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A M Allen

Publications and source records attributed to A M Allen.

At least 19 recordsLinked to original sources
PubMed1992

Mapping of angiotensin II receptor subtype heterogeneity in rat brain.

Angiotensin II (Ang II) exerts a number of central actions on fluid and electrolyte homeostasis, autonomic activity, and neuroendocrine regulation. In order to evaluate likely sites where these actions are mediated, Ang II receptor binding was localized in rat brain by in vitro autoradiography with the aid of the antagonist analogue 125I-[Sar1, Ile8]Ang II. Two subtypes of Ang II receptor have been identified using recently developed peptide and nonpeptide antagonists. In the periphery, the receptor subtypes differ in distribution, second messenger coupling, and function. Brain Ang II receptor subtypes were therefore differentiated into AT-1 (type I) and AT-2 (type II) subtypes by using unlabelled nonpeptide antagonists specific for the two Ang II subtypes. AT-1 binding was determined to be that inhibited by Dup 753 (10 microM) and AT-2 binding to be that inhibited by PD 123177 (10 microM). The reducing agent dithiothreitol (DTT) decreased binding to AT-1 receptors and enhanced binding to AT-2 receptors. Many brain structures, such as the vascular organ of the lamina terminalis, subfornical organ, median preoptic nucleus, area postrema, nucleus of the solitary tract, and dorsal motor nucleus of the vagus, which are known to be related to the central actions of Ang II, contain exclusively AT-1 Ang II receptors. By contrast, the locus coeruleus, ventral and dorsal parts of lateral septum, superior colliculus and subthalamic nucleus, many nuclei of the thalamus, and nuclei of the inferior olive contain predominantly AT-2 Ang II receptors. The detailed binding characteristics of each subtype were determined by competition studies with a series of analogues of angiotensin and antagonists. The pharmacological specificity obtained in rat superior colliculus and the nucleus of the solitary tract agreed well with published data on AT-1 and AT-2 receptors, respectively. There was a high degree of correlation between the distribution of Ang II binding sites with published data on Ang II-immunoreactive fields and on the sites of Ang II-responsive neurons. The present study also reveals pharmacological heterogeneity of brain Ang II receptors. The subtype-specific receptor mapping described here is relevant to understanding the role of angiotensin peptides in the central nervous system and newly discovered central actions of nonpeptide Ang II receptor antagonists.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1992

Angiotensin II receptor binding associated with nigrostriatal dopaminergic neurons in human basal ganglia.

In the human brain, receptor binding sites for angiotensin are found in the striatum and in the substantia nigra pars compacta overlying dopamine-containing cell bodies. In contrast, angiotensin-converting enzyme occurs in the substantia nigra pars reticulata and is enriched in the striosomes of the striatum. In this study, using quantitative in vitro autoradiography, we demonstrate decreased angiotensin receptor binding in the substantia nigra and striatum of postmortem brains from patients with Parkinson's disease. In the same brains the density of binding to angiotensin-converting enzyme shows no consistent change. We propose, from these results, that angiotensin receptors in the striatum are located presynaptically on dopaminergic terminals projecting from the substantia nigra. In contrast, the results support previous studies in rats demonstrating that angiotensin-converting enzyme is associated with striatal neurons projecting to the substantia nigra pars reticulata. These findings raise the possibility that newly emerging drugs that interact with the angiotensin system, particularly converting enzyme inhibitors and new nonpeptide angiotensin receptor blockers, may modulate the brain dopamine system.

Aged↗
PubMed1992

High resolution localization of angiotensin II receptors in rat renal medulla.

The cellular localization of angiotensin II (Ang II) receptors in the inner stripe of the outer medulla of the rat kidney was investigated by using high resolution light and electron microscopic autoradiography. Fresh tissue blocks from the inner stripe of the outer medulla were incubated with 125I-[Sar1, Ile8] Ang II and prepared for microscopic autoradiography. At the light microscopic level, 125I-[Sar1, Ile8] Ang II was found to penetrate into the tissue and to bind specifically to sites outlining renal tubules and vasa recta bundles. Electron microscopic autoradiography revealed that silver grains were detected over interstitial cells located between the tubules and components of the vasa recta bundles, but no silver grains were detected overlying the cells of the thin descending or thick ascending limbs of the loop of Henle, the collecting ducts, the vasa recta, or other blood vessels. These interstitial cells contained abundant endoplasmic reticulum, microfilaments, occasional lipid droplets and extensive cytoplasmic processes which closely related to the basement membranes of the vasa recta and loops of Henle. The cells therefore closely resemble type 1 interstitial cells. Since Ang II binding sites are absent in the inner medulla, the cells labelled by this technique must be a subset of type 1 interstitial cells, distinct from the typical lipid-laden interstitial cells most abundant in the inner medulla. These findings demonstrate that type 1 interstitial cells are the primary sites for a high density of Ang II receptors located in the inner stripe of the outer medulla.

