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Biomedical subjects

M Viswanathan

Publications and source records attributed to M Viswanathan.

At least 55 records · Page 3Linked to original sources
PubMed1996

Smooth muscle DNA replication in response to angiotensin II is regulated differently in the neointima and media at different times after balloon injury in the rat carotid artery. Role of AT1 receptor expression.

We have reported that angiotensin II (Ang II) infusion to rats during the third and fourth weeks after vascular injury stimulates DNA replication in a larger proportion of smooth muscle cells (SMCs) in the arterial neointima than in the underlying media or the normal arterial media. Whether this increased responsiveness to Ang II is a transient or stable property of neointimal cells after vascular injury remained unclear. The present study examined smooth muscle DNA replication in response to Ang II infusion (250 ng.kg-1.min-1 for 2 weeks) at 3 to 4, 9 to 10, or 27 to 28 weeks after balloon injury to the rat carotid artery. Control rats received Ringer's lactate. BrdU (0.8 mg.kg-1.d-1) was coinfused to label replicating DNA. The increased replicative response to Ang II in the neointima versus the normal arterial media did not persist beyond the period of rapid lesion growth shortly after injury, even in neointimal areas without endothelial regeneration. By 9 to 10 weeks after injury, replication frequencies were comparable in the neointima and the normal arterial wall. In the presence of a regenerated endothelium, neointimal DNA replication was lowered but not abolished. After the early period, however, the most marked difference may be the loss of ability of medial SMCs to respond mitogenically to systemic Ang II. As a consequence, Ang II-induced DNA replication in injured arteries was greater in the neointima than in the underlying media at all times studied after injury. DNA replication levels correlated with AT1 receptor levels in the injured artery neointima but not media, as shown by receptor binding in vascular sections at 3 and 10 weeks after injury. The growth response to systemic Ang II is differentially regulated in adjacent smooth muscle layers in the injured arterial wall in vivo via mechanisms that include, but are not restricted to, the regulation of AT1 receptor expression in SMCs.

Angiotensin II↗
PubMed1995

Expression of a novel angiotensin II receptor subtype in gerbil brain.

Angiotensin II receptors are highly localized in adult gerbil brain. Apparent receptor number is high in subfornical organ, vascular organ of the lamina terminalis, nucleus of the solitary tract, hippocampus, and in the anterior pituitary gland. In the hippocampus, binding is localized to the stratum oriens, radiatum, the lacunar molecular layers of the CA1 subfield, and the molecular layer of the gyrus dentatus, with a medial to lateral and anterior to posterior gradient in receptor expression. Binding is absent from the pyramidal layer of the CA1 subfield and from the granular cell layer of the gyrus dentatus, areas rich in angiotensin IV binding. Characterization in the hippocampus revealed the presence of a high affinity receptor, sensitive to incubation with the guanine nucleotide GTP gamma S, and displaced by angiotensin II = angiotensin III < Sar1-Ile8-angiotensin II, but not by angiotensin IV or other angiotensin fragments, the AT1 receptor antagonist losartan, or the AT2 ligands CGP 42112 or PD 123177. In other brain areas, binding was equally insensitive to displacement by AT1 or AT2 ligands, with the exception of binding in the olfactory bulb, which was totally displaced by CGP 42112 and PD 123177, but not by losartan. In the gerbil, most of the brain and pituitary angiotensin II receptors are different from the AT1, AT2 and AT4 subtypes, and should be considered 'atypical' until further characterization.

Angiotensin II↗
PubMed1995

Expression of non-angiotensin II -125I-CGP 42112 binding sites on activated microglia after kainic acid induced neurodegeneration.

[125I]CGP 42112, first developed to identify angiotensin II receptor subtype 2 (AT2), was recently shown to bind to a novel non-angiotensin binding site in injured rat brain tissue. We addressed the question whether non-angiotensin [125I]CGP 42112 binding appears after kainic acid induced hippocampal neurodegeneration, a process of neuronal cell death at a distance from the toxin injection site. After intraventricular kainic acid injection, we found non-angiotensin [125I]CGP 42112 binding in the hippocampal areas CA3 (4 and 14 days after injection), CA1 and CA4 and the subiculum (14 days after injection). In addition, 14 days after kainic acid injection, [125I]CGP 42112 binding was found in 50% of the animals, in the thalamus, amygdala and piriform cortex, areas receiving projections from the hippocampus and suffering kainic acid induced delayed neurodegeneration. The loss of neurons in these regions was accompanied by an accumulation of activated microglia as demonstrated by immunostaining with the specific antibodies OX-42 and ED1. The time course and regional pattern of OX-42/ED1 positive immunostaining was identical with the appearance and distribution of the non-angiotensin [125I]CGP 42112 binding site. The non-angiotensin [125I]CGP 42112 binding was not detected in brain regions unaffected by kainic acid injection. Our findings indicate the expression of a novel [125I]CGP 42112 binding site on activated microglia. This site appears at a distance from the lesion and may be of importance in the process of neuronal death and brain tissue repair.

Angiotensin II↗
PubMed1995

Insulin receptor substrate-1 gene mutations in NIDDM; implications for the study of polygenic disease.

