A brief review of the biochemistry and physiological functions of the renin‐angiotensin system is... more A brief review of the biochemistry and physiological functions of the renin‐angiotensin system is presented. A critical analysis is given of the various methods, both bioassay and radioimmunoassay, for measuring plasma renin and angiotensin levels. With the development of radioimmunoassay, specific, precise and rapid measurements of renin and angiotensin levels may now be made. Various factors that may influence the plasma level of renin are discussed, and the clinical applications for plasma renin measurements are listed.
A realistic scientific world view (until relatively recently) may have allowed that some areas of... more A realistic scientific world view (until relatively recently) may have allowed that some areas of crucial individual importance, for example, longevity, the mechanisms of ageing and certain aspects of the patho-aetiology of disease, presented such complex problems that a full understanding was unlikely in our time. As investigation gathered pace over the course of the 20th century, exciting new fields opened and this has led to the establishment of a firm scientific basis to medical practice.We have come so far that it is easy to forget that the major challenges in unravelling the basis of most human disease still lie ahead of us. At the onset of the 21st century, with spectacular recent advances in biomedical science, there is a general view held both by the profession and the public that major insights into ill-understood human illnesses will occur in the near future, with tangible benefits to humanity at large. The completion of the human genome project has opened a new era in medical research. Maximization of the opportunities presented, arguably the most important task in modern biology, requires not only a broad understanding, but precise delineation at a molecular and biochemical level of the complex interactions between genome and environment that lead to phenotype. Achievement of a reasonable rate of advance in sophisticated genotype–phenotype correlations will require improvements in the field of bioinformatics (necessary to store and analyse complex data); in phenotypic analysis (more precise measurement of biological phenomena); and in collection of genetic data from sufficient subjects to begin to tease out the effects of a range of polymorphisms in an orchestra of interactive genes.This will require an international effort of even greater scale than that seen so far in the genome project. Some of the important areas that must be advanced to optimize success will be discussed briefly.
Arginine vasopressin (AVP) acts on at least two receptor types, classified on the basis of their ... more Arginine vasopressin (AVP) acts on at least two receptor types, classified on the basis of their second messengers. The V1 receptor acts via mobilization of intracellular calcium through phosphatidylinositol hydrolysis and influences blood pressure and hepatic glycogenolysis. The V2 receptor acts via cAMP through activation of adenylate cyclase and causes antidiuresis. Previous studies of the different AVP receptors have been hampered by the use of nonselective radioligands, such as [3H]AVP (which binds to all types of V1 and V2 receptors, certain oxytocin receptors, and neurophysins) as well as the difficulty of measurement of second messengers. This paper describes the use of selective V1 and V2 radioligands with in vitro autoradiography to study V1 and V2 binding sites in rat tissues. [125I][1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid), 7-sarcosine] arginine vasopressin ([125I][d(CH2)5,Sarcosine7]AVP), a selective V1 antagonist radioligand, bound to regions of the brain, testis, superior cervical ganglion, liver, blood vessels, and renal medulla. Pharmacological characterization of [125I][d(CH2)5,Sarcosine7]AVP binding was consistent with that expected for binding to V1 receptors. There was no specific binding demonstrable to pituitary, renal glomeruli, gut, heart, spinal cord, ovary, adrenal medulla, or adrenal cortex. [3H]1-deamino [8-D-arginine] vasopressin [( 3H]DDAVP), a potent V2 receptor agonist radioligand, was used to study V2 receptors. Specific binding was only identified in the kidney consistent with the known distribution of antidiuretic V2 receptors on renal collecting tubules. No binding was demonstrated on endothelium or liver where DDAVP might influence clotting factor release, nor in the brain, spinal cord, sympathetic ganglia, heart or vascular smooth muscle, regions where DDAVP might cause vasodilatation. These studies demonstrate the use of these radioligands to study V1 and V2 receptors in a variety of tissues. Also, since these ligands are selective they are of particular use to study the different receptor subtypes in tissues where V1 and V2 receptors coexist, such as in the kidney.
