Biomedical subjects

B Mayer

Publications and source records attributed to B Mayer.

At least 91 records · Page 5Linked to original sources

PubMed1999

Enzymatic function of nitric oxide synthases.

Nitric oxide (NO) is synthesised from L-arginine by the enzyme NO synthase (NOS). The complex reaction involves the transfer of electrons from NADPH, via the flavins FAD and FMN in the carboxy-terminal reductase domain, to the haem in the amino-terminal oxygenase domain, where the substrate L-arginine is oxidised to L-citrulline and NO. The haem is essential for dimerisation as well as NO production. The pteridine tetrahydrobiopterin (BH4) is a key feature of NOS, affecting dimerisation and electron transfer, although its full role in catalysis remains to be determined. NOS can also catalyse superoxide anion production, depending on substrate and cofactor availability. There are three main isoforms of the enzyme, named neuronal NOS (nNOS), inducible NOS (iNOS), and endothelial NOS (eNOS), which differ in their dependence on Ca2+, as well as in their expression and activities. These unique features give rise to the distinct subcellular localisations and mechanistic features which are responsible for the physiological and pathophysiological roles of each isoform.

Animals↗

PubMed1999

c-Src association with and phosphorylation of p58gag, a membrane- and microfilament-associated retroviral Gag-like protein in a xenotransplantable rat mammary tumor.

The retroviral Gag-like protein p58gag expressed in a highly metastatic ascites rat mammary adenocarcinoma has been implicated in cell surface changes contributing to xenotransplantability. p58gag is present in the cells in a plasma membrane- and microfilament-associated signal transduction particle containing Src and is phosphorylated on tyrosine. Overlay analyses and affinity chromatography with glutathione S-transferase (GST) fusion proteins of Src homology-3 (SH3) domains showed direct binding of the Src but not the Crk SH3 domain to p58gag. This association was confirmed by co-immunoprecipitation of partially purified p58gag from ascites cell lysates with platelet Src. Further, a GST-p58gag fusion protein bound full length c-Src from either platelets or c-Src-expressing insect cells. The GST-p58gag fusion protein, but not GST, was phosphorylated by platelet or insect cell-expressed c-Src, but not by a kinase negative c-Src variant. The binding of GST-p58gag to c-Src was almost completely abolished by a 50-fold excess of the GST-SH3 domain of Src, and a parallel decrease in tyrosine phosphorylation of p58gag was observed. These results demonstrate that p58gag is tyrosine-phosphorylated as a consequence of its specific association with c-Src via its SH3 domain. These observations suggest a mechanism by which Gag proteins may contribute to retroviral maturation or pathogenesis through binding and relocalization of SH3 domain-containing proteins such as Src-like tyrosine kinases to sites of association of microfilaments with the plasma membrane.

Adenocarcinoma↗

PubMed1999

Activation of neuronal nitric-oxide synthase by the 5-methyl analog of tetrahydrobiopterin. Functional evidence against reductive oxygen activation by the pterin cofactor.

Tetrahydrobiopterin ((6R)-5,6,7,8-tetrahydro-L-biopterin (H4biopterin)) is an essential cofactor of nitric-oxide synthases (NOSs), but its role in enzyme function is not known. Binding of the pterin affects the electronic structure of the prosthetic heme group in the oxygenase domain and results in a pronounced stabilization of the active homodimeric structure of the protein. However, these allosteric effects are also produced by the potent pterin antagonist of NOS, 4-amino-H4biopterin, suggesting that the natural cofactor has an additional, as yet unknown catalytic function. Here we show that the 5-methyl analog of H4biopterin, which does not react with O2, is a functionally active pterin cofactor of neuronal NOS. Activation of the H4biopterin-free enzyme occurred in a biphasic manner with half-maximally effective concentrations of approximately 0.2 microM and 10 mM 5-methyl-H4biopterin. Thus, the affinity of the 5-methyl compound was 3 orders of magnitude lower than that of the natural cofactor, allowing the direct demonstration of the functional anticooperativity of the two pterin binding sites of dimeric NOS. In contrast to H4biopterin, which inactivates nitric oxide (NO) through nonenzymatic superoxide formation, up to 1 mM of the 5-methyl derivative did not consume O2 and had no effect on NO steady-state concentrations measured electrochemically with a Clark-type NO electrode. Therefore, reconstitution with 5-methyl-H4biopterin allowed, for the first time, the detection of enzymatic NO formation in the absence of superoxide or NO scavengers. These results unequivocally identify free NO as a NOS product and indicate that reductive O2 activation by the pterin cofactor is not essential to NO biosynthesis.

