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Development of specific angiotensin II receptor ligands has recently provided evidence for the existence of two angiotensin II receptor subtypes, termed AT1 and AT2, which differ in their signal transduction mechanisms and in the effects they mediate. In brain, both receptor subtypes are present. Most of the known central actions of angiotensin II, for example the regulation of blood pressure and of electrolyte and water balance, seem to be mediated by the AT1 receptor, while the role of the AT2 receptor is still an enigma. This review by Thomas Unger and colleagues summarizes the current knowledge and latest hypotheses in this rapidly developing field.
Trends Pharmacol Sci 1992 Sep
PMID:Angiotensin receptor subtypes in the brain. 152 81

Angiotensin (AII) is associated with increased vascular smooth muscle growth and we have found increased levels of tissue AII during healing of wounded skin. Here we have determined changes in skin AII receptors during wound healing in adult male Sprague-Dawley rats. An abdominal surgical incision was made under anesthesia and rats were sacrificed at different times after wounding. Specific binding of 125I-AII was significantly decreased at 12, 18 and 24 hours in the wounded tissue compared to control tissue from the same rat. By 3 days the binding had recovered to baseline levels. Receptors were mostly AT1, with a high and a low affinity site in the skin both in control and healing tissue. The Bmax of the high affinity site was significantly decreased in healing tissue but there was no significant change in Kd. Our results demonstrate that adult rat skin contains predominantly AT1 receptors and also that these receptors are downregulated for 12-24 hours after wounding.
Biochem Biophys Res Commun 1992 Sep 16
PMID:Changes in skin angiotensin II receptors in rats during wound healing. 153 Jun 5

The angiotensin II (ANG II) receptor has recently been shown to exhibit subtypes with respect to antagonist binding. Of particular interest are the potent nonpeptide antagonists, DUP 753 and PD 121981, which exhibit selectivity for the subtype 1 (AT1) and subtype 2 (AT2) receptors, respectively. We used these high-affinity antagonists in competition with 125I-[Sar1,Ile8]ANG II to determine autoradiographically the distribution of these ANG II-receptor subtypes in the renal cortex of rats and rhesus monkeys. Binding of the radioligand to receptor in sections of rat renal cortex was inhibited by DUP 753; inhibition by PD 121981 was not detected. By contrast, AT1 and AT2 receptors are present in the renal cortex of rhesus monkeys in regionally distinct structures. DUP 753 inhibited binding to the ANG II receptor in glomeruli. PD 121981 inhibited binding to arterial smooth muscle and the juxtaglomerular (JG) apparatus. The JG apparatus also exhibits radioligand binding, which is inhibited by DUP 753. The effect of DUP 753 and PD 123177 (a more water-soluble analogue of PD 121981) on changes in plasma renin activity was examined to determine if one or both of these subtypes participate in the ANG II-mediated negative feedback of control of renin release. Although DUP 753 increased plasma renin activity to the same extent as the angiotensin-converting enzyme inhibitor, enalaprilat, in rats and rhesus monkeys, the AT2 antagonists did not affect renin release in either species. Thus both subtypes of ANG II receptor are present in rhesus monkey cortex, but a function for only the AT1 subtype was demonstrated.
Am J Physiol 1991 Sep
PMID:Angiotensin II receptor subtypes in renal cortex of rats and rhesus monkeys. 165 32