Binding of 125I-[Sara,IleS]angiotensin II in the human hypothalamus was mapped by in vitro autora... more Binding of 125I-[Sara,IleS]angiotensin II in the human hypothalamus was mapped by in vitro autoradiography carried out on frozen sections of hypothalamus from two human brains. Regions showing the greatest specific binding of this radioligand were the organum vasculosum of the lamina terminalis, median preoptic nucleus, subfornical organ, median eminence, arcuate nucleus and paraventricular nucleus. These regions may be sites of angiotensin II receptors involved in the regulation of blood pressure, fluid balance and pituitary hormone secretion.
A viroid-like RNA was detected from coleus (Coleus blumei) in China. It consisted of 274 nucleoti... more A viroid-like RNA was detected from coleus (Coleus blumei) in China. It consisted of 274 nucleotides and had 66% sequence identity with a member of the closest known viroid species. The predicted secondary structure is rod-shaped with extensive base pairing, and it has the conserved region characteristic of the genus Coleviroid. Two terminal sequences that are highly conserved among some
The 125I-labeled agonist analog [1-sarcosine]angiotensin II ([Sar']AII) bound with high specifici... more The 125I-labeled agonist analog [1-sarcosine]angiotensin II ([Sar']AII) bound with high specificity and affinity (Ka = 2 x 109 M-1) to a single class of receptor sites in rat brain. This ligand was used to analyze the distribution of All receptors in rat brain by in vitro autoradiography followed by computerized densitometry and color coding. A very high density of All receptors was found in the subfornical organ, paraventricular and periventricular nuclei of the hypothalamus, nucleus of the tractus solitarius, and area postrema. A high concentration of receptors was found in the suprachiasmatic nucleus of the hypothalamus, lateral olfactory tracts, nuclei of the accessory and lateral olfactory tracts, triangular septal nucleus, subthalamic nucleus, locus coeruleus, and inferior olivary nuclei. Moderate receptor concentrations were
In addition to its traditional role as a circulating hormone, angiotensin is also involved in loc... more In addition to its traditional role as a circulating hormone, angiotensin is also involved in local functions through the activity of tissue renin-angiotensin systems that occur in many organs, including the brain. In the brain, both systemic and presumptive neurally derived angiotensin and angiotensin metabolites act through specific receptors to modulate many functions. This review examines the distribution of these specific angiotensin receptors and discusses evidence regarding the function of angiotensin peptides in various brain regions. Angiotensin AT1 and AT2 receptors occur in characteristic distributions that are highly correlated with the distribution of angiotensin-like immunoreactivity in nerve terminals. Acting through the AT1 receptor in the brain, angiotensin has effects on fluid and electrolyte homeostasis, neuroendocrine systems, autonomic pathways regulating cardiovascular function and behavior. Angiotensin AT1 receptors are also found in many afferent and efferent components of the peripheral autonomic nervous system. The role of the AT2 receptor in the brain is less well understood, although recent knockout studies point to an involvement with behavioral and cardiovascular functions. In addition to the AT1 and AT2 receptors, receptors for other fragments of angiotensin have been proposed. The AT4 binding site, which binds angiotensin, has a widespread distribution in the brain quite distinct from that of the AT1 and AT2 receptors. It is associated with many cholinergic neuronal groups and also several sensory nuclei, but its function remains to be determined. Our discovery that another brain-derived peptide binds to the AT4 binding site in the brain and may represent the native ligand is discussed. Overall, the distribution of angiotensin receptors in the brain indicate that they play diverse and important physiological roles in the nervous system.