Animals↗

PubMed1999

Dynamics of carbon monoxide binding with neuronal nitric oxide synthase.

The dynamics of CO rebinding with neuronal NO synthase (nNOS) following laser flash photolysis have been investigated from 293 to 77 K in the absence and presence of its substrate L-arginine. The distribution functions of the rate parameters P(k) and of the activation enthalpy P(H) were determined using the maximum entropy method. In a fluid solvent near room temperature, bimolecular rebinding is biphasic, as previously reported by several groups. However, measurement of the rotational correlation time shows that the apparent biphasic rebinding is not relevant to the genuine dynamics of NOS. In addition to native dimeric nNOS, another species (possibly aggregated or partially unfolded conformation) with different hydrodynamic characteristics is responsible for the faster rebinding process. In a rigid environment at low temperature, the geminate internal rebinding is not affected by the presence of the nonnative species. nNOS exhibits a bimodal distribution of CO activation enthalpy with P(H) consisting of two distinct bands with temperature-dependent amplitudes down to 77 K. The similarity of these findings with those recently reported for cytochromes P-450 suggests a common hierarchical organization of conformational substates, with a splitting of each conformational substate into a doublet. Thus, thiolate-coordinated heme proteins are in clear contrast to histidine-coordinated oxygen-transport heme proteins. The present results with nNOS provide additional support to previous arguments incriminating the thiolate ligand as responsible for the splitting of conformational substates.

Animals↗

PubMed1999

NADPH-diaphorase and NOS enzymatic activities in some neurons of reptilian gut and their relationships with two neuropeptides.

The distribution of neurons containing the enzymes NADPH-diaphorase (NADPH-d) and nitric oxide synthase (NOS) has been studied in the gastrointestinal tract of lizard (Podarcis s. sicula) and snake (Thamnophis sirtalis). The techniques employed were the NADPH-d/nitroblue tetrazolium histochemical method, and the indirect immunofluorescence applied to cryostat sections and to whole-mount preparations. The colocalization of NADPH-d with NOS, with vasoactive intestinal polypeptide (VIP) and with galanin (Gal) was also studied, and a Western blot analysis using an antibody directed against mammalian Gal was performed on lizard stomach extracts. NADPH-d positive nerve cell bodies and fibres were found in the myenteric and submucous plexuses throughout the gastrointestinal tract of both reptiles. These nerve structures were also present in the other intramural nerve plexuses, although in smaller quantities. Both in lizard and snake, the stomach revealed a positive nerve population that was more dense than elsewhere in the gut. The population of the NADPH-d-positive neurons observed in the lizard was larger than that observed in the snake. The distribution of both populations was similar to those that have been described in the gut of several mammalian and non-mammalian vertebrates. Both in lizard and snake, a one-to-one correspondence was noted between NOS- and NADPH-d-containing nerve cell bodies, and the nitrergic neurons containing Gal appeared to be more numerous than those containing VIP. Western blot analysis recognised a single band with a molecular weight (3.4 kDa) very similar to that of porcine Gal. It is hypothesised that at least some of the nitrergic neurons of the lizard and snake gut are inhibitory motor neurons innervating the circular smooth musculature. In addition, the colocalization of NOS and VIP in neurons enhances their inhibitory action. The role of the neurons containing both NOS and Gal remains unknown.

