection of angiotensin II. Thus, although the AT2 receptor is not required for embryonic development, it plays a role in the central nervous system and cardiovascular functions that are mediated by the renin-angiotensin system.
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PMID:Behavioural and cardiovascular effects of disrupting the angiotensin II type-2 receptor in mice. 747 66

Thyroid dysfunction produces marked cardiovascular responses; the renin-angiotensin system (RAS) is important in control of the cardiovascular system. We have measured changes in the plasma RAS and in angiotensin II (AT) receptors in experimentally hyperthyroid, euthyroid, or hypothyroid rats. Hyperthyroidism activated the plasma RAS, increasing plasma angiotensinogen by 85% after 7-day triiodothyronine (T3) treatment, plasma renin activity (PRA) by 47% and concentration by 52%, and plasma AT by 1.250%. Hypothyroidism reduced plasma angiotensinogen by 71%, PRA by 73%, and plasma AT by 81% without altering plasma renin concentration (PRC). Plasma aldosterone was reduced by 39% in hyperthyroid rats and by 95% in hypothyroid rats. AT receptors were characterized in heart, liver, adrenal gland, and kidney. Cardiac, liver, and kidney AT receptor densities increased in hyperthyroidism by 73, 113, and 75%, respectively; adrenal gland receptor density decreased by 39%. Similar results were observed in hypothyroidism except that adrenal gland receptor density was markedly increased by 205%. AT receptor subtypes were characterized in ventricular homogenates by the selective antagonist losartan. Hyperthyroidism markedly increased AT2-subtype density by 204% in left ventricle, and by 304% in right ventricle and decreased AT1-subtype density by 38% and 31% in left and right ventricles, respectively. AT2-subtype density increased by 168% in hypothyroid rats; AT1-subtype density was unchanged. Thyroid dysfunction causes significant changes in the RAS and in AT receptor density, especially of the AT2 subtype. Although a physiological function has not yet been reported for AT2 receptors, our results suggest that selective AT2-receptor antagonists may prove therapeutically useful in treatment of cardiovascular disease in thyroid dysfunction.
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PMID:Renin-angiotensin system in thyroid dysfunction in rats. 750 37

Recent studies have revealed that angiotensin II (Ang II) interacts with two pharmacologically different types of seven-transmembrane domain receptors, hence named Ang II type 1 and type 2 (AT1 and AT2) receptors. cDNAs for the AT1 receptor have been cloned, and the existence of two receptor subtypes, AT1A and AT1B, has been revealed in rat and mouse. This study presents a new approach for the specific quantification of AT1A and AT1B receptor mRNAs by reverse transcription and polymerase chain reaction amplification in the presence of an AT1 receptor mutant cRNA as internal standard. Absolute quantities of mRNA are then determined by extrapolation using the standard curve generated with the internal standard. Moreover, addition of this internal standard to each tube controls for both reverse transcription and polymerase chain reaction amplification in each sample. In male Wistar rats, the highest absolute AT1A receptor mRNA levels were found in liver and kidney and those for AT1B receptor mRNA in the pituitary. Expressed as a percentage of total AT1A+AT1B receptor mRNA content, AT1A receptor mRNA content was 100% in liver, 85% in lung, 73% in kidney, 65% in aorta, 48% in adrenals, and 15% in the hypophysis. Since this approach can determine absolute AT1A and AT1B receptor mRNA quantities in different organs, it allows the study of the regulation of their expression under different pathophysiological conditions. After sodium depletion, known to induce hyperactivity of the renin-angiotensin system, adrenal AT1A and AT1B receptor mRNA levels were increased by 60% and 110%, respectively. In contrast, in renovascular hypertension (two-kidney, one clip), also associated with elevated circulating plasma renin activity, adrenal AT1B receptor mRNA levels decreased by 50%, whereas there was no change in those of AT1A. Therefore, the differential distribution and regulation of these two receptor subtypes suggest that each of them might be involved in the mediation of different biological effects of Ang II.
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PMID:Tissular expression and regulation of type 1 angiotensin II receptor subtypes by quantitative reverse transcriptase-polymerase chain reaction analysis. 752 76

We examined the pharmacological properties of U-97018, a novel nonpeptide angiotensin II (AII) receptor antagonist, in various in vitro and in vivo studies. U-97018 selectively displaced 125I-AII specific binding in the membrane fraction derived from the rat mesenteric artery and adrenal cortex (AT1 subtype) with IC50 of 1.3 +/- 0.2 and 7.7 +/- 1.3 nM, respectively, without altering the AII binding of the rat adrenal medulla (AT2 subtype). In rat adrenal cortical cells, U-97018 inhibited 1 nM AII-induced aldosterone secretion with an IC50 of 0.48 nM; it shifted concentration-secretion response curve for AII to the right and inhibited the maximal response to AII, yielding a pKB of 9.8. Similarly, U-97018 showed insurmountable antagonism with a pKB of 10.6 against the AII-induced contraction in the isolated rabbit aorta. U-97018 had no direct effect on the activities of renin and angiotensin converting enzyme in vitro. In pithed rats, U-97018 inhibited the AII-induced pressor response with an ED50 of 0.28 mg/kg, i.v. without any partial agonistic activity. In anesthetized rats and dogs, intraduodenal administration of U-97018 at a dose of 1 mg/kg inhibited the AII-induced pressor response by about 60%. In spontaneously hypertensive rats, U-97018 at 10 mg/kg p.o. produced antihypertensive effects which lasted for 24 hr after administration. Thus, U-97018 is an orally active, insurmountable AII receptor antagonist without any agonistic activity.
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PMID:Pharmacological characterization of the nonpeptide angiotensin II receptor antagonist, U-97018. 756 67


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