Localization and interactions of vasoactive peptide receptors in renomedullary interstitial cells... more Localization and interactions of vasoactive peptide receptors in renomedullary interstitial cells of the kidney. Vasoactive peptides regulate renal medullary microcirculation and tubular function, but the localization of their receptors and mechanisms of actions are currently unknown. Using electron microscopic autoradiography, we have mapped the receptors for angiotensin II (Ang II [AT 1 and AT 2 ]), endothelin (ET A and ET B), and bradykinin (B 2) in the rat renal medulla. Although these peptide receptors show distinct vascular and tubular distributions, they overlap strikingly in renomedullary interstitial cells (RMICs) of the inner stripe and the papilla. Using reverse transcription-polymerase chain reaction (RT-PCR) and Southern analysis, mRNAs for AT 1A , ET A , and B 2 receptors were detected in cultured adult RMICs. Ang II increases intracellular inositol 1,4,5-triphosphate (IP 3) and [Ca 2ϩ ] i and stimulates [ 3 H]thymidine incorporation and extracellular matrix (ECM) synthesis via AT 1A receptors. Endothelin and bradykinin also stimulate cell proliferation and ECM synthesis in RMICs through ET A and B 2 receptors, respectively, but the actions of endothelin are modulated by concurrent nitric oxide production. By contrast, AT 2 receptor mRNA was detected only in embryonic RMICs, in which Ang II inhibits cell proliferation through this receptor. These results suggest that multiple vasoactive peptides may interact with RMICs to exert endocrine and/or paracrine influences on renal medullary microcirculation and tubular function.
Vasoactive peptides regulate renal medullary microcirculation and tubular function, but the local... more Vasoactive peptides regulate renal medullary microcirculation and tubular function, but the localization of their receptors and mechanisms of actions are currently unknown. Using electron microscopic autoradiography, we have mapped the receptors for angiotensin II (Ang II [AT 1 and AT 2 ]), endothelin (ET A and ET B ), and bradykinin (B 2 ) in the rat renal medulla. Although these peptide receptors show distinct vascular and tubular distributions, they overlap strikingly in renomedullary interstitial cells (RMICs) of the inner stripe and the papilla. Using reverse transcription-polymerase chain reaction (RT-PCR) and Southern analysis, mRNAs for AT 1A , ET A , and B 2 receptors were detected in cultured adult RMICs. Ang II increases intracellular inositol 1,4,5-triphosphate (IP 3 ) and [Ca 2ϩ ] i and stimulates [ 3 H]thymidine incorporation and extracellular matrix (ECM) synthesis via AT 1A receptors. Endothelin and bradykinin also stimulate cell proliferation and ECM synthesis in RMICs through ET A and B 2 receptors, respectively, but the actions of endothelin are modulated by concurrent nitric oxide production. By contrast, AT 2 receptor mRNA was detected only in embryonic RMICs, in which Ang II inhibits cell proliferation through this receptor. These results suggest that multiple vasoactive peptides may interact with RMICs to exert endocrine and/or paracrine influences on renal medullary microcirculation and tubular function.
Quantitative in vitro autoradiography was used to assess the post mortem stability of angiotensin... more Quantitative in vitro autoradiography was used to assess the post mortem stability of angiotensin II receptors and angiotensin converting enzyme in adult sheep brainstems. There was no significant loss of angiotensin II receptor binding in brainstems stored for up to 24 h at 23 degrees C or for 8 h at 23 degrees C followed by 64 h at 4 degrees C. There was no significant decrease in angiotensin converting enzyme binding in the same nuclei after up to 48 h at 23 degrees C or after 8 h at 23 degrees C followed by up to 64 h at 4 degrees C. Interpretation of neurochemical studies of human brain tissue obtained at autopsy requires assessment of the post mortem stability of the molecules being studied. Our results indicate that angiotensin II receptors and angiotensin converting enzyme are remarkably stable in sheep brainstems after post mortem delays in excess of those usually encountered in hospital autopsies.
