Biomedical subjects

D Alcorn

Publications and source records attributed to D Alcorn.

At least 37 records · Page 2Linked to original sources

PubMed1997

Localization of bradykinin B2 binding sites in rat kidney following chronic ACE inhibitor treatment.

Bradykinin exerts important influences on renal hemodynamics and tubular function by acting on renal bradykinin B2 receptors. However, the precise sites and mechanisms of its actions on the kidney are not known. To help elucidate the mechanisms of renal actions of bradykinin in vivo, we have employed high resolution electron microscopic autoradiography to localize bradykinin B2 binding sites in the rat kidney following intravenous administration of a radiolabeled ligand, 125I-HPP-Hoe140 (3-4-Hydroxyphenyl-propionyl-DArg0-[Hyp3-Thi5-D-Tic 7-Oic8]-bradykinin), a derivative of the highly selective bradykinin B2 receptor antagonist, Hoe140. In non-treated rats, bradykinin B2 binding sites were localized to the cell bodies and the luminal brush border of the proximal convoluted tubules in the cortex. In the medulla (except for the outer stripe of the outer medulla), binding occurred in the distal tubules, thin limbs of the loop of Henle, collecting ducts, peritubular capillary endothelium and renomedullary interstitial cells. To exclude the possibility that the radioligand may bind to angiotensin converting enzyme, rats were pretreated with the angiotensin converting enzyme inhibitor, perindopril. In these rats, binding to the cell bodies and the luminal brush border of the proximal convoluted tubules in the cortex was completely abolished, while binding remained unaltered in the medulla. Further studies using high performance liquid chromatography revealed that while the radioligand was degraded following systemic administration in nontreated rats, the degradation was significantly reduced in the rats pretreated chronically with perindopril. These results indicate that binding detected in the proximal tubules in the normal rats is due primarily to the tubular uptake of the degraded radioligand, and that bradykinin B2 binding sites occur predominantly in the renal tubules, vascular endothelium, and renomedullary interstitial cells of the renal medulla.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1997

Localization and functional properties of angiotensin II AT1 receptors in the kidney: focus on renomedullary interstitial cells.

The renal medulla plays an important role in maintaining body fluid and electrolyte balance and long-term blood pressure homeostasis through its unique structural and functional properties. Among several humoral, paracrine factors or autocoids, angiotensin II (Ang II) has been implicated in the regulation of renal medullary function, including the medullary/papillary microcirculation, urine concentration, and blood pressure, but the mechanisms by which Ang II exerts influences in the renal medulla are largely unknown. The purpose of this review is to summarize the cellular localization, regulation, and functional properties of Ang II AT1 receptors in the kidney, with special emphasis on type I renomedullary interstitial cells (RMICs) in the renal medulla and cultured RMICs. High densities of AT1 receptors have been localized in type I RMICs in the inner stripe of the outer medulla by high resolution light and electron microscopic autoradiography following in vitro or in vivo labelling, or in cultured RMICs. Furthermore, reverse transcription polymerase chain reaction and Southern blot analysis now confirm that AT1 receptors in cultured RMICs are exclusively of the AT1A subtype. In cultured RMICs, Ang II markedly increases intracellular inositol 1,4,5-triphosphate (IP3) concentration, and stimulates cell proliferation and extracellular matrix synthesis, and these cellular responses are exclusively mediated by AT1 receptors. Considering the co-occurrence of high levels of renin, renin substrate angiotensinogen, and Ang II in the interstitial fluid compartment, and AT1 receptors in type I RMICs of the renal medulla, the AT1 receptor-bearing RMICs may be more responsive to the locally formed interstitial Ang II than to the circulating peptide. Since RMICs also contain the receptors for other vasoactive peptides, such as endothelin (ET[A] and ET[B]), natriuretic peptides (NPR[A] and NPR[B]), and bradykinin (B2), and synthesize prostaglandins and medullipins, they may serve as an important site for functional interactions between Ang II and other vasoactive peptides in modulating renal medullary function. More studies using different experimental approaches are therefore required to explore and elucidate the functional role of renal interstitial Ang II and AT1 receptors in RMICs in the physiological control of renal medullary function and in the pathophysiology of hypertension and progressive renal diseases.