Variations in the coding regions of the insulin receptor substrate-1 (IRS-1) gene have recently been suggested to contribute to the susceptibility of non-insulin-dependent diabetes mellitus (NIDDM). The purpose of this study was to examine the role of the IRS-1 missense mutations at codons 972 (glycine to arginine) and 513 (alanine to proline) in two diverse populations from South India and Finland at high risk for NIDDM. DNA was amplified and digested with restriction enzymes BstN1 to detect the codon 972 mutation and Dra III to detect the codon 513 mutation. The codon 513 mutation was not found in the study subjects. The codon 972 mutation was present in 10.3% of 126 middle-aged NIDDM subjects and 5.3% of 95 matched control subjects in the South Indians (p = 0.17). In elderly Finnish subjects the frequency of the mutation was 7.5% in 40 NIDDM subjects and 7% in 42 matched control subjects. The frequency of codon 972 mutation in the South Indian NIDDM subjects was very similar to the two previously published studies in Danish and French subjects although each study individually fails to reach conventional levels of significance. The data from all four ethnic groups were analysed together after ascertaining that significant heterogeneity did not exist between the studies. Overall, the frequency of the codon 972 mutation is found in 10.7% NIDDM subjects and 5.8% control subjects (p = 0.02). These studies suggest that the codon 972 mutation of the IRS-1 gene might act as a susceptibility gene predisposing to NIDDM in certain ethnic groups.

Adult↗
PubMed1995

Proteinuria in NIDDM in south India: analysis of predictive factors.

There are few data on the risk factors for diabetic nephropathy in the Asian Indian population, although several studies have shown a high prevalence of the disease in this ethnic group. This study also aimed to assess the role of hyperglycaemia and hypertension in the causation and course of nephropathy in this population, which has low rates of obesity. Retrospective analysis of two groups of non-insulin dependent diabetic (NIDDM) patients, one without proteinuria (< 100 mg/day, n = 25) and the other with proteinuria (> or = 500 mg/day, n = 25), matched for age, sex, duration of diabetes and body mass index (BMI) was done to study the factors predisposing to proteinuria and also its progression during a 2 year follow-up. Logistic regression analysis showed that the factors contributory to proteinuria were initial HbA1 and initial systolic blood pressure. The average proteinuria during the follow-up was dependent on the initial and average systolic and diastolic blood pressure values. No correlation was seen between cholesterol or triglyceride values and the change in proteinuria. Creatinine clearance deteriorated in the proteinuric group and this was related to the presence of proteinuria and initial diastolic blood pressure. This study emphasizes the importance of blood pressure in the progression of diabetic nephropathy, even in people who have low BMI. Therefore, good control of blood pressure has an important role to play in the management of this condition.

Blood Glucose↗
PubMed1995

Kidney angiotensin II receptors and converting enzyme in neonatal and adult Wistar-Kyoto and spontaneously hypertensive rats.

The aim of the present study was to correlate the development of the renin angiotensin system (RAS) in the kidney of the rat with the development of genetic hypertension. Immature (1-week-old) and adult (12-week-old) normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive kidney rats (SHR) were used for quantification of angiotensin II (ANG II) receptors and angiotensin converting enzyme (ACE) binding sites using quantitative autoradiography. In both neonatal and adult animals of either strain, ANG II receptors were of AT1 subtype. In all kidney areas of 1-week-old rats. ANG II receptor density was higher in SHR than WKY. Binding density increased with age in WKY rats; thus, in the glomeruli and the outer stripe of the outer medulla of 12-week-old WKY, binding was significantly higher than that present in age-matched SHR. [125I]351A binding to ACE was highest in the outer medulla and not detectable in glomeruli. In 1-week-old rats, binding to ACE was higher in WKY than in SHR strain. No differences in ACE binding were found between adult SHR and WKY rats, with the exception of the inner stripe of the outer medulla, where no binding was detected in SHR. Our results support the hypothesis that the RAS in kidney is developmentally regulated and is involved in the development and maintenance of genetic hypertension in SHR.

Age Factors↗
PubMed1995

Characterization of endothelinA receptors in cerebral and peripheral arteries of the rat.

We have characterized and quantified endothelin receptors in rat brain (anterior cerebral) and peripheral (aorta, carotid, and caudal) arteries, with the use of [125I]endothelin and quantitative autoradiography. Endothelin binding was saturable, of high affinity, and totally displaced by the selective endothelin ETA antagonist BQ 123. A single class of ETA receptors is located in the medial layer of peripheral and cerebral arteries, and its quantification by autoradiography allows study of their regulation and function.

Animals↗
PubMed1995

Noradrenaline-induced hypothermia is suppressed in the vagotomized cold-exposed pigeon.

Vagotomized (VX) pigeons studied 2 days after surgery exhibited a significant decrease in cloacal temperature (Tb) and respiratory rate (Rf), and an increase in heart rate (Hf) and metabolic rate (M) at the thermoneutral zone, when compared with sham-operated (SVX) pigeons. The effect of intravenous noradrenaline (NA) on Tb, Rf, Hf and M was examined in SVX and VX-pigeons at 15 degrees C. Following NA administration, the Tb and Rf in the SVX-birds dropped from the preinjection level, but in VX-pigeons, they were not significantly altered. In SVX-pigeons, a total suppression of shivering was apparent following NA-injection, while in the majority of VX-pigeons, shivering was only slightly affected or even increased. The Hf in both SVX- and VX-birds increased following NA-injection. The responses to reserpine were qualitatively similar to NA, although much slower. There were no differences between SVX- and VX-birds with regard to Tb, M and Rf following acetylcholine (ACh) and eserine (Ese) injection. Hf increased after ACh+Ese administration in SVX-pigeons, but in VX-birds, it decreased after an initial surge. Shivering was suppressed for 18-20 min in SVX-birds and 30-50 min in VX-birds. It is suggested that the lack of the hypothermic effect of NA in VX-birds is due to the maintenance of oxygen uptake with unimpaired capacity for shivering.