Animals↗

PubMed1999

Differential maturational patterns of nitric oxide synthase-I and NADPH diaphorase in functionally distinct cortical areas of the mouse cerebral cortex.

Nitric oxide (NO) regulates several functions both in the developing and the adult central nervous systems (CNS). During development, NO is assumed to contribute to the histogenetic differentiation of the CNS especially through the modulation of programmed neuronal death. The embryonal and postnatal changes in the distribution of the cortical NO producing system were studied in Balb/c mice using immunocytochemistry for nitric oxide synthase-I (NOS-I) and NADPH-diaphorase (NADPH-d) enzyme histochemistry. NOS-I reactive neurons (RN) appeared first at embryonic day 14 (E14) in the spinal cord in the vicinity of the central canal, and later, at E16-18, in the thalamus and striatum. The first cortical region to present NOS-I reactivity was the parietal cortex, which happened at E18-20. After E20 the number of NOS-I RN increased in every cortical area, plateauing at postnatal day 4 (P4). In parietal regions, however, the highest density of NOS-I RN was observed already at P1. The neuronal packing density (PD) of NOS-I RN declined until adulthood, interrupted by a transient increase in some cortical areas at the onset of puberty. The heterochronous appearance of NOS-I during pre- and postnatal development of different brain regions and the sequence of up- and downregulation of expression until adult stages points to an important role of NO in brain development and functional differentiation.

Animals↗

PubMed1999

Innervation of the fibro-elastic type of the penis: an immunohistochemical study in the male pig.

The occurrence and colocalization of several biologically active neuropeptides, catecholamine-, acetylcholine- or nitric oxide-synthesizing enzymes-tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (D beta H), choline acetyl-transferase (ChAT) and nitric oxide synthase (NOS I), respectively, as well as the vesicular acetylcholine transporter (VAChT) were investigated in the penile glans (GP), corpus and crura (CP), as well as in the retractor penis muscle (RPM) of juvenile and adult boars. Immunohistochemistry revealed that nerves immunoreactive (IR) to TH, D beta H, vasoactive intestinal polypeptide (VIP) and somatostatin (SOM) were the most numerous, followed (in decreasing order of density) by nerves IR to NOS, neuropeptide Y (NPY), substance P (SP), calcitonin gene-related peptide (CGRP), galanin (GAL), Leu5-enkephalin (LENK) and ChAT/VAChT. The CP contained the largest number of nerve fibres followed by the RPM, GP and corpus. Enzyme/peptide-containing nerves were associated with both the vascular and non-vascular penile structures. However, differences existed for their density and intrapenile distribution. Nerve terminals IR for different combinations of VIP, GAL or SOM were more frequent than those IR for NOS or CGRP in the non-vascular penile structures while the vasculature and the RPM received a prominent TH/D beta H-, VIP-, SOM- or NOS-IR nerve input. The present data indicate that the porcine penis receives nerve fibres that exhibit diverse chemical codes and that differences in the chemical coding of the nerve fibres may depend on their penile target-structure.

Age Factors↗

PubMed1999

Neuronal nitric oxide synthase (nNOS) expression in the epithelial neuroendocrine cell system and nerve fibers in the gill of the catfish, Heteropneustes fossilis.

We studied immunohistochemically the localization of neuronal nitric oxide synthase (nNOS) in gills of an Indian catfish species, Heteropneustes fossilis. It is shown that most of the epithelial neuroendocrine cells that are present in gill filaments and lamellae stained positively. Co-localization of nNOS and endothelin was also shown in neuroendocrine cells. A dense plexus of nNOS-containing nerve fibers was present beneath the gill epithelium, associated with efferent filament arteries and the basal side of neuroendocrine cells. nNOS immunopositive neurons were not found in gill areas. nNOS immunopositive neuroendocrine cells appeared to differ from neuroepithelial cells in gills of various teleost species, which are considered as oxygen-sensitive receptors and are present in the distal halves of gill filaments. Other types of neuroendocrine cells have been identified previously in other areas of gills using antibodies to serotonin and endothelin peptides. These cell types are likely to be involved in chemical regulation of the physiology of gill cells. In relation to the function of the other cell types, our data on nNOS localization suggest that NO is a wide-spread transmitter in the gill of the Indian catfish. It may play a role both in the local regulation of vascular tone and in inhibitory innervation of the gill.