Connective Tissue Cells↗

PubMed1997

Expression of aquaporin-1 (AQP1) in the adult and developing sheep kidney.

The distributions of aquaporin-1 mRNA and protein were studied by hybridization histochemistry with a homologous riboprobe and immunohistochemistry, in the adult sheep kidney. Heaviest labelling occurred in the thin descending limb (DTL) of the loop of Henle in the inner stripe of the outer medulla, with apparent decreasing expression in the inner medulla, outer stripe of the outer medulla and cortex, but no quantitation was performed. Only proximal tubules (PT) (convoluted and straight) and DTL labelled. The glomerulus showed no labelling, consistent with the pattern in the rat but different to that in the human. During ontogeny, no labelling occurred in the mesonephros at 27 or 41 days of gestation (term = 145-150 days) but other structures did label at 27 days (heart, lung bud, blood vessels surrounding developing spinal cord). Labelling first occurred faintly in the metanephros at 41 days of gestation and increased throughout gestation consistent with morphological development of nephrons.

Age Factors↗

PubMed1996

Adrenaline cells of the rat adrenal cortex and medulla contain renin and prorenin.

The distribution and content of renin in Sprague-Dawley (SD) and transgenic (mREN-2)27 rats (TG) were compared to further define the cellular basis and function of the adrenal renin-angiotensin system. Antibody binding (to rat and mouse renin protein and prosequence) was visualised in serial paraffin sections using an avidin-biotin peroxidase technique. Chromaffin and adrenaline cells were identified by tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase immunoreactivity, respectively. In SD zona glomerulosa (ZG), renin and its prosequence localised to small steroid cells while in homozygous (receiving lisinopril) and heterozygous (untreated) TG, steroid cells labelled in all cortical zones. In addition, throughout the cortex of each strain, large polyhedral adrenaline chromaffin cells occurring singly or in small groups and occasionally in rays labelled for renin and prosequence. Similar large adrenaline cells immunolabelled for all antisera in medulla while other cells were only TH-positive. Total adrenal renin content was 53 times higher in heterozygous transgenics than SD rats and was mainly (74%) prorenin. In SD, 37% of cortical renin was prorenin but in adrenal medulla only active renin was detected. Thus, from present and previous work both renin and prorenin occur not only in mitochondrial dense bodies of the ZG, but also in secretory granules of adrenaline chromaffin cells in both cortex and medulla implying in situ synthesis and paracrine functions.

Adrenal Cortex↗

PubMed1996

Light-microscopic immunolocalization of fibroblast growth factor-1 and -2 in adult rat kidney.

The fibroblast growth factors (FGFs) are a family of conserved polypeptides known to regulate cell differentiation and proliferation. We have used avidin-biotin-enhanced indirect immunohistochemistry to localize FGF-1 and FGF-2 in the rat kidney. The most consistent specific immunostaining pattern is found in paraffin sections from kidneys perfusion-fixed with 4% paraformaldehyde in 0.1 M phosphate buffer. Intracellular immunoreactivity for FGF-1 and FGF-2 is co-localized in visceral (podocytes) and parietal (Bowman's capsule) glomerular epithelial cells, S3 segments of proximal tubules, distal tubules and collecting ducts in the cortex, and thick ascending limbs and collecting ducts in the medulla. Immunoreactivity is also observed within urothelium and the tunica adventitia of large blood vessels. No immunostaining is found in cortical S1 or S2 segments of proximal tubules, in frozen sections prepared from unfixed or 4% paraformaldehyde perfusion-fixed kidneys, or in paraffin sections from Bouin-fixed kidneys. Immersion fixation with 4% paraformaldehyde gives a similar staining pattern in paraffin sections to that achieved with perfusion fixation. However, in paraffin sections fixed with methyl Carnoy's fixative, immunoreactivity is primarily localized to the tunica media of blood vessels, with little tubular or glomerular immunostaining. Thus, variation in immunolocalization patterns for FGFs can be partially attributed to differences in fixative, preparative technique and antibody specificity.

Animals↗

PubMed1996

Ontogeny of hormonal and excretory function of the meso- and metanephros in the ovine fetus.