Animals↗
PubMed1992

Measuring total plasma amino acid concentrations as a test of exocrine pancreatic function.

Endogenous and exogenous stimulation of the pancreas was studied to determine whether changes in protein output could be linked to decreased total plasma amino acid concentrations. In fasted rats, diversion of pancreatic juice resulted in a transient increase in protein output and a linked fall in total plasma amino acid. In fed animals, however, diversion of juice did not result in any change in protein output or total plasma amino acid concentrations, although protein output was two-fold greater than in fasted animals. Similarly, after atropine treatment, diversion of juice failed to result in any change in protein output or total plasma amino acid in either fed or fasted animals. Stimulation of the gland with increasing doses of cholecystokinin ranging from 1.25 to 10.00 Crick Harper Raper Units, resulted in dose response increases in protein output and corresponding dose response falls in total plasma amino acid concentrations. Maximum decrease in total plasma amino acid concentrations was seen at 50% from the baseline with 5.00 Crick Harper Raper Units of cholecystokinin. These results show that with exogenous and endogenous stimulation in fasted animals, a highly significant, inverse relationship exists between protein output and total plasma amino acid. This relationship is the basis for a reliable, non-invasive test of pancreatic function that allows free mobility, although a period of fasting is required in order to increase the sensitivity of the test.

Amino Acids↗
PubMed1992

Histopathologic observations in weanling B6C3F1 mice and F344/N rats and their adult parental strains.

Weanling Fischer 344/N (F344) rats and the first filial hybrid of C57BL/6 x C3H (B6C3F1) mice and retired breeders from the parental stocks of these strains were monitored over a 5-yr-period by examining the histopathology of selected organs and comparing those results to viral and mycoplasmal serology and the intestinal tract bacterial flora of each animal on an individual basis. Serology gave no evidence of viral infection, but Mycoplasma arthriditis antibodies were detected. Reactivity of serum of adult C57BL/6 female mice with control cells or media (tissue culture, TC) was seen in a significant number of mice. TC reactivity correlated positively with lymphoid perivascular infiltrates, predominantly of the lungs, suggesting an allergic response in development of the lesions. Other lesions of note consisted of Harderian gland inflammation of rats, focal necrotizing lesions of the liver of both species, and thickening of the pleura and adjacent pulmonary interstitium of weanling rats. Embolization of bacteria from the gastrointestinal tract to the liver was considered a possible cause of the liver necrosis in both species. Although lesions of the lung and Harderian gland of the rats are similar to those caused by known viral agents, the cause of the latter could not be determined as these animals were negative for viral antibodies and the former was considered to be related to incomplete pulmonary development in the young rat. Features differentiating the lesions observed in animals of this survey from those caused by viral infection are discussed.

Aging↗
PubMed1991

Localization and characterization of angiotensin II receptor binding sites in the human basal ganglia, thalamus, midbrain pons, and cerebellum.

Angiotensin II (Ang II) binding sites were localized in the thalamus, basal ganglia, midbrain, and pons of the human central nervous system by in vitro autoradiography, employing 125I-[Sar1, Ile8]angiotensin II as the radioligand. High-density binding occurs in the substantia nigra pars compacta, the interpeduncular nucleus and two of the raphe nuclei, the raphe magnus, and median raphe nucleus. Moderate densities occur in the caudate nucleus, putamen, bed nucleus of the stria terminalis, rostral linear nucleus, caudal linear nucleus, dorsal and paramedian raphe nuclei, locus coeruleus, and region of the subcoeruleus, oral dorsal paramedian nucleus, and A5/periolivary region. Low levels occur in the region between the subthalamic nucleus and the zona incerta, the mediodorsal thalamic nucleus, the central gray, the lateral and medial parabrachial nuclei, and the molecular layer of the cerebellum. The high density of Ang II receptor binding in the substantia nigra occurs over pigmented, presumably dopaminergic, neurons. The binding in this site, and in the striatum, is not observed in any of the other species we have studied. It displays similar pharmacological characteristics to the Ang II receptor binding site in other regions of the human brain. Overall we demonstrate a discrete pattern of Ang II receptor binding sites in the human brain, which shows a high correlation with the distribution observed in other mammalian species.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1991

Angiotensin II receptor subtypes in rat brain.