In addition to its traditional role as a circulating hormone, angiotensin is also involved in loc... more In addition to its traditional role as a circulating hormone, angiotensin is also involved in local functions through the activity of tissue renin-angiotensin systems that occur in many organs, including the brain. In the brain, both systemic and presumptive neurally derived angiotensin and angiotensin metabolites act through specific receptors to modulate many functions. This review examines the distribution of these specific angiotensin receptors and discusses evidence regarding the function of angiotensin peptides in various brain regions. Angiotensin AT1 and AT2 receptors occur in characteristic distributions that are highly correlated with the distribution of angiotensin-like immunoreactivity in nerve terminals. Acting through the AT1 receptor in the brain, angiotensin has effects on fluid and electrolyte homeostasis, neuroendocrine systems, autonomic pathways regulating cardiovascular function and behavior. Angiotensin AT1 receptors are also found in many afferent and efferent components of the peripheral autonomic nervous system. The role of the AT2 receptor in the brain is less well understood, although recent knockout studies point to an involvement with behavioral and cardiovascular functions. In addition to the AT1 and AT2 receptors, receptors for other fragments of angiotensin have been proposed. The AT4 binding site, which binds angiotensin, has a widespread distribution in the brain quite distinct from that of the AT1 and AT2 receptors. It is associated with many cholinergic neuronal groups and also several sensory nuclei, but its function remains to be determined. Our discovery that another brain-derived peptide binds to the AT4 binding site in the brain and may represent the native ligand is discussed. Overall, the distribution of angiotensin receptors in the brain indicate that they play diverse and important physiological roles in the nervous system.
To test the hypothesis that proliferation of host dopaminergic tissue in response to injury plays... more To test the hypothesis that proliferation of host dopaminergic tissue in response to injury plays an important role in the response to intrastriatal grafting, we transplanted autologous adrenal medullary to striatum in normal C57-black mice and compared this procedure with transplantation of non-dopaminergic tissue (frontal cortex) or a non-cellular matrix (Gelfoam). [3H]Mazindol autoradiography revealed that all three protocols resulted in a marked proliferation of dopamine uptake sites 10 months after transplantation.
The distribution of angiotensin II binding sites has been mapped at segmental levels throughout t... more The distribution of angiotensin II binding sites has been mapped at segmental levels throughout the spinal cord of the sheep using in vitro autoradiographic methods. Binding of 125I-[Sar1.Ile8] Ang II is most prominent in the lateral horns of the thoracolumbar and sacral regions containing the sympathetic and parasympathetic preganglionic neurons respectively. Binding is also present in the dorsal horns of the grey matter, in the central canal region, dorsal root ganglia and associated with non-neuronal elements such as the ependyma surrounding the central canal, and blood vessels. Displacement with receptor antagonists specific for AT1 and AT2 subtypes, indicates that angiotensin II receptors in the spinal cord are of the AT1 type. These data help to interpret the physiological actions of angiotensin II in the spinal cord, particularly with respect to its autonomic components.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2008
Approximately one-quarter of people over the age of 65 are estimated to suffer some form of cogni... more Approximately one-quarter of people over the age of 65 are estimated to suffer some form of cognitive impairment, underscoring the need for effective cognitive-enhancing agents. Insulin-regulated aminopeptidase (IRAP) is potentially an innovative target for the development of cognitive enhancers, as its peptide inhibitors exhibit memory-enhancing effects in both normal and memory-impaired rodents. Using a homology model of the catalytic domain of IRAP and virtual screening, we have identified a class of nonpeptide, small-molecule inhibitors of IRAP. Structure-based computational development of an initial "hit" resulted in the identification of two divergent families of compounds. Subsequent medicinal chemistry performed on the highest affinity compound produced inhibitors with nanomolar affinities (K(i) 20-700 nM) for IRAP. In vivo efficacy of one of these inhibitors was demonstrated in rats with an acute dose (1 nmol in 1 microl) administered into the lateral ventricles, ...
