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M A Millan

Publications and source records attributed to M A Millan.

At least 19 recordsLinked to original sources
PubMed1993

Angiotensin II binding sites in the rat fetus: characterization of receptor subtypes and interaction with guanyl nucleotides.

Angiotensin II (AII) receptor subtypes were studied in the 18-day gestation fetal rat, using two non-peptide AII antagonists: (2-n-butyl-4-chloro-5-hydroxymethyl-1-(2'-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl)imidazol (DuP 753; type 1 (AT1) specific), and 1-(4-amino-3-methylphenyl)methyl-5-diphenacetyl -4,5,6,7-tetrahydro-1-H-imidazo[4,5-c]pyridine-6-carboxylic acid (PD 123177; type 2 (AT2) specific). Autoradiography using 125I(-)[Sar1,Ile8]AII showed that 10 microM PD 123177 decreased binding to near-nonspecific levels in skin, skeletal muscle and adrenal medulla, whereas 10 microM DuP 753 blocked binding in the liver and lung. Studies in skin and liver membranes confirmed the autoradiographic data: AT1 receptors were predominant in the liver (95%), and AT2 in the skin (97%). There was no cross-reactivity between receptor subtype and the heterologous antagonist up to a concentration of 10 microM. In both skin and liver, 2 mM dithiothreitol enhanced the binding of AT2 receptors by increasing receptor affinity, but inhibited binding of AT1 by decreasing the receptor number. In the absence of antagonists, guanyl nucleotides, added at equilibrium, caused marked dissociation of 125I-AII binding in liver membranes, but had minimal effect in skin. However, dissociation occurred in the skin when AT2 sites were blocked with 10 microM PD 123177, and in liver, dissociation was not observed when AT1 sites were blocked with DuP 753. Hence, in contrast to classical AII target tissues, which contain predominantly AT1, most of the sites in fetal skin and skeletal muscle are AT2. The demonstration that the effects of guanyl nucleotides are selective for receptor subtype suggests that the AT1 receptor, but not the AT2, is coupled to cell function via guanyl nucleotide binding proteins. The functional importance of the AT2 receptors and their role in fetal physiology is under current investigation.

Adrenal Glands↗
PubMed1991

Differential distribution of AT1 and AT2 angiotensin II receptor subtypes in the rat brain during development.

Angiotensin II (AII) receptor subtypes were analyzed in the brains of adult and 2-week-old rats by in vitro autoradiography with 125I-labeled [Sar1,Ile8]AII and competition studies with three AII antagonists: the nonpeptide antagonist, DuP 753, which is specific for AT1 receptors that mediate the calcium-inositol phospholipid signaling actions of AII; and nonpeptide (PD 123177) and peptide (CGP 42112A) antagonists that are selective for AT2 receptors of yet unknown function. In the adult rat brain, DuP 753 inhibited radioligand binding to the circumventricular organs and paraventricular nucleus but not to the lateral septum, subthalamic nucleus, and inferior olive. However, binding of 125I-labeled [Sar1,Ile8]AII in the latter regions was inhibited by the AT2 receptor antagonists PD 123177 and CGP 42112A. These areas showed similar displacement by the AT2 receptor subtype-specific antagonists in 2-week-old rats. In addition, radioligand binding at multiple sites of transient expression of AII receptors in 2-week-old rats, including several thalamic nuclei, the nuclei of the 3rd and 12th cranial nerves, geniculate bodies, cerebellum, and cingulate cortex, was displaced by the AT2 antagonists but not by DuP 753. These studies have demonstrated the presence of two AII receptor subtypes in the brain, one (AT1) in areas related to regulation of blood pressure, water intake, and pituitary hormone secretion, and one (AT2) whose function is not yet defined. The abundance and location of brain AT2 receptors in young animals, and the age-related changes in relative expression of the receptor subtypes, suggest that AII exerts specific actions according to the developmental stage of the central nervous system.

Aging↗
PubMed1991

Amphibian myocardial angiotensin II receptors are distinct from mammalian AT1 and AT2 receptor subtypes.