Using reverse-transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry we investigated the ontogeny of renin, angiotensinogen and angiotensin converting enzyme (ACE) in the mesonephros at 27 and 41 days of gestation, and the metanephros at 41 and 64 days of gestation in ovine fetuses (term is 145 to 150 days). The volume and composition of fetal urine, stored as allantoic fluid were measured in 12 fetuses at 27 days, and 13 fetuses at 41 days. Renin, angiotensinogen and ACE were identified in both meso- and metanephroi at 41 days but not in the mesonephros at 27 to 30 days. Allantoic fluid volumes were 21 +/- 3 and 45 +/- 5 ml at 27 to 30 days and 41 days, respectively. This fluid was significantly different in composition to that of amniotic fluid or maternal plasma. The results suggest that the mesonephros can substantially modify its glomerular filtrate by 27 days of gestation, and can produce local angiotensin II by 41 days.

Allantoin↗

PubMed1996

Evidence for a renomedullary vasodepressor hormone.

1. Recent physiological experiments have established that increasing the perfusion pressure of the kidney causes the release of vasodepressor substance from the renal medulla. 2. The substance is not a platelet activating factor, a prostaglandin or nitric oxide and the vasodepressor response to increased renal perfusion is not due simply to inhibition of renin release. 3. The mechanisms by which the renomedullary vasodepressor substance lowers arterial pressure remain to be determined. Sympathoinhibition may account for part of the response, but the hypotension still occurs in autonomic ganglion blocked animals. 4. The source of substance appears to be the renomedullary interstitial cells, though the control of the production and release of the substance remain to be determined. 5. The substance may be a lipid but it is yet to be fully isolated and identified. 6. The threshold for release of the substance appears to be close to normal resting arterial blood pressure. 7. Despite strong evidence that the renal medulla releases a vasodepressor hormone in response to increased renal perfusion pressure, much is still to be determined regarding the physiology of this hormone and its involvement in the aetiology of hypertension.

Kidney Medulla↗

PubMed1996

Effects of angiotensin II on cultured rat renomedullary interstitial cells are mediated by AT1A receptors.

Renomedullary interstitial cells (RMICs) are prominent in the inner medullary interstitium and have binding sites for several vasoactive agents, including angiotensin II (ANG II). Although the functional role of RMICs remains largely unknown, it is likely that the interaction between RMICs and vasoactive peptides is important in the regulation of renal function. The current investigation characterizes the cellular responses following treatment of RMICs with ANG II. Studies were performed on RMICs isolated from Sprague-Dawley rat kidneys. 125I-labeled [Sar1,Ile8]ANG II specifically bound to RMICs at sites determined by reverse transcription-polymerase chain reaction to be of the AT1A subtype. ANG II (10(-6) and 10(-10) M) had no effect on either basal or forskolin-stimulated adenosine 3',5'-cyclic monophosphate accumulation in RMICs but increased intracellular inositol 1,4,5-trisphosphate concentration after 10 s and intracellular calcium concentration after 18 s. For RMICs plated at low densities, ANG II (10(-6) M) induced an increase in [3H]thymidine incorporation, mediated through the AT1-receptor subtype. For RMICs plated at high densities, ANG II (10(-6) M) induced an increase in extracellular matrix synthesis as detected by trans-35S incorporation, an effect also mediated by AT1 receptors. We conclude that ANG II AT1A receptors on cultured RMICs are coupled to intracellular second messenger pathways leading to hyperplasia and synthesis of extracellular matrix.

Angiotensin II↗

PubMed1996

Glomerular dimensions in spontaneously hypertensive rats: effects of AT1 antagonism.