Animals↗

PubMed1999

Unconscious processes, subliminal stimulation, and anxiety.

Ever since Poetzl's studies, subliminal stimulation has been used as a paradigm to explore the connection between unconscious processes and psychopathology. Inspired by the psychodynamic tradition, folk psychology attributes a dramatic power to subliminal stimulation. In contrast, most modern researchers argue that effects of subliminal stimulation are rather limited. Does that mean that the unconscious is irrelevant to psychopathology? Not necessarily. Ohman and Soares' hypothesis about the preattentive origins of phobic reactions represents a good example of a model in which a "quick and dirty" unconscious may produce pathogenic effects. Although the empirical basis of this model is still meagre, its attractiveness hinges on the assumption that "quick and dirty" processes that make up the first second of human information processing are essential for higher level analysis and performance. In line with this, recent studies have indicated that the attentional bias that accompanies pathological anxiety, might be an unconscious phenomenon. Theories that focus on unconscious cognitive processes involved in pathological anxiety are certainly interesting, but it should be emphasized that there are other aspects of automaticity (i.e., involuntariness) that may be as relevant to psychopathology as absence of awareness.

Anxiety↗

PubMed1999

Sources for structure formation and switches in metabolic pathways.

Zonation of function, i.e. localization of metabolic activity in certain regions of histologically uniform tissues, is an often observed phenomenon. Moreover, experiments show that such metabolic patterns are highly dynamical. Since in the pathways of intermediary metabolism no autocatalytic reactions are observed, different types of metabolic regulation are sources of the non-linearities necessary for structure formation. Two models of biochemical reactions frequently encountered in metabolic pathways, namely a bisubstrate kinetics model with substrate inhibition, and an allosteric model with product regulation, are presented. It is shown, that they are well-suited to reproduce the dynamical behavior suggested by experimental findings, like their capability to act as switches, or their ability for spatio-temporal pattern formation in mature tissues.

Allosteric Regulation↗

PubMed1999

Different nitric oxide synthase inhibitors cause rapid and differential alterations in the ligand-binding capacity of transmitter receptors in the rat cerebral cortex.

Inhibitors of nitric oxide (NO) synthesis reduce postlesional neuronal death during reperfusion injury by reducing the NO-mediated increase in excitatory neurotransmitter-release. The protective effects of various NO-synthase (NOS) inhibitors differ due to their isoform selectivity. The effects of NO-mediated excessive neurotransmitter supply are transmitted via specific neurotransmitter receptors expressed by the target cells. We report changes in the ligand-binding of different excitatory and inhibitory neurotransmitter-receptors studied by in vitro receptor autoradiography after in vivo-application of NOS-inhibitors. Since the constitutively expressed neuronal NOS-I is area-specifically distributed within the rat cortex, numerous cortical areas were studied in non-lesioned rats, in order to analyze the area-specific effects of NOS-inhibitors. The results showed that the NOS-I-specific inhibitor 7-nitroindazole increased binding of 3H-muscimol, 3H-pirenzepine and 3H-kainate, whereas the less isoform-specific, general NOS-inhibitor L-nitroarginine increased binding of 3H-muscimol and 3H-AMPA in most cortical areas, leaving 3H-kainate binding almost unchanged. The water soluble L-nitroarginine-methylester caused similar effects to those of L-nitroarginine which changed over a period of chronic treatment. The inhibitory GABAA-receptors were increased after NOS-inhibition in most cortical areas, whereas binding of 3H-Oxotremorine-M (acetylcholine receptors), 3H-MK-801 (NMDA-receptors) and 3H-AMPA (AMPA receptors) was affected differently among the cortical areas. Strongest alterations of ligand-binding capacity after administration of NOS-inhibitors were seen in cortical areas known to contain the highest packing densities of NOS-I-positive interneurons such as the piriform and entorhinal cortices, indicating that, in normal animals, neurotransmission and probably cognitive information processing would be affected by the pharmacological modulation of nitric oxide production.