A brief review of the biochemistry and physiological functions of the renin‐angiotensin system is... more A brief review of the biochemistry and physiological functions of the renin‐angiotensin system is presented. A critical analysis is given of the various methods, both bioassay and radioimmunoassay, for measuring plasma renin and angiotensin levels. With the development of radioimmunoassay, specific, precise and rapid measurements of renin and angiotensin levels may now be made. Various factors that may influence the plasma level of renin are discussed, and the clinical applications for plasma renin measurements are listed.
A realistic scientific world view (until relatively recently) may have allowed that some areas of... more A realistic scientific world view (until relatively recently) may have allowed that some areas of crucial individual importance, for example, longevity, the mechanisms of ageing and certain aspects of the patho-aetiology of disease, presented such complex problems that a full understanding was unlikely in our time. As investigation gathered pace over the course of the 20th century, exciting new fields opened and this has led to the establishment of a firm scientific basis to medical practice.We have come so far that it is easy to forget that the major challenges in unravelling the basis of most human disease still lie ahead of us. At the onset of the 21st century, with spectacular recent advances in biomedical science, there is a general view held both by the profession and the public that major insights into ill-understood human illnesses will occur in the near future, with tangible benefits to humanity at large. The completion of the human genome project has opened a new era in medical research. Maximization of the opportunities presented, arguably the most important task in modern biology, requires not only a broad understanding, but precise delineation at a molecular and biochemical level of the complex interactions between genome and environment that lead to phenotype. Achievement of a reasonable rate of advance in sophisticated genotype–phenotype correlations will require improvements in the field of bioinformatics (necessary to store and analyse complex data); in phenotypic analysis (more precise measurement of biological phenomena); and in collection of genetic data from sufficient subjects to begin to tease out the effects of a range of polymorphisms in an orchestra of interactive genes.This will require an international effort of even greater scale than that seen so far in the genome project. Some of the important areas that must be advanced to optimize success will be discussed briefly.
Arginine vasopressin (AVP) acts on at least two receptor types, classified on the basis of their ... more Arginine vasopressin (AVP) acts on at least two receptor types, classified on the basis of their second messengers. The V1 receptor acts via mobilization of intracellular calcium through phosphatidylinositol hydrolysis and influences blood pressure and hepatic glycogenolysis. The V2 receptor acts via cAMP through activation of adenylate cyclase and causes antidiuresis. Previous studies of the different AVP receptors have been hampered by the use of nonselective radioligands, such as [3H]AVP (which binds to all types of V1 and V2 receptors, certain oxytocin receptors, and neurophysins) as well as the difficulty of measurement of second messengers. This paper describes the use of selective V1 and V2 radioligands with in vitro autoradiography to study V1 and V2 binding sites in rat tissues. [125I][1-(beta-mercapto-beta,beta-cyclopentamethylene propionic acid), 7-sarcosine] arginine vasopressin ([125I][d(CH2)5,Sarcosine7]AVP), a selective V1 antagonist radioligand, bound to regions of the brain, testis, superior cervical ganglion, liver, blood vessels, and renal medulla. Pharmacological characterization of [125I][d(CH2)5,Sarcosine7]AVP binding was consistent with that expected for binding to V1 receptors. There was no specific binding demonstrable to pituitary, renal glomeruli, gut, heart, spinal cord, ovary, adrenal medulla, or adrenal cortex. [3H]1-deamino [8-D-arginine] vasopressin [( 3H]DDAVP), a potent V2 receptor agonist radioligand, was used to study V2 receptors. Specific binding was only identified in the kidney consistent with the known distribution of antidiuretic V2 receptors on renal collecting tubules. No binding was demonstrated on endothelium or liver where DDAVP might influence clotting factor release, nor in the brain, spinal cord, sympathetic ganglia, heart or vascular smooth muscle, regions where DDAVP might cause vasodilatation. These studies demonstrate the use of these radioligands to study V1 and V2 receptors in a variety of tissues. Also, since these ligands are selective they are of particular use to study the different receptor subtypes in tissues where V1 and V2 receptors coexist, such as in the kidney.