OBJECTIVE: A reduction in glomerular number and/or size has been implicated in the development of hypertension. This study investigated whether differences in glomerular number and/or size occur during the development of hypertension in the spontaneously hypertensive rat (SHR) and whether angiotensin II is responsible for any glomerular differences. METHODS: SHR (n=6) and Wistar-Kyoto (WKY) rats (n=6) were administered the angiotensin II type I receptor antagonist TCV-116 from 4 to 10 weeks of age. At 10 weeks of age, the kidneys from these rats and those from untreated SHR (n=6) and WKY rats (n=6) controls were perfusion fixed at physiological pressures and analysed using unbiased stereological techniques. RESULTS: There were no significant differences in glomerular number, glomerular volume or total glomerular volume between SHR and WKY rats. Treatment of SHR with TCV-116 significantly lowered systolic blood pressure but had no significant effect on glomerular number or volume or total glomerular volume. Treatment of WKY rats with TCV-116 reduced systolic blood pressure, body weight, glomerular volume and total glomerular volume; however, total glomerular volume per body weight of treated WKY rats was not significantly different from that of untreated WKY rats. CONCLUSION: There were no differences in glomerular number or volume in SHR compared with WKY rats at 10 weeks of age. We therefore conclude that glomerular changes are not responsible for the development of hypertension in SHR. Angiotensin II, via the type 1 receptor, does not contribute to glomerular growth during the development of hypertension in the SHR.

Angiotensin Receptor Antagonists↗

PubMed1996

Angiotensin receptors and development: the kidney.

1. This brief review examines the evidence that angiotensin II (AngII) is essential for kidney development. 2. Several components of the renin-angiotensin system (RAS) are detected in the foetal kidney early in development. 3. Angiotensin II is essential for normal foetal and neonatal renal function. 4. Angiotensin II receptors transduce important signals leading to growth and development. 5. Angiotensin receptor subtypes show spatial and temporal specificity of localization throughout renal development. 6. Angiotensin converting enzyme (ACE) inhibition or AngII receptor blockade (specifically AT1 subtype blockade) results in functional and structural abnormalities of the developing kidney in both experimental and clinical situations. 7. While chronic postnatal RAS blockade in rats is associated with structural damage to tubules and blood vessels of the kidney, reports differ on whether treatment also affects glomerular induction and growth. 8. In metanephric organ culture, glomerular induction proceeds despite AngII receptor blockade. 9. In summary, the evidence suggests that AngII is not essential for nephron induction and glomerular development in the rat kidney. However, AngII is essential for normal growth and development of renal tubules and vasculature.

Angiotensin II↗

PubMed1996

Structural changes in the renal vasculature in the spontaneously hypertensive rat: no effect of angiotensin II blockade.

1. There is strong evidence for a renal basis to the development of hypertension in the spontaneously hypertensive rat (SHR). Alterations of the SHR renal vasculature, including the glomerulus, may be involved in the initiation and maintenance of hypertension in this animal model. 2. The arterial walls of pre-glomerular vessels of the SHR are hypertrophied compared with WKY vessels. Unlike other vascular beds in the SHR, this hypertrophy is independent of angiotensin II (AngII). 3. Glomerular number and volume are similar between SHR and the normotensive Wistar-Kyoto (WKY) rats. These results provide no support for the theory that a reduced filtration surface area within the kidneys of the SHR contributes to the elevated blood pressure in these animals. 4. Intrarenal hypertrophy may have similar haemodynamic consequences to clipping of the main renal artery, as in Goldblatt hypertension. Further analysis of the role of pre-glomerular arterial hypertrophy is warranted to determine its involvement in the initiation and maintenance of hypertension in the SHR.

Angiotensin II↗

PubMed1996

Presence of angiotensin II AT2 receptor binding sites in the adventitia of human kidney vasculature.

1. Angiotensin II (AngII) receptor subtypes in adult human kidney were pharmacologically characterized by in vitro autoradiography using the AngII receptor subtype-selective antagonists, losartan and PD 123319, and the sensitivity to the reducing agent, dithiothreitol. 2. High densities of AngII AT1 receptor binding occur in the glomeruli and the inner stripe of the outer medulla, while a moderate AT1 receptor binding is localized in the proximal convoluted tubules. 3. AT2 receptor binding is observed predominantly in the intrarenal large blood vessels, including the arcuate, inter- and intra-lobular arteries, and in the renal capsule. 4. In the major renal artery, AT1 receptor binding is abundant in the media and adventitia, while AT2 receptor binding is observed mainly in the adventitia. 5. At the light microscopic level using emulsion autoradiography, AT1 receptors are localized in the glomeruli and juxtaglomerular apparatus, as expected. However, in larger renal blood vessels, including the arcuate arteries, inter- and intra-lobular arteries, intense AT2 receptor labelling occurs primarily in the adventitia, while the endothelium and vascular smooth muscle layers contain only low levels of AngII receptor binding. 6. These results indicate that the adult human kidney displays two pharmacologically distinct AngII receptor subtypes, with AT1 predominating in the glomeruli, juxtaglomerular apparatus, proximal tubules and the inner stripe of the outer medulla, while AT2 predominates in the adventitia of the arcuate and interlobular arteries and the renal capsule. The functional significance of AT2 receptor binding sites in the adventitia of adult human kidney vessels remains to be elucidated.