Animals↗

PubMed1999

Selective assembly of cyclodextrins on poly(ethylene oxide)-poly(propylene oxide) block copolymers.

This paper presents a computational study on the formation of a molecular necklace formed by specific threading of cyclodextrins (CDs) on block copolymers. Structural as well as energetic principles for the selective complexation of alpha- and beta-cyclodextrin with poly(ethylene oxide)-poly(propylene oxide) block copolymers (PEO-PPO) are elucidated considering a diblock copolymer of equimolecular composition (PEO)4-(PPO)4 as guest. A non-statistical distribution of CDs, i.e. alpha-CDs primarily located on the PEO chain and beta-CDs on PPO blocks of the polymer, is based on a variety of structural features and energetic preferences considering both potential as well as solvation energies. This selectivity becomes already obvious considering 1:1 complexes between PEO and PPO monomers and the two CDs, but is increasingly evident when calculating higher order ensembles. Besides the host-guest interaction, docking between CDs themselves is an important, also non-statistical, prerequisite for the self-assembly of highly ordered tubes. The formation of intermolecular hydrogen bonds between adjacent CDs in a tubular aggregate gives an important contribution to the overall stability of the molecular necklace. The net effect, based on the preferential interaction between host and guest as well as between the host molecules themselves, results in the formation of a stable, highly ordered macromolecular, multicomponent aggregate.

Cyclodextrins↗

PubMed1999

Preferential inhibition of inducible nitric oxide synthase in intact cells by the 4-amino analogue of tetrahydrobiopterin.

In the present study we demonstrate that the 4-amino analogue of tetrahydrobiopterin, 2,4-diamino-5,6,7,8-tetrahydro-6-(l-erythro-1, 2-dihydroxypropyl)pteridine (4-amino-H4biopterin) binds with high affinity to recombinant endothelial NO synthase and concomitantly inhibits enzyme activity [IC50 = 14.8 +/- 7.5 microm in the presence of added 5,6,7,8-tetrahydro-l-erythrobiopterin (H4biopterin) 10 microm] as efficiently as previously shown for inducible NO synthase [Mayer, B., Wu, C.Q., Gorren, A.C.F., Pfeiffer, S., Schmidt, K., Clark, P., Stuehr, D.J. & Werner, E.R. (1997) Biochemistry 36, 8422-8427]. In cultured porcine endothelial cells, however, 4-amino-H4biopterin was less effective in inhibiting NO formation (IC50 = 420 +/- 36 microm) as compared with inhibition of the inducible isoform in murine fibroblasts (IC50 = 15 +/- 4.9 microm) and in human DLD-1 adenocarcinoma cells (IC50 = 55 +/- 10.3 microm). In all cells investigated, the inhibitory effect of 4-amino-H4biopterin was markedly enhanced by depletion of intracellular H4biopterin and could be overcome by increasing intracellular H4biopterin concentrations. Endothelial cells contained lower amounts of H4biopterin [5.2 +/- 0.3 pmol.(mg protein)-1] than fibroblasts [19.4 +/- 2.7 pmol.(mg protein)-1] and DLD-1 cells [8.3 +/- 1.1 pmol.(mg protein)-1], so that the selectivity of 4-amino-H4biopterin towards inducible NO synthase was not explained by differences in the H4biopterin levels. Because 4-amino-H4biopterin did not suppress expression of NO synthase in cytokine-treated cells, we suggest that high-affinity binding of the inhibitor during protein expression may be responsible for the preferential inhibition of the inducible isozyme in intact cells.

Animals↗

PubMed1999

Pharmacokinetics and pharmacodynamics of vecuronium in rats with systemic inflammatory response syndrome: treatment with NG-monomethyl-L-arginine.