Binding of 125I-[Sara,IleS]angiotensin II in the human hypothalamus was mapped by in vitro autora... more Binding of 125I-[Sara,IleS]angiotensin II in the human hypothalamus was mapped by in vitro autoradiography carried out on frozen sections of hypothalamus from two human brains. Regions showing the greatest specific binding of this radioligand were the organum vasculosum of the lamina terminalis, median preoptic nucleus, subfornical organ, median eminence, arcuate nucleus and paraventricular nucleus. These regions may be sites of angiotensin II receptors involved in the regulation of blood pressure, fluid balance and pituitary hormone secretion.
A viroid-like RNA was detected from coleus (Coleus blumei) in China. It consisted of 274 nucleoti... more A viroid-like RNA was detected from coleus (Coleus blumei) in China. It consisted of 274 nucleotides and had 66% sequence identity with a member of the closest known viroid species. The predicted secondary structure is rod-shaped with extensive base pairing, and it has the conserved region characteristic of the genus Coleviroid. Two terminal sequences that are highly conserved among some
The 125I-labeled agonist analog [1-sarcosine]angiotensin II ([Sar']AII) bound with high specifici... more The 125I-labeled agonist analog [1-sarcosine]angiotensin II ([Sar']AII) bound with high specificity and affinity (Ka = 2 x 109 M-1) to a single class of receptor sites in rat brain. This ligand was used to analyze the distribution of All receptors in rat brain by in vitro autoradiography followed by computerized densitometry and color coding. A very high density of All receptors was found in the subfornical organ, paraventricular and periventricular nuclei of the hypothalamus, nucleus of the tractus solitarius, and area postrema. A high concentration of receptors was found in the suprachiasmatic nucleus of the hypothalamus, lateral olfactory tracts, nuclei of the accessory and lateral olfactory tracts, triangular septal nucleus, subthalamic nucleus, locus coeruleus, and inferior olivary nuclei. Moderate receptor concentrations were
In addition to its traditional role as a circulating hormone, angiotensin is also involved in loc... more In addition to its traditional role as a circulating hormone, angiotensin is also involved in local functions through the activity of tissue renin-angiotensin systems that occur in many organs, including the brain. In the brain, both systemic and presumptive neurally derived angiotensin and angiotensin metabolites act through specific receptors to modulate many functions. This review examines the distribution of these specific angiotensin receptors and discusses evidence regarding the function of angiotensin peptides in various brain regions. Angiotensin AT1 and AT2 receptors occur in characteristic distributions that are highly correlated with the distribution of angiotensin-like immunoreactivity in nerve terminals. Acting through the AT1 receptor in the brain, angiotensin has effects on fluid and electrolyte homeostasis, neuroendocrine systems, autonomic pathways regulating cardiovascular function and behavior. Angiotensin AT1 receptors are also found in many afferent and efferent components of the peripheral autonomic nervous system. The role of the AT2 receptor in the brain is less well understood, although recent knockout studies point to an involvement with behavioral and cardiovascular functions. In addition to the AT1 and AT2 receptors, receptors for other fragments of angiotensin have been proposed. The AT4 binding site, which binds angiotensin, has a widespread distribution in the brain quite distinct from that of the AT1 and AT2 receptors. It is associated with many cholinergic neuronal groups and also several sensory nuclei, but its function remains to be determined. Our discovery that another brain-derived peptide binds to the AT4 binding site in the brain and may represent the native ligand is discussed. Overall, the distribution of angiotensin receptors in the brain indicate that they play diverse and important physiological roles in the nervous system.