High-affinity receptors for angiotensin II were identified on Xenopus laevis cardiac membranes and characterized by binding-inhibition studies with peptide and non-peptide AII antagonists. Scatchard analysis of the binding data identified a high-affinity site with Kd1 = 1.6 nM and Bmax1 = 3.7 pmol/mg protein and a low-affinity site with Kd2 = 22 nM and Bmax 2 = 9.5 pmol/mg protein. Treatment with dithiothreitol reduced the number of binding sites by greater than 70%. The rank order of potency for ALL analogs was (agent, IC50) [Sar1,Ile8]AII, 0.91 nM greater than AII, 2.0 nM greater than AI, 5.3 nM greater than [Sar1, Ala8]AII, 19 nM much greater than CGP42112A, 1.2 microM much much greater than DuP 753 approximately PD-123177, greater than 100 microM. The relative potencies of these compounds differ markedly from their activities on the two known mammalian AII receptor subtypes, AT1 and AT2. These results indicate that amphibian AII receptors are pharmacologically distinct from both the AT1 and AT2 receptors characterized in mammalian tissues.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1990

Angiotensin II-induced calcium mobilization in oocytes by signal transfer through gap junctions.

Angiotensin II (AII) stimulates rapid increases in the concentration of cytosolic calcium in follicular oocytes from Xenopus laevis. This calcium response was not present in denuded oocytes, indicating that it is mediated by AII receptors on the adherent follicular cells. The endogenous AII receptors differed in their binding properties from mammalian AII receptors expressed on the oocyte surface after injection of rat adrenal messenger RNA. Also, the calcium responses to activation of the amphibian AII receptor, but not the expressed mammalian AII receptor, were blocked reversibly by octanol and intracellular acidification, treatments that inhibit cell coupling through gap junctions. In addition, AII increased the rate of progesterone-induced maturation. Thus, an AII-induced calcium-mobilizing signal is transferred from follicle cells to the oocyte through gap junctions and may play a physiological role in oocyte maturation.

Aequorin↗
PubMed1990

Characterization and distribution of angiotensin-II receptors in the primate fetus.

The binding characteristics and distribution of angiotensin-II (AII) receptors were studied in Cynomolgus monkey fetuses and one second trimester human fetus. In contrast to the adult monkey, in which binding was confined to the adrenal gland, kidney, and smooth muscle, autoradiographic studies in the monkey fetus revealed the presence of high density binding in mesenchymal tissue throughout the body, especially in skeletal muscle and dermis. In the kidney at 11 weeks, binding was mainly associated with connective tissue surrounding primitive nephrons, while at 17 weeks, binding distribution was similar to that in the adult primate kidney, being confined to the glomeruli and smooth muscle of blood vessels, with low binding in the tubules. In fetal monkey adrenal, binding was high in the medulla and connective tissue of the capsule, and low in the zona glomerulosa, while in the adult, binding was high in the zona glomerulosa and medulla. In membrane preparations from fetal monkey skin and skeletal muscle, binding was specific for AII analogs, but in contrast to the adult adrenal, it was not affected by guanyl nucleotides. Scatchard analysis showed a single class of sites with a Kd of 0.6 +/- 0.1 nM and a capacity of 3060 +/- 8.3 fmol/mg, higher than that of the adult adrenal glomerulosa (605 +/- 30 fmol/mg). Specific binding for AII analogs was also present in human fetal skin and skeletal muscle membranes, where Scatchard analysis indicated a Kd of 0.8 nM and a binding capacity of 640 fmol/mg. The transient expression of abundant AII receptors during the phase of rapid growth in the fetus in conjunction with the known effects of AII on cellular growth suggest a role for AII during fetal development in the primate.

Adrenal Glands↗
PubMed1989

Novel sites of expression of functional angiotensin II receptors in the late gestation fetus.

In the adult, the peptide hormone angiotensin II (AII) is primarily known as a regulator of circulatory homeostasis, but recent evidence also suggests a role in cell growth. This study of AII in late gestation rat fetuses revealed the unexpected presence of receptors in skeletal muscle and connective tissue, in addition to those in recognized adult target tissues. The AII receptors in this novel location decreased by 80 percent 1 day after birth and were almost undetectable in the adult. Studies in fetal skin fibroblasts showed that the receptors were coupled to phospholipid breakdown, with concomitant increases in inositol phosphate and cytosolic calcium. The abundance, timing of expression, and unique localization of functional AII receptors in the fetus suggest a role for AII in fetal development.