BACKGROUND: Insufficient detoxification caused by nitric oxide-related inhibition of cytochrome P450 may be important for metabolism of numerous drugs, including vecuronium. The present study investigated the pharmacodynamics and pharmacokinetics of vecuronium in rats with inflammatory liver dysfunction. METHODS: Male Sprague-Dawley rats (n = 56) were randomly allocated into two groups: In the sepsis group, liver inflammation was established by injection of 56 mg/kg heat-killed Corynebacterium parvum; control rats received the solvent. At day 4, groups were subdivided according to treatment with the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine (250 mg/kg) or placebo. The aminopyrine breath test was performed to assess cytochrome P450 activity. Rats were anesthetized with propofol and mechanically ventilated. Duration of action of vecuronium (1.2 mg/kg) was measured by evoked mechanomyography (stimulation of the sciatic nerve, contraction of the gastrocnemius muscle). In seven rats of each subgroup a 50% neuromuscular blockade was established by a continuous vecuronium infusion. Vecuronium plasma levels were measured and plasma clearance of vecuronium was calculated. Nitric oxide synthesis was assessed by measuring nitrite/nitrate serum levels. RESULTS: In sepsis/placebo rats, vecuronium-induced neuromuscular blockade was prolonged (144% of contro/placebo), vecuronium plasma levels at 50% neuromuscular blockade were increased (122% of control/placebo), and plasma clearance was decreased (68% of control/placebo). N(G)-monomethyl-L-arginine therapy in rats with sepsis improved cytochrome P450 activity and plasma clearance of vecuronium, shortened duration of action of vecuronium, but did not alter the elevated vecuronium plasma levels. CONCLUSIONS: A systemic inflammatory response syndrome with liver dysfunction results in decreased sensitivity to and a decreased elimination of vecuronium. Modulation of nitric oxide synthesis may be a strategy that can be used in the future to improve xenobiotic metabolism in sepsis.

Alanine Transaminase↗

PubMed1999

Nitric oxide synthase expression in the opossum superior colliculus: a histochemical, immunohistochemical and biochemical study.

The expression of neuronal nitric oxide synthase (nNOS) in the superior colliculus (SC) of the opossum Didelphis marsupialis was studied by NADPH diaphorase (NADPH-d) histochemistry and nNOS immunohistochemistry. In addition, the activity of nNOS was quantified by measurement of [(3)H]-L-arginine conversion to [(3)H]-L-citrulline in tissue extracts from SC superficial layers in opossums and rats. Our results show that the number of NADPH-d stained cells was small and virtually identical in stratum opticum (SO) and stratum griseum superficiale (SGS) and their staining was very light, particularly in SGS. Neuropil staining was heavier in the stratum zonale (SZ) than in SGS or SO. The intermediate and deep layers contained heavily stained cells and moderate neuropil staining. Surprisingly, nNOS-immunoreactive cells were far more numerous than NADPH-d+ cells in every layer. The production of [(3)H]-L-citrulline from [(3)H]-L-arginine in tissue extracts enriched in superficial layers indicated that nNOS specific activity is as high in the opossum as in the rat. Our results suggest that the location of nNOS-expressing neurons in retino-receptive layers may be related to inter-specific differences in the processing of visual information.

Animals↗

PubMed1999

Histochemical and immunocytochemical study of nitrergic innervation in human nasal mucosa.

Nitric oxide (NO) is a free radical gas that has been found to be produced in neuronal cells by the action of the enzyme brain nitric oxide synthase (bNOS). The aim of this study was to identify NO-containing nerve structures in the human nasal mucosa by localizing bNOS and to find out whether NO production is attached to the parasympathetic system. For this purpose, immunocytochemistry with antibodies to bNOS and neurofilament was performed. Additionally, nicotinamide-adenine dinucleotide phosphate diaphorase (NADPH-d), an enzyme that correlates with the localization of NO synthase, and acetylcholinesterase were visualized in a histochemical double staining technique on frozen sections. The NADPH-d and bNOS reactions were found in axons of nerve bundles and in subepithelial, glandular, and vascular nerve fibers. Arteries showed a distinctly developed nitric innervation, whereas no activity was found in nerve fibers supplying veins. A high coexistence of NADPH-d in parasympathetic nerves could be detected. These findings suggest that NO takes part in the nerve control functions of the human nasal mucosa.