Localization and interactions of vasoactive peptide receptors in renomedullary interstitial cells... more Localization and interactions of vasoactive peptide receptors in renomedullary interstitial cells of the kidney. Vasoactive peptides regulate renal medullary microcirculation and tubular function, but the localization of their receptors and mechanisms of actions are currently unknown. Using electron microscopic autoradiography, we have mapped the receptors for angiotensin II (Ang II [AT 1 and AT 2 ]), endothelin (ET A and ET B), and bradykinin (B 2) in the rat renal medulla. Although these peptide receptors show distinct vascular and tubular distributions, they overlap strikingly in renomedullary interstitial cells (RMICs) of the inner stripe and the papilla. Using reverse transcription-polymerase chain reaction (RT-PCR) and Southern analysis, mRNAs for AT 1A , ET A , and B 2 receptors were detected in cultured adult RMICs. Ang II increases intracellular inositol 1,4,5-triphosphate (IP 3) and [Ca 2ϩ ] i and stimulates [ 3 H]thymidine incorporation and extracellular matrix (ECM) synthesis via AT 1A receptors. Endothelin and bradykinin also stimulate cell proliferation and ECM synthesis in RMICs through ET A and B 2 receptors, respectively, but the actions of endothelin are modulated by concurrent nitric oxide production. By contrast, AT 2 receptor mRNA was detected only in embryonic RMICs, in which Ang II inhibits cell proliferation through this receptor. These results suggest that multiple vasoactive peptides may interact with RMICs to exert endocrine and/or paracrine influences on renal medullary microcirculation and tubular function.
Vasoactive peptides regulate renal medullary microcirculation and tubular function, but the local... more Vasoactive peptides regulate renal medullary microcirculation and tubular function, but the localization of their receptors and mechanisms of actions are currently unknown. Using electron microscopic autoradiography, we have mapped the receptors for angiotensin II (Ang II [AT 1 and AT 2 ]), endothelin (ET A and ET B ), and bradykinin (B 2 ) in the rat renal medulla. Although these peptide receptors show distinct vascular and tubular distributions, they overlap strikingly in renomedullary interstitial cells (RMICs) of the inner stripe and the papilla. Using reverse transcription-polymerase chain reaction (RT-PCR) and Southern analysis, mRNAs for AT 1A , ET A , and B 2 receptors were detected in cultured adult RMICs. Ang II increases intracellular inositol 1,4,5-triphosphate (IP 3 ) and [Ca 2ϩ ] i and stimulates [ 3 H]thymidine incorporation and extracellular matrix (ECM) synthesis via AT 1A receptors. Endothelin and bradykinin also stimulate cell proliferation and ECM synthesis in RMICs through ET A and B 2 receptors, respectively, but the actions of endothelin are modulated by concurrent nitric oxide production. By contrast, AT 2 receptor mRNA was detected only in embryonic RMICs, in which Ang II inhibits cell proliferation through this receptor. These results suggest that multiple vasoactive peptides may interact with RMICs to exert endocrine and/or paracrine influences on renal medullary microcirculation and tubular function.
Quantitative in vitro autoradiography was used to assess the post mortem stability of angiotensin... more Quantitative in vitro autoradiography was used to assess the post mortem stability of angiotensin II receptors and angiotensin converting enzyme in adult sheep brainstems. There was no significant loss of angiotensin II receptor binding in brainstems stored for up to 24 h at 23 degrees C or for 8 h at 23 degrees C followed by 64 h at 4 degrees C. There was no significant decrease in angiotensin converting enzyme binding in the same nuclei after up to 48 h at 23 degrees C or after 8 h at 23 degrees C followed by up to 64 h at 4 degrees C. Interpretation of neurochemical studies of human brain tissue obtained at autopsy requires assessment of the post mortem stability of the molecules being studied. Our results indicate that angiotensin II receptors and angiotensin converting enzyme are remarkably stable in sheep brainstems after post mortem delays in excess of those usually encountered in hospital autopsies.