Adult↗

PubMed1996

Granting your wish.

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Dental Hygienists↗

PubMed1995

Enalapril does not prevent renal arterial hypertrophy in spontaneously hypertensive rats.

Angiotensin-converting enzyme inhibitors prevent the development of vessel wall hypertrophy in some vascular beds in spontaneously hypertensive rats (SHR), but their effects on hypertrophy of renal arterial vessels have not been studied. We therefore used stereological techniques to study wall and lumen dimensions of the interlobular (cortical radial) and arcuate arteries in the kidneys of SHR (n = 7), SHR treated from 4 to 10 weeks of age with enalapril (25 to 30 mg/kg per day; SHR-E, n = 7), and Wistar-Kyoto rats (WKY, n = 7). All kidneys were perfusion-fixed at 10 weeks. Systolic blood pressure was 199 +/- 9, 139 +/- 11, and 156 +/- 8 mm Hg in the SHR, SHR-E, and WKY groups, respectively. For the interlobular arteries, the volume density of artery wall, wall-to-lumen ratio, and wall thickness in the untreated SHR were significantly greater than in the WKY (0.84 +/- 0.09 versus 0.69 +/- 0.07 x 10(-3), 0.75 +/- 0.20 versus 0.53 +/- 0.08, and 13.6 +/- 3.3 versus 10.6 +/- 0.8 microns, respectively), but values in the SHR-E were similar to those in the untreated SHR (1.10 +/- 0.20 x 10(-3), 0.88 +/- 0.22, and 14.0 +/- 2.6 microns, respectively). For the arcuate arteries, wall thickness and volume density were significantly greater in SHR than WKY (17.3 +/- 3.0 versus 13.9 +/- 1.7 microns and 1.63 +/- 0.51 versus 1.14 +/- 0.27 x 10(-3), respectively), and values in the SHR-E (15.7 +/- 1.7 microns and 1.69 +/- 0.50 x 10(-3), respectively) were not significantly different from those in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Pre-glomerular structural changes in the renal vasculature in hypertension.

This paper reviews the evidence for the occurrence of hypertrophy of the renal arterial vessels in experimental and human hypertension. In spontaneously hypertensive rats (SHR), the walls of the interlobar, arcuate and interlobular arteries appear to be hypertrophied in both the "pre-hypertensive phase" and in established hypertension. The lumen diameter of the afferent arteriole in SHR is reduced, but this is probably not due to wall hypertrophy. The renal arterial hypertrophy is not reversed by chronic angiotensin converting enzyme inhibition in SHR, in contrast to findings in other vascular beds. Renal arterial hypertrophy also occurs in other forms of hypertension including in the kidney contralateral to a renal artery stenosis, and in hypertension following sino-aortic denervation. Whilst it is not possible to document changes in wall dimensions of intrarenal arteries during the development of human hypertension, renal haemodynamic abnormalities currently attributed to renal vasoconstriction in early human hypertension are also compatible with renal arterial hypertrophy. These abnormalities include increased resting renal vascular resistance and augmented renal vascular resistance responses to vasoconstrictor agents. It is argued that hypertrophy of renal vasculature to increase pre-glomerular resistance will have dual effects: it will increase total peripheral resistance (the kidneys account for about 20% of total peripheral resistance), and it will effect renal haemodynamics distally in a manner similar to narrowing of the main renal artery. It remains to be shown experimentally whether renal arterial hypertrophy could be the primary cause of some forms of hypertension.

Animals↗

PubMed1995

Renin-containing Müller cells of the retina display endocrine features.