Acetylcholinesterase↗

PubMed1999

Neuronal anomalies and normal muscle morphology at the hypomotile ileocecocolonic region of patients affected by idiopathic chronic constipation.

Patients suffering from idiopathic slow-transit chronic constipation have a delayed colonic transit referable to a decrease or loss of propagating contractions. Myogenic and/or neural mechanisms have been implicated in the pathophysiology of this dysfunction and neuronal abnormalities have been described at the ascending, descending and sigmoid colon. The morphology and motile behaviour of the ileocecocolonic region, which in healthy subjects regulates cecum filling and emptying, have never been investigated in such disease. Therefore, we endoscopically ascertained whether a motility impairment was present at these junctional areas and neither spontaneous nor provoked occlusive contractions were found at the cecocolonic junction. Light and electron microscope examination of the entire colon revealed apparently normal features of neurons, smooth muscle cells and interstitial cells of Cajal, while immunohistochemistry and quantitative analysis demonstrated neuronal anomalies at the junctional areas. These anomalies consisted of low total neuron density and significantly few VIP-immunoreactive neurons at the two enteric plexuses, significantly few NOS-immunoreactive neurons at the myenteric plexus and significantly more NOS-immunoreactive neurons at the submucous plexus. These findings exclude a myopathy and demonstrate the existence of a neuropathy. In particular, the presence at the ileocecocolonic region of few VIP- and NO-producing neurons suggests that there might be a reduced VIP and NO production which may result in a compromised relaxation and/or onset of propagating contractions, slowing down bolus transit. The presence at the proximal colon of such an abnormality might explain why left colectomy and/or cecorectal anastomosis are unsuccessful in patients with this disease.

Adult↗

PubMed1999

Normalizing the expression of nitric oxide synthase by low-dose AT1 receptor antagonism parallels improved vascular morphology in hypertensive rats.

In essential hypertension, stroke and kidney damage may result from an impaired interaction of vasoregulatory systems. Stroke-prone spontaneously hypertensive rats (SHRSP) were studied to analyze the effects of a low-dose treatment of the angiotensin II type 1 receptor (AT1) blocker candesartan cilexetil on the expression of nitric oxide synthases (NOS) and on vascular structure. Both treated and untreated SHRSP were kept on a stroke-promoting dietary regimen, and compared with Wistar Kyoto rats (WKY). Early mortality of untreated SHRSP was prevented by the treatment. In untreated SHRSP, cerebral intraparenchymal vessels of the parietal lobe showed lesions of the vascular wall and its periphery, such as proteinaceous deposits, perivascular dilated spaces, increase in phagocytic cells, and decreased actin immunostaining. Renal lesions were more pronounced comprising arteriolar occlusion, extensive loss of actin, increased alpha1(IV) collagen expression, and glomerular sclerotic as well as tubulointerstitial lesions. Beneficial effects of the AT1 blockade were more pronounced in brain than in kidney. Activity profile of NOS showed increased NADPH diaphorase staining in media and endothelium of SHRSP; endothelial NOS3 immunoreactivity was decreased, but instead, inducible NOS2 increased in untreated SHRSP. These changes were largely prevented in the treated group. NOS activity in macula densa cells was unchanged, whereas afferent arteriolar renin levels were increased in untreated SHRSP. Results demonstrate an effective reduction of hypertensive vascular changes with a nonpressor dose of candesartan. A "role switch" of vascular NOS in hypertension from physiologic NOS3 toward deleterious NOS2 is suggested, and its prevention by the AT1 blocker points to an angiotensin II-dependent, nitric oxide-mediated pathway that may impair endothelial function and aggravate defects of the blood-brain barrier and kidney structures.

Angiotensin Receptor Antagonists↗