1. Angiotensin II (AII) receptor binding was localized in the rat brain by in vitro autoradiography using the antagonist analogue, 125I-[Sar1, Ile8] AII. AII receptor binding was then differentiated into type I and type II subtypes by displacement with unlabelled non-peptide antagonists specific for AII subtypes. 2. Type I binding was determined as that inhibited by Dup753 (10 mumol/L) and type II binding as that inhibited by XD329-1 (10 mumol/L). The reducing agent dithiothreitol (DTT) decreased the binding to type I receptors and enhanced the binding to type II receptors. 3. Structures such as the vascular organ of the lamina terminalis, subfornical organ, median preoptic nucleus, area postrema, nucleus of the solitary tract, which are known to be related to some central actions of AII, contain exclusively type I AII receptors. 4. In contrast, the locus coeruleus, ventral and dorsal parts of lateral septum, superior colliculus, subthalamic nucleus, some nuclei of the thalamus, and the nuclei of the inferior olive contain predominantly type II AII receptors. 5. These results reveal important pharmacological heterogeneity of brain AII receptors which suggest different regional functions and are relevant to the central actions of emerging classes of new non-peptide AII receptor antagonists.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1991

Angiotensin II receptor subtypes in rat brain and peripheral tissues.

Angiotensin II (Ang II) receptor binding was localized in rat adrenal gland, kidney, and brain by in vitro autoradiography using the antagonist analogue 125I-[Sar1, Ile8]Ang II and differentiated into type I (AT-1) and type II (AT-2) subtypes using unlabelled non-peptide antagonists specific for Ang II subtypes. AT-1 binding was determined as that remaining in the presence of an excess of the AT-2 antagonist, PD 123177 (10 microM), and AT-2 binding as that remaining in the presence of an excess of the AT-1 antagonist, DUP753 (10 microM). The reducing agent dithiothreitol decreased the binding to AT-1 receptors and enhanced the binding to AT-2 receptors. The rat adrenal gland contains both AT-1 and AT-2 receptors in the ratio of approximately 3:2 in the cortex and 1:9 in the medulla. By contrast, in the kidney only AT-1 receptors were evident in glomeruli, proximal tubule, and inner stripe of the outer medulla. In the brain, the pattern of Ang II receptor subtypes varies greatly from region to region. Many brain structures known to be involved in blood pressure regulation and fluid and electrolyte balance, such as circumventricular organs (including vascular organ of the lamina terminalis, subfornical organ, median eminence, and area postrema), median preoptic nucleus, hypothalamic paraventricular nucleus, and regions in the medulla oblongata involved in autonomic control (nucleus of the solitary tract, dorsal motor nucleus of the vagus, and intermediate reticular nucleus), contain exclusively AT-1 receptors. By contrast, locus coeruleus, lateral septal nuclei, superior colliculus, subthalamic nucleus, many nuclei of the thalamus, and nuclei of the inferior olive contain predominantly AT-2 receptors. The detailed binding characteristics of each subtype were determined by competition studies with a series of antagonists. The pharmacological specificity obtained in kidney, adrenal cortex and adrenal medulla, superior colliculus, and nucleus of the solitary tract produces specificity patterns which confirm the assignments of AT-1 and AT-2 receptors described above. The present study reveals important pharmacological heterogeneity of Ang II receptors in key target organs. The subtype-specific receptor mapping described here is relevant to the understanding of the role of angiotensin peptides in peripheral organs and in the central nervous system and is relevant to the actions of non-peptide Ang II receptor antagonists.

Adrenal Glands↗
PubMed1991

Localization of angiotensin converting enzyme in rat heart.

Angiotensin converting enzyme (ACE) was localized in rat heart by quantitative in vitro autoradiography with 125I-351A as the radioligand. The binding association constant (KA) of the radioligand was measured in membrane-rich fractions of atrium, ventricle, and lung by a radioinhibitor binding assay. A single class of high-affinity binding sites was detected in each tissue, and a significant difference was found between KA values for atria and ventricles with a rank order of atria greater than lungs greater than ventricles. For autoradiography, coronal sections (10 micron) of the frozen heart were incubated with 125I-351A and exposed to x-ray film. The autoradiographs were quantitated by computerized image analysis. The highest density of ACE in the heart was found on valve leaflets (aortic, pulmonary, mitral, and tricuspid), which contrasted markedly with very low ACE labeling in the endocardium. The coronary arteries also showed dense labeling of ACE. The right atrium had a moderate density of ACE, which was higher than the left atrium and the ventricles. Both the endothelial and adventitial layers of the aorta and pulmonary artery displayed high densities of ACE, with very low density in the media. ACE was not detected in either the sinoatrial node or atrioventricular node. These results reveal a markedly nonuniform localization of ACE in the rat heart and suggest possible sites for local angiotensin II generation and bradykinin or other peptide metabolism.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Hemorrhagic cardiomyopathy and hemothorax in vitamin K deficient mice.