In addition to its traditional role as a circulating hormone, angiotensin is also involved in loc... more In addition to its traditional role as a circulating hormone, angiotensin is also involved in local functions through the activity of tissue renin-angiotensin systems that occur in many organs, including the brain. In the brain, both systemic and presumptive neurally derived angiotensin and angiotensin metabolites act through specific receptors to modulate many functions. This review examines the distribution of these specific angiotensin receptors and discusses evidence regarding the function of angiotensin peptides in various brain regions. Angiotensin AT1 and AT2 receptors occur in characteristic distributions that are highly correlated with the distribution of angiotensin-like immunoreactivity in nerve terminals. Acting through the AT1 receptor in the brain, angiotensin has effects on fluid and electrolyte homeostasis, neuroendocrine systems, autonomic pathways regulating cardiovascular function and behavior. Angiotensin AT1 receptors are also found in many afferent and efferent components of the peripheral autonomic nervous system. The role of the AT2 receptor in the brain is less well understood, although recent knockout studies point to an involvement with behavioral and cardiovascular functions. In addition to the AT1 and AT2 receptors, receptors for other fragments of angiotensin have been proposed. The AT4 binding site, which binds angiotensin, has a widespread distribution in the brain quite distinct from that of the AT1 and AT2 receptors. It is associated with many cholinergic neuronal groups and also several sensory nuclei, but its function remains to be determined. Our discovery that another brain-derived peptide binds to the AT4 binding site in the brain and may represent the native ligand is discussed. Overall, the distribution of angiotensin receptors in the brain indicate that they play diverse and important physiological roles in the nervous system.
To test the hypothesis that proliferation of host dopaminergic tissue in response to injury plays... more To test the hypothesis that proliferation of host dopaminergic tissue in response to injury plays an important role in the response to intrastriatal grafting, we transplanted autologous adrenal medullary to striatum in normal C57-black mice and compared this procedure with transplantation of non-dopaminergic tissue (frontal cortex) or a non-cellular matrix (Gelfoam). [3H]Mazindol autoradiography revealed that all three protocols resulted in a marked proliferation of dopamine uptake sites 10 months after transplantation.
The distribution of angiotensin II binding sites has been mapped at segmental levels throughout t... more The distribution of angiotensin II binding sites has been mapped at segmental levels throughout the spinal cord of the sheep using in vitro autoradiographic methods. Binding of 125I-[Sar1.Ile8] Ang II is most prominent in the lateral horns of the thoracolumbar and sacral regions containing the sympathetic and parasympathetic preganglionic neurons respectively. Binding is also present in the dorsal horns of the grey matter, in the central canal region, dorsal root ganglia and associated with non-neuronal elements such as the ependyma surrounding the central canal, and blood vessels. Displacement with receptor antagonists specific for AT1 and AT2 subtypes, indicates that angiotensin II receptors in the spinal cord are of the AT1 type. These data help to interpret the physiological actions of angiotensin II in the spinal cord, particularly with respect to its autonomic components.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2008
Approximately one-quarter of people over the age of 65 are estimated to suffer some form of cogni... more Approximately one-quarter of people over the age of 65 are estimated to suffer some form of cognitive impairment, underscoring the need for effective cognitive-enhancing agents. Insulin-regulated aminopeptidase (IRAP) is potentially an innovative target for the development of cognitive enhancers, as its peptide inhibitors exhibit memory-enhancing effects in both normal and memory-impaired rodents. Using a homology model of the catalytic domain of IRAP and virtual screening, we have identified a class of nonpeptide, small-molecule inhibitors of IRAP. Structure-based computational development of an initial "hit" resulted in the identification of two divergent families of compounds. Subsequent medicinal chemistry performed on the highest affinity compound produced inhibitors with nanomolar affinities (K(i) 20-700 nM) for IRAP. In vivo efficacy of one of these inhibitors was demonstrated in rats with an acute dose (1 nmol in 1 microl) administered into the lateral ventricles, ...
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Papers by F. Mendelsohn