PURPOSE: An ocular renin-angiotensin system has been implicated in the proliferation of retinal blood vessels and blindness in diabetes mellitus. Its cellular basis has not been established. The objective was to identify sites of renin synthesis, secretion, and processing in eyes from humans, BALB/c mice, Sprague-Dawley rats, and a hypertensive transgenic rat model (mREN-2) that displays amplified extrarenal renin synthesis. METHODS: Paraffin sections of eyes were incubated with antisera to renin protein, prorenin, vimentin, and Müller cells. Enzyme kinetic renin assay was performed on extracts of whole eyes (excluding lens and vitreous) and comparisons made with adrenal glands and kidneys. For detection of renin mRNA, retinas were separately pooled from BALB/c and Swiss mice. RESULTS: In normal rodent and autopsy human eyes, labeling for renin, vimentin, and Müller cell protein was observed in the cytoplasm of all macroglial Müller cells, with renin labeling most obvious in endfeet closely apposed to retinal blood vessels. Prorenin labeling was not detected. Less intense renin labeling, again without prorenin, was seen in nonpigmented ciliary epithelium of rodents. In transgenic (mREN-2) rat eyes, renin and prorenin labeling of Müller cells and nonpigmented ciliary epithelium were intense. Prorenin was localized to the posterior region of Müller cells but only sparsely to endfeet in rodent retinas, and renin was present only in an active form in amounts one third that of one adrenal. Renin mRNA was readily detected. In human retina, renin was present in active and pro-forms, and the total amount was approximately one fiftieth that of adrenal. CONCLUSION: Renin is synthesized in the retina and is specifically localized to the macroglial Müller cells. Nonpigmented ciliary epithelium also contains renin. The presence of prorenin in the posterior part of the Müller cell, with active renin throughout but notably in endfeet in apposition to retinal capillaries, suggests directional processing of renin. These findings are consistent with earlier suggestions that retinal neovascularization may be associated with Müller cell dysfunction.

Aged↗

PubMed1994

Immunohistochemical studies of renin-containing cells in the developing sheep kidney.

BACKGROUND: Renin-containing (RC) cells in small ruminant kidneys have been known to be widely distributed along the blood vessels. In the present study, RC cells in developing sheep kidneys were studied to investigate not only the appearance but distribution with the potential physiological significance using immunohistochemical and histoplanimetrical techniques. METHODS: Seven fetal, 12 newborn, and 3 adult metanephric kidneys were used and immunostained by anti-renin antiserum. In the histoplanimetrical analysis, the numerical values of RC cells existing at the walls of 3 major arterial types in the kidneys were calculated. RESULTS: At day 44 of gestation, RC cells were already demonstrated in the walls of renal, interlobar, and afferent vessels, located in the deep cortex and the medulla. In intermediate gestational periods, RC cells were detected throughout the intrarenal arterial trees. In late gestational periods, RC cells expressed in the walls of interlobar/arcuate and interlobular arteries tended to decrease or disappear gradually, while they were distributed predominantly in the afferent glomerular vessels. In newborn lambs, especially days 1 to 3 after birth, increased numbers of RC cells were demonstrated throughout the arterial trees in the kidneys. In older lambs, RC cells located in the interlobar/arcuate arteries and the proximal region of the interlobular arteries decreased in number and gradually disappeared. Some RC cells were still distributed in the distal portion of the interlobular artery even in the adult sheep. CONCLUSIONS: These results suggest that the wide distribution of RC cells in sheep kidney is formed in perinatal life, and that the neuronal regulation is associated with the maintenance of this distribution.

Aging↗

PubMed1994

The contributions of renin and vasopressin to the adaptation of the Australian spinifex hopping mouse (Notomys alexis) to free water deprivation.

Xeric-adaptation was studied during 28 days of total water deprivation (TWD) in Notomys alexis. Beyond 7 days, the initial reductions in body weight and increases in haematocrit, plasma renin and juxtaglomerular (JG) cell morphological activity returned to normal. Mus musculus showed similar changes at 7 days but could not be maintained thereafter. TWD decreased the blood pressure of Notomys but endogenous angiotensin and vasopressin did not support pressure to a greater extent than controls, as revealed by selective antagonists. The normal morphology of the JG apparatus in Notomys was similar to other rodents. Fluid volume and blood pressure maintenance during TWD in Notomys do not depend upon enhanced activities of the renin-angiotensin and antidiuretic hormonal systems.

Adaptation, Physiological↗