The cause of a fatal condition characterized by hemorrhagic cardiomyopathy, hemothorax, and coagulation defects in hysterectomy-derived male mice was investigated. Microscopic heart alterations included multifocal hemorrhage and necrosis with variable degrees of acute inflammation and fibroplasia that were most severe in the region of the atrioventricular junction. A spontaneous outbreak was arrested by increasing menadione Na-bisulfite (vitamin K) in the feed to 20 ppm. The complete syndrome including hemorrhagic cardiomyopathy was readily reproduced in germ-free male mice given a vitamin K-free diet, and in conventional male and female mice given Warfarin in the diet. We concluded that the cause of this condition was vitamin K deficiency.

Animals↗
PubMed1990

In vitro autoradiographic localization of binding to angiotensin receptors in the rat heart.

The distribution of binding to angiotensin II receptors in the rat heart was determined by quantitative in vitro autoradiography employing 125I-[Sar1, Ile8] angiotensin II as the radioligand. Low density binding occurs in the myocardium of both the atriums and ventricles and in the media of the aorta, pulmonary arteries and superior caval vein. Dense punctate binding is found over parasympathetic nerve bundles and some cells of the intracardiac ganglions. Binding is very low in nerves which do not stain for acetylcholinesterase. A moderate to high density of binding sites occurs throughout the conduction system, including the sinus node (low), the atrioventricular node (high) and the atrioventricular bundle (moderate). An extremely high density of binding is observed over the remnant of the arterial duct. These findings demonstrate many sites at which angiotensin II could exert its cardiac actions, including anatomical evidence supporting an action on cardiac myocytes, terminals of the vagal nerves, parasympathetic ganglion cells, and the conduction system.

Angiotensin II↗
PubMed1989

Localization of angiotensin II binding sites in the bovine adrenal medulla using a labelled specific antagonist.

Angiotensin II binding sites have been localized in sections of bovine adrenal glands and on living cultured bovine adrenal medullary cells using [125I]-[Sar1,Ile8]-angiotensin II and autoradiographic techniques. Binding sites were observed over both adrenaline and noradrenaline chromaffin cells. However, they were present in higher density over adrenaline cells, as determined by the distribution of phenylethanolamine N-methyltransferase mRNA by in situ hybridization histochemistry and of glyoxylic acid-induced fluorescence of noradrenaline. Binding sites were also observed in low density over nerve tracts within the bovine adrenal gland. Living cultured bovine adrenal medullary cells possessed angiotensin II binding sites. Not all cells were labelled. At least 73% of identified dispersed chromaffin cells in these cultures were labelled. Some chromaffin cells were not labelled with the ligand, and at least some non-chromaffin cells in the cultures did possess angiotensin II binding sites. The results provide direct anatomical support for the known ability of angiotensin II to elicit catecholamine secretion from perfused adrenal glands and from cultured adrenal chromaffin cells. They also suggest that some of the effects of angiotensin II on calcium fluxes and second messenger levels measured in cultured adrenal medullary cell preparations may be due to angiotensin II acting on non-chromaffin cells present in these cultures.

Adrenal Medulla↗
PubMed1988

Localization of angiotensin II receptor binding in rabbit brain by in vitro autoradiography.