Angiotensin II↗
PubMed1989

Angiotensin II receptors in the gonads.

The presence of components of the renin-angiotensin system in ovaries and testes suggests that angiotensin II (AII) is involved in gonadal function, and thus we sought to characterize receptors for AII in rat and primate gonads. In the testes, autoradiographic studies showed receptors in the interstitium in all species. In rat interstitial cells fractionated by Percoll gradient, AII receptors coincided with hCG receptors indicating that AII receptors are located on the Leydig cells. In Leydig cells and membranes from rat and rhesus monkey prepuberal testes, AII receptors were specific for AII analogues and of high affinity (Kd=nM). During development, AII receptor content in rat testes decreases with age parallel to a fall in the ratio of interstitial to tubular tissue. In the ovary, the distribution of AII receptors was dependent on the stage of development, being high in the germinal epithelium and stromal tissue between five and 15 days, and becoming localized in secondary follicles in 20-and 40-day-old rats. No binding was found in primordial or primary follicles. In rhesus monkey ovary, AII receptors were higher in stromal tissue and lower in granulosa and luteal cells of the follicles. Characterization of the binding in rat and monkey ovarian membranes showed a single class of sites with a Kd in the nmol/L range and specificity similar to that of the adrenal glomerulosa and testicular AII receptors. Receptors for AII were also present in membrane fractions from PMSG/hCG primed rat ovaries. Infusion of AII (25 ng/min) or captopril (1.4 micrograms/min) during the PMSG/hCG induction period had no effect on ovarian weight or AII receptor concentration in the ovaries.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1989

Distribution of angiotensin II receptors and renin in the mouse fetus.

To investigate the ontogeny of the renin-angiotensin system we studied the characteristics and location of angiotensin II (AII) receptors in mouse fetuses and examined sites of renin mRNA expression by in situ hybridization and Northern blot analysis. Autoradiographic analysis of the binding of 125I-[Sar1,Ala8]AII to slide-mounted frozen sections of 17-day-old DBA/2N mice revealed abundant AII receptors widely distributed throughout the body. High receptor density was found in primitive mesenchymal tissue under the epidermis and surrounding muscle and cartilage, in skeletal and smooth muscle, and in all layers of the adrenal cortex. Lower receptor density was seen in the kidney, liver, and lungs. The autoradiographic staining was abolished by incubation of the sections with excess unlabeled AII. Scatchard analysis of the binding of 125I-[Sar1,Ala8,]AII to membrane-rich fractions of eviscerated fetuses showed a single type of high affinity receptors with a Kd of 2.9 x 10(-9) M and a receptor concentration of 3300 fmol/mg protein. Localization of renin mRNA was analyzed by in situ hybridization using an antisense 35S-labeled riboprobe transcribed from a mouse renin2 cDNA clone. Hybridization to fetal tissue sections showed high intensity staining in the kidney and adrenal cortex. Northern blot analysis confirmed the high expression of renin mRNA in the fetal kidney. The presence of an active renin-angiotensin system in the fetus was confirmed by the demonstration of renin-like activity and bioactive AII in fetal extracts. The widespread distribution of AII receptors in the fetus, compared to the discrete localization to specialized tissues in the adult, may indicate a unique role for the peptide during development.

Angiotensin II↗
PubMed1988

Angiotensin II receptors in testes.

Receptors for angiotensin II (AII) were identified and characterized in testes of rats and several primate species. Autoradiographic analysis of the binding of 125I-labeled [Sar1,Ile8]AII to rat, rhesus monkey, cebus monkey, and human testicular slide-mounted frozen sections indicated specific binding to Leydig cells in the interstitium. In rat collagenase-dispersed interstitial cells fractionated by Percoll gradient, AII receptor content was parallel to that of hCG receptors, confirming that the AII receptors are in the Leydig cells. In rat dispersed Leydig cells, binding was specific for AII and its analogs and of high affinity (Kd, 4.8 nM), with a receptor concentration of 15 fmol/10(6) cells. Studies of AII receptors in rat testes during development reveals the presence of high receptor density in newborn rats which decreases toward the adult age (4934 +/- 309, 1460 +/- 228, 772 +/- 169, and 82 +/- 12 fmol/mg protein at 5, 15, 20, and 30 days of age, respectively) with no change in affinity. At all ages receptors were located in the interstitium, and the decrease in binding was parallel to the decrease in the interstitial to tubular ratio observed with age. AII receptor properties in membrane-rich fractions from prepuberal testes were similar in the rat and rhesus monkey. Binding was time and temperature dependent, reaching a plateau at 60 min at 37 C, and was increased by divalent cations, EGTA, and dithiothreitol up to 0.5 mM. In membranes from prepuberal monkey testes, AII receptors were specific for AII analogs and of high affinity (Kd, 4.2 nM) with a receptor concentration of 7599 +/- 1342 fmol/mg protein. The presence of AII receptors in Leydig cells in rat and primate testes in conjunction with reports of the presence of other components of the renin-angiotensin system in the testes suggests that the peptide has a physiological role in testicular function.

Aging↗
PubMed1988

Corticotropin-releasing factor receptors and pituitary adrenal responses during immobilization stress.

The regulation of pituitary and brain CRF receptors and corticotroph responses during stress were studied in rats subjected to prolonged immobilization. Plasma ACTH levels showed the characteristic biphasic changes, with a rapid 23-fold increase in 15 min, followed by a decrease to about twice the basal levels after 6-h immobilization. In contrast, plasma corticosterone levels were markedly elevated throughout the duration of the stress. Pituitary CRF receptor content, measured by binding of [125I]Tyr-ovine CRF to pituitary membrane-rich fractions, was unchanged after 2.5 h, but was reduced by 28 +/- 2.7% (+/- SE) and 47.6 +/- 1.1% after 18 and 48 h of immobilization, respectively. These results were confirmed by autoradiography in slide-mounted frozen pituitary sections. In contrast, no changes in CRF receptor content were observed in brain areas, including olfactory bulb, frontoparietal cortex, hippocampus, amygdala, and lateral septum. A concomitant decrease in immunoreactive (ir) CRF content in the median eminence of rats immobilized for 48 h is consistent with the hypothesis that increased release of CRF into the portal circulation occurs during chronic stress. Despite pituitary CRF receptor loss and reduced in vitro responses to CRF, the increases in plasma ACTH and corticosterone in vivo after ether exposure or CRF injection were greater and more prolonged in rats immobilized for 48 h than in nonimmobilized controls. The decrease in pituitary CRF receptors was accompanied by decreased CRF-stimulated cAMP and ACTH release in cultured pituitary cells from 48-h restrained rats. However, concomitant incubation of cells with CRF and vasopressin restored cAMP and ACTH responses to control levels, suggesting that the simultaneous release of both regulators from the hypothalamus determines the plasma ACTH level. These findings indicate that the decrease in plasma ACTH during the adaptation phase to stress is accompanied by decreases in pituitary CRF receptors. However, the enhanced pituitary response to a superimposed stress or CRF injection implies that the decrease in plasma ACTH levels during prolonged stress may be due to adaptive changes at the central level. These findings emphasize the importance of the integrated actions of CRF and other regulators in the control of the pituitary adrenal-axis during stress.

Adrenal Glands↗
PubMed1987

Differential regulation of brain and pituitary corticotropin-releasing factor receptors by corticosterone.

The regulatory actions of CRF during the neuroendocrine response to stress are mediated by specific receptors within the nervous system and the anterior pituitary gland. Glucocorticoids exert negative feedback inhibition on ACTH secretion by interacting at the pituitary corticotrophs and the central nervous system. To determine whether glucocorticoids influence ACTH secretion by regulating the concentration of CRF receptor sites, binding of [125I]Tyr-oCRF to pituitary and brain membrane-rich particles was studied after glucocorticoid treatment. Corticosterone administration (0.5-150 mg/day) for 1-4 days in adult male rats caused a dose-dependent decrease in the number of CRF receptors in the anterior pituitary in parallel with the reduction in ACTH secretion. In the brain, binding studies in membrane-rich fractions or by autoradiography in slide-mounted frozen sections revealed no changes in CRF receptors in the cortex, hippocampus, amygdala, septal area, and olfactory bulb, although circulating corticosterone levels were higher than during stress. The selective down-regulation of anterior pituitary CRF receptors after corticosterone administration, without alterations in brain CRF receptors, is similar to the change in CRF receptors previously reported after adrenalectomy and indicates that receptor regulatory mechanisms in secretory cells differ from those in neural tissue. Furthermore, the decrease in pituitary CRF receptors after physiological increases in circulating glucocorticoids may contribute to the inhibitory effects of adrenal steroids on ACTH secretion.

Adrenocorticotropic Hormone↗
PubMed1987

Receptors and actions of corticotropin-releasing hormone in the primate pituitary gland.

Receptors for CRH were identified in the pituitary gland of several primate species, and their binding characteristics were compared to the ability of CRH to elicit ACTH and cAMP responses in vitro. Autoradiographic analysis of the binding of [125I]Tyr-ovine CRH to frozen pituitary sections revealed CRH receptors in the intermediate and anterior lobes of human, marmoset, and cynomolgus monkey pituitaries. In the cynomolgus monkey, a high density of CRH receptors was present throughout the anterior and intermediate lobes. In the human pituitary, binding was concentrated in the anteromedial portion of the gland, whereas in the marmoset, binding was dense in the intermediate lobe and scattered as clusters throughout the anterior lobe. In membrane-rich fractions from the cynomolgus pituitary binding of [125I]Tyr-ovine CRH was time and temperature dependent, and was specific for CRH-related peptides; specific binding was increased by divalent cations and inhibited by guanyl nucleotides. Scatchard analyses of the binding data revealed a single class of high affinity sites [Kd, 1.93 +/- 0.23 (+/- SEM) nM], with a receptor concentration of 605 +/- 121 fmol/mg. In marmoset pituitary membranes, there were fewer receptors (200 +/- 15 fmol/mg), in agreement with the lower autoradiographic density of CRH binding. In anterior pituitary cell cultures from cynomolgus monkeys, CRH caused a dose-dependent stimulation of cAMP production and ACTH release, with half-maximum effective concentrations in the range of the CRH receptor affinity. Vasopressin and norepinephrine stimulated ACTH release to a much lesser extent, but both potentiated the stimulatory effect of CRH. Angiotensin II had no effect alone, but it also potentiated the effect of CRH. These data demonstrate the presence of CRH receptors in the primate pituitary, with characteristics similar to those in other species in their binding properties, coupling to adenylate cyclase, and functional interactions with other regulators of ACTH secretion that mediate the stimulatory effect of the peptide in the corticotroph.

Adrenocorticotropic Hormone↗
PubMed1987

Brain receptors for hypothalamic hormones.

Angiotensin II and CRF are but two of the several regulatory peptides which exert specific actions in the brain that are complementary with their peripheral effects upon end organs such as the anterior pituitary and adrenal glands. In the pituitary, the two peptides act in a coordinate manner on the corticotroph to regulate ACTH release. In the adrenal gland, angiotensin II receptors are abundant in the zona glomerulosa but are also present in the medulla, where the occurrence of CRF receptors and actions on catecholamine release reveals an additional site at which the two peptides exert related actions, in this case in the peripheral neuroendocrine system. Within the brain, the mapping of AII and CRF binding sites by topical autoradiography has provided new information about the distribution and potential functions of receptors for the two peptides. The central receptors for AII are distributed in a characteristic pattern in brain regions concerned with drinking, regulation of adrenergic function and arterial blood pressure, and control of pituitary hormone secretion. Thus, in addition to its recognized modulatory effects in the peripheral adrenergic system, angiotensin II may be involved in the central control of catecholamine release and action. A central action of AII on the release of regulatory peptides such as vasopressin and CRF, both of which are present in neurones of the paraventricular nucleus, is indicated by the high concentration of AII receptors in this region. Also, the high density of AII receptors in the median eminence suggests that AII modulates the hypothalamic secretion of neuropeptides such as CRF by actions at their site of release, as well as on the cell bodies of neurones responsible for peptide synthesis. The highly localized pattern of AII receptors at numerous specific sites in the brain differs from the more general distribution of many other CNS receptors, and reflects the selective actions of AII on discrete neural systems that subserve precisely integrated functions within the central nervous system. The widespread distribution of CRF receptors, with prominent localization in the cortical and limbic regions, is consistent with the more general neuroregulatory actions of CRF in the brain, and with the presence of immunoreactive CRF in several regions of the brain including the cortex, limbic system, and centers involved in the control of autonomic function. The cortical and limbic receptors are clearly relevant to the effects of centrally administered CRF on both behavioral and visceral responses, with prominent autonomic changes including increased catecholamine release and hypertension.

Angiotensin II↗
PubMed1986

Distribution of corticotropin-releasing factor receptors in primate brain.

The distribution and properties of receptors for corticotropin-releasing factor (CRF) were analyzed in the brain of cynomolgus monkeys. Binding of [125I]tyrosine-labeled ovine CRF to frontal cortex and amygdala membrane-rich fractions was saturable, specific, and time- and temperature-dependent, reaching equilibrium in 30 min at 23 degrees C. Scatchard analysis of the binding data indicated one class of high-affinity sites with a Kd of 1 nM and a concentration of 125 fmol/mg (approximately equal to 30% of the receptor number in monkey anterior pituitary membranes). As in the rat pituitary and brain, CRF receptors in monkey cerebral cortex and amygdala were coupled to adenylate cyclase. Autoradiographic analysis of specific CRF binding in brain sections revealed that the receptors were widely distributed in the cerebral cortex and limbic system. Receptor density was highest in the pars tuberalis of the pituitary and throughout the cerebral cortex, specifically in the prefrontal, frontal, orbital, cingulate, insular, and temporal areas, and in the cerebellar cortex. A very high binding density was also present in the hippocampus, mainly in the dentate gyrus, and in the arcuate nucleus and nucleus tuberis lateralis. A high binding density was present in the amygdaloid complex and mamillary bodies, olfactory tubercle, and medial portion of the dorsomedial nucleus of the thalamus. A moderate binding density was found in the nucleus accumbens, claustrum, caudate-putamen, paraventricular and posterior lateral nuclei of the thalamus, inferior colliculus, and dorsal parabrachial nucleus. A low binding density was present in the superior colliculus, locus coeruleus, substantia gelatinosa, preoptic area, septal area, and bed nucleus of the stria terminalis. These data demonstrate that receptors for CRF are present within the primate brain at areas related to the central control of visceral function and behavior, suggesting that brain CRF may serve as a neurotransmitter in the coordination of endocrine and neural mechanisms involved in the response to stress.

Adenylyl Cyclases↗
PubMed1986

Receptor-mediated actions of corticotropin-releasing factor in pituitary gland and nervous system.

High-affinity corticotropin-releasing factor (CRF) receptors which mediate the actions of the hypothalamic peptide on adrenocorticotropic hormone (ACTH) release have been identified in the rat anterior pituitary gland. Occupancy of the pituitary receptor by CRF agonists stimulates ACTH release via activation of adenylate cyclase and cyclic adenosine monophosphate dependent protein kinase. In the regulation of ACTH secretion, the effects of CRF on the corticotroph are integrated with the stimulatory actions of cyclic adenosine monophosphate-independent stimuli such as angiotensin II, vasopressin and norepinephrine, and the inhibitory effects of glucocorticoids and somatostatin. In contrast to the major importance of the inhibitory effect of glucocorticoid feedback on ACTH secretion, somatostatin has relatively little effect on CRF-stimulated ACTH release in the normal rat corticotroph. Following adrenalectomy, the progressive elevation of plasma ACTH levels is accompanied by a concomitant decrease in pituitary CRF receptors. The postadrenalectomy loss of CRF receptors, which is prevented by dexamethasone treatment, is caused by a combination of occupancy and processing of the pituitary sites during increased secretion of the hypothalamic peptide. Recently, specific receptors for CRF have been localized in the rat and monkey brain and adrenal medulla, where they are also coupled to adenylate cyclase. Brain CRF receptors are most abundant in the cerebral and cerebellar cortices and in structures related to the limbic system and control of the autonomic nervous system. The actions of CRF on the central and peripheral nervous systems, as well as on the pituitary gland, emphasize the role of CRF as a key hormone in the integrated response to stress.

Adrenocorticotropic Hormone↗
PubMed1986

Angiotensin II receptors in the kidney.

Angiotensin II (AngII) receptors have been localized in rat kidney by using the high-affinity agonist analog 125I-labeled [Sar1]AngII as a probe for in vitro autoradiography. Receptors were associated with four morphologically distinct patterns of distribution. First, a high density of receptors occurs in glomeruli. These are diffusely distributed, consistent with a mesangial localization. AngII receptor density shows a cortical gradient, which is highest in superficial and midcortical glomeruli and lowest in juxtamedullary glomeruli. Receptors associated with both superficial and deep glomeruli show down-regulation during low-sodium intake. Second, low levels of tubular AngII binding were seen in the outer cortex. Third, a very high density of AngII receptors occurs in longitudinal bands in the inner zone of the outer medulla in association with vasa recta bundles. Receptors in this site also show down-regulation during low dietary sodium intake. Fourth, a moderate density of receptors occurs diffusely throughout the inner zone of the outer medulla in the interbundle areas. These results suggest that AngII exerts a number of different intrarenal regulatory actions. In addition to the known vascular, glomerular, and proximal tubular effects of AngII, these findings focus attention on possible actions of AngII in the renal medulla where it could regulate medullary blood flow and thereby modify the function of the countercurrent concentrating system.

Angiotensin II↗
PubMed1984

The role of angiotensin II receptors in vascular regulation.

Plasma-membrane receptors for angiotensin II (AII) have been identified in many AII-responsive tissues involved in the control of blood pressure via direct or indirect actions on vascular contractility. The specific, high-affinity receptors for AII in adrenal zona glomerulosa, vascular smooth muscle, kidney, brain, and anterior pituitary gland exhibit generally similar binding properties. However, the AII receptors in adrenal zona glomerulosa and vascular smooth muscle undergo reciprocal regulatory changes during alterations in sodium intake. These appear to be mediated by changes in circulating AII and are accompanied by parallel changes in sensitivity to AII. The AII receptors in the anterior pituitary gland are located in lactotrophs and corticotrophs and mediate the stimulatory actions of AII upon prolactin and ACTH secretion, acting in conjunction with other hypothalamic regulators. The anterior pituitary receptors are not affected by changes in sodium balance or AII infusion, in contrast to adrenal and vascular AII receptors, but exhibit similar ligand-binding properties to the sites present in other tissues. In the brain, AII receptors are present in several discrete regions and are particularly concentrated in the circumventricular organs. During dehydration, AII receptors are increased in the subfornical organ, but show no significant changes in the other circumventricular organs. The increase in subfornical-organ receptors is analogous to the up-regulation of AII sites in the adrenal cortex during sodium deficiency and may have a potentiating action upon the dipsogenic role of AII during dehydration. Mapping of AII receptors of the brain by topical autoradiography has revealed a highly characteristic pattern of distribution in brain regions concerned with drinking, adrenergic control, blood-pressure regulation, and hypothalamic control of pituitary-hormone secretion. In the rat kidney, AII receptors have been localized in the cortex and medulla by topical autoradiography with 125I-[Sar1]AII. The renal cortical receptors appear to be localized in glomeruli, whereas the AII receptors in the renal medulla are distributed diffusely in medullary tissue and also as localized radiating stripes which correspond to the vasa rectae bundles. The location of the renal receptors for AII in cortical and medullary sites emphasizes the multiplicity of actions of the octapeptide upon the individual compartments of the kidney.

Adrenal Glands↗