Angiotensin II (AII) receptor subtypes and their potential coupling mechanisms were studied using recently developed peptide and nonpeptide antagonists in rat and bovine adrenal zona glomerulosa cells, as well as in membranes prepared from rat and bovine adrenal cortex and medulla. Comparison of the potencies of these novel antagonists to displace 125I-[Sar1,Ile8]AII from its binding sites revealed two distinct AII binding sites in membranes prepared from rat adrenal capsules (zona glomerulosa) and from rat adrenal inner zones containing the medulla. About 85% of the binding sites of the glomerulosa zone and 30% of those of the inner zones were of the AT1 subtype, with relative affinities for the nonpeptide antagonists Dup 753 and PD 123177 and the peptide antagonist CGP 42112A in the order of Dup 753 much greater than CGP 42112A greater than PD 123177. In contrast, the relative binding potencies for the other (AT2) population of binding sites were CGP 42112A greater than PD 123177 much greater than Dup 753. Neither AII nor its peptide antagonist [Sar1,Ile8]AII could distinguish between the two sets of binding sites. The effects of the new antagonists on functional responses of rat adrenal glomerulosa cells demonstrated that both AII-stimulated aldosterone production and the AII-induced inhibition of adrenocorticotropic hormone-stimulated cAMP formation were mediated by the AT1 receptor subtype. In bovine adrenals, only AT1 receptors were detected in membranes prepared from the cortex and the medulla, as well as in cultured glomerulosa cells. The relative inhibitory potency of Dup 753 was lower by an order of magnitude at bovine than at rat AT1 receptors. The inhibition of AII-induced aldosterone production by the various antagonists was closely correlated with their inhibitory potencies on 125I-[Sar1,Ile8]AII binding to bovine glomerulosa cells. These data suggest that the known effects of AII in adrenal glomerulosa cells are mediated through the AT1 receptor subtype and that the distribution and/or specificity of the AT2 receptors shows marked species variations.
Mol Pharmacol 1991 Sep
PMID:Angiotensin II receptor subtypes and biological responses in the adrenal cortex and medulla. 165 13

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.
Eur J Pharmacol 1991 Sep 24
PMID:Nonpeptide angiotensin II receptor antagonists. Studies with DuP 753 and EXP3174 in dogs. 174 55

The angiotensin II receptor subtype-specific antagonists Dup 753 (AT1) and PD 123177 (AT2) were used to characterize the angiotensin II receptor subtypes present in 18 day gestation fetal Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rat brain using in vitro receptor autoradiography. The AT2 subtype was predominant in the brain of both rat strains, even in areas that display predominantly the AT1 subtype in the adult rat brain.
Brain Res 1991 Sep 27
PMID:The AT2 angiotensin receptor subtype predominates in the 18 day gestation fetal rat brain. 176 Jul 41

Both neurons and astrocytes contain specific receptors for angiotensin II (AII). We used selective ligands for the AT1 and AT2 types of AII receptors to investigate the expression of functional receptor subtypes in astrocyte cultures and neuron cultures from 1-day-old (neonatal) rat brain. In astrocyte cultures, competition of 125I-labeled AII (125I-AII) specific binding with AT1 (DuP753) or AT2 (PD123177, CGP42112A, [Phe(p-NH2)6]AII) selective receptor ligands revealed a potency series of AII greater than DuP753 much greater than CGP42112A greater than [Phe(p-NH2)6]AII greater than PD123177. These results suggest a predominance of the AT1 receptor subtype in neonatal astrocytes. Also, in astrocyte cultures, AII stimulated increases in inositolphospholipid hydrolysis that were significantly reduced by the AT1 receptor antagonist DuP753 but not altered by the AT2 receptor antagonist PD123177. In neonatal neuron cultures, competition of 125I-AII specific binding with the above ligands revealed a potency series of CGP42112A = AII greater than [Phe(p- NH2)6]AII greater than PD123177 much greater than DuP753. 125I-AII specific binding to neonate neuronal cultures was reduced 73-84% by 1 microM PD123177, and the residual 125I-AII specific binding was eliminated by DuP753. Also, in neuron cultures, AII induced decreases in basal cGMP that were completely blocked by PD123177 or CGP42112A but not by DuP753. Our results suggest that astrocyte cultures from neonatal rat brains contain predominantly AT1 receptors that are coupled to a stimulation of inositophospholipid hydrolysis. In contrast, neuron cultures from neonatal rat brain contain mostly AT2 receptors that are coupled to a reduction in basal cGMP levels, but a smaller population of AT1 receptors is also present in these neurons.
Proc Natl Acad Sci U S A 1991 Sep 01
PMID:Angiotensin II receptor subtypes are coupled with distinct signal-transduction mechanisms in neurons and astrocytes from rat brain. 188 96

Angiotensin II is known primarily for its effects on blood pressure and electrolyte homeostasis, but recent studies suggest that angiotensin II may play a role in the regulation of cellular growth. This study was undertaken to identify the angiotensin II receptor subtypes expressed during fetal and neonatal development and to characterize their cellular localization. Using an in situ receptor binding assay on sagittal frozen sections of fetal and neonatal rats, bound 125I-[Sar1,Ile8]-angiotensin II was visualized by film and emulsion autoradiography. Bound radioligand was detected by E11 (embryonic day 11) and maximal binding occurred by E19-21. Radioligand binding remained unaltered 30 min after birth, whereas a noticeable and stable decrease was observed 12 h postparturition. The highly abundant angiotensin II receptors were shown to be AT2 by the marked reduction in radioligand binding achieved with PD123177 (10(-7)M), a specific AT2 receptor antagonist, whereas DuP 753 (10(-5)M), an AT1 receptor antagonist, had little effect. Emulsion autoradiography showed radioligand binding in the undifferentiated mesenchyme of the submucosal layers of the intestine and stomach, connective tissue and choroid surrounding the retina, subdermal mesenchyme adjacent to developing cartilage, diaphragm, and tongue. Residual AT2 receptors were found on the dorsal subdermal region of the tongue 72 h after birth. AT1 receptors were detected in the placenta at E13 and in the aorta, kidney, lung, liver, and adrenal gland at E19-21, consistent with an adult distribution. The transient expression of AT2 receptors in the mesenchyme of the fetus suggests a role of angiotensin II in fetal development.
J Clin Invest 1991 Sep
PMID:Expression of AT2 receptors in the developing rat fetus. 188 77

Quantitative autoradiography using the agonist 125I-Sar1-angiotensin II was used to localize and characterize angiotensin II (AT) receptors in the anterior cerebral artery of the male rat. This artery showed a moderately high number of AT receptors, localized throughout the arterial wall. The number of receptors was higher (125 +/- 7 fmol/mg protein) in arteries from young 2-wk-old rats compared with those in adult 8-wk-old rats (43 +/- 2 fmol/mg protein). In the anterior cerebral artery, AT binding was insensitive to displacement with the selective AT1 antagonist DuP 753 but was readily displaced by the selective AT2 antagonist CGP-42112 A (concentration eliciting 50% of maximum inhibition: 6 +/- 1 x 10(-10) M). This indicated that the AT receptors in the cerebral artery were of the AT2 subtype. Our observations suggest that AT may exert its effects on cerebral circulation by stimulation of AT2 receptors and that these receptors may play a role during cerebrovascular development.
Am J Physiol 1991 Sep
PMID:Characterization of AT2 angiotensin II receptors in rat anterior cerebral arteries. 188 16

The present study examines the effects of prolonged angiotensin II antagonism in spontaneously hypertensive rats by using an angiotensin II receptor antagonist (DuP 753) that is devoid of agonistic properties and selective for the subtype 1 of the angiotensin II (AT1) receptor. The antihypertensive effects of DuP 753 and its effects on circulating parameters of the renin-angiotensin system were compared with those of a converting enzyme inhibitor (benazeprilat). To minimize any influence of differences in the pharmacokinetic properties of the two blockers, administration was by continuous intravenous infusion. The experiments were performed in conscious, freely moving rats with continuous 24-hour monitoring of blood pressure. DuP 753 (10 or 30 mg/kg/day) lowered mean arterial pressure to the same extent as benazeprilat (3 or 10 mg/kg/day) during a 48-hour period. The antihypertensive effect was sustained when the treatment was extended to 7 days (DuP 753, 10 mg/kg/day; benazeprilat, 3 mg/kg/day). Neither of the compounds affected the baseline or diurnal rhythm of heart rate. Plasma concentrations of renin and angiotensin II were increased sevenfold and 10-fold, respectively, in the rats treated with DuP 753. In rats treated with benazeprilat, plasma renin concentration increased threefold, whereas angiotensin II was unchanged. Heart weights were significantly reduced to a similar extent by DuP 753 and benazeprilat. Both compounds also induced a smaller but significant decrease in blood pressure in Wistar-Kyoto rats. Our results indicate that the antihypertensive effects of converting enzyme inhibitors in spontaneously hypertensive rats are mainly due to the blockade of the renin-angiotensin system. In this rat model, angiotensin II appears to play an important role in the maintenance of hypertension that is mediated via the AT1 receptor.
Hypertension 1991 Sep
PMID:Prolonged angiotensin II antagonism in spontaneously hypertensive rats. Hemodynamic and biochemical consequences. 188 42


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