Binding of 125I-[Sar1,Ile8] angiotensin II (AII) to sections of brains from both wild and laboratory rabbits was determined by in vitro autoradiography. In the forebrain, specific high density binding was observed in the olfactory bulb, organum vasculosum of the lamina terminalis (OVLT), subfornical organ, median eminence, lateral septum, median preoptic nucleus and hypothalamic paraventricular, supraoptic and arcuate nuclei. In the midbrain, binding of the radioligand was observed in the interpeduncular and parabrachial nuclei, in the locus coeruleus, and ventrolateral pons. In the hind brain, there was dense binding of 125I-[Sar1,Ile8] AII to the nucleus of the solitary tract (NTS) and to both rostral and caudal parts of the reticular formation of the ventrolateral medulla oblongata. Weaker specific binding of the radioligand to the molecular layer of the cerebellum, to the nucleus of the spinal trigeminal tract, dorsal motor nucleus of the vagus, area postema, and to a band of tissue connecting the NTS to the ventrolateral medulla was also observed. Binding of the ligand to circumventricular organs such as the OVLT, subfornical organ, and median eminence suggests that these are sites in the brain of the rabbit at which blood-borne AII may exert influences on the central regulation of fluid balance and pituitary hormone secretion, although AII of neuronal origin could also act at these sites. Binding of the radioligand in several other brain regions suggests that angiotensin II of cerebral origin may be involved in a number of different aspects of brain function in the rabbit. The finding of dense binding in the NTS and ventrolateral medulla, which are involved in autonomic activity and are also sites of catecholamine-containing neurons, raises the possibility of angiotensin interaction with these neurons and involvement in autonomic function.

Angiotensin II↗
PubMed1988

Localization and characterization of angiotensin II receptor binding and angiotensin converting enzyme in the human medulla oblongata.

Angiotensin II receptor and angiotensin converting enzyme distributions in the human medulla oblongata were localised by quantitative in vitro autoradiography. Angiotensin II receptors were labelled with the antagonist analogue 125I-[Sar1, Ile8] AII while angiotensin converting enzyme was labelled with 125I-351A, a derivative of the specific converting enzyme inhibitor, lisinopril. Angiotensin II receptor binding and angiotensin converting enzyme are present in high concentrations in the nucleus of the solitary tract, the dorsal motor nucleus of vagus, the rostral and caudal ventrolateral reticular nucleus, and in a band connecting the dorsal and ventral regions. In the rostral and caudal ventrolateral reticular nucleus, angiotensin II receptors are distributed in a punctate pattern that registers with neuronal cell bodies. The distribution and density of these cell bodies closely resemble those of catecholamine-containing neurones mapped by others. In view of the known interactions of angiotensin II with both central and peripheral catecholamine-containing neurons of laboratory animals, the current anatomical findings suggest similar interactions between these neuroactive compounds in the human central nervous system. The presence of angiotensin II receptors and angiotensin converting enzyme in the nucleus of the solitary tract, dorsal motor nucleus of vagus, and rostral and caudal ventrolateral reticular nucleus demonstrates sites for central angiotensin II to exert its known actions on vasopressin release and autonomic functions including blood pressure control. These data also suggest a possible interaction between angiotensin II and central catecholeminergic systems.

Aged↗
PubMed1988

Angiotensin receptors and the vagal system.

Angiotensin II (Ang II) is known to attenuate the vagal component of the baroreflex at both central and peripheral cardiac sites. Ang II receptor binding sites occur in both the nucleus of the solitary tract (NTS), where they are associated with vagal afferent terminals, and in the dorsal motor nucleus of vagus. In this study we have examined the distribution of Ang II binding sites in the cell bodies of vagal afferents in the nodose ganglion, and investigated whether these receptors are transported in the vagus nerve. Dense Ang II receptor binding was observed over neuronal cell bodies in the nodose ganglion and, in streaks, in the vagus nerve. Vagal ligation distal to the nodose ganglion resulted in a marked accumulation of receptor binding sites, proximal to the ligature, with a moderate increase on the distal side. These results demonstrate that Ang II receptor binding sites occur in the nodose ganglion and are transported centrally in the vagus to be located on presynaptic terminals in the NTS and also peripherally where they may occur on terminals of the vagus.

Animals↗
PubMed1988

Comparative neuroanatomy of angiotensin II receptor localization in the mammalian hypothalamus.

1. The distribution of angiotensin II (AII) receptor binding sites in the hypothalamus of rat, rabbit, sheep and human was determined by in vitro autoradiography using 125I-[Sar1,Ile8]-AII as radioligand. 2. High receptor binding levels were observed in the continuum of tissue comprising the anterior wall of the third ventricle, including the subfornical organ, the median pre-optic nucleus and the organum vasculosum of the lamina terminalis. 3. High levels of binding sites were also found in the paraventricular and supra-optic nuclei, the median eminence and the arcuate nucleus. 4. These findings demonstrate sites in the hypothalamus of rat, rabbit, sheep and human where AII could exert its known actions on fluid and electrolyte balance, pituitary hormone release and cardiovascular function.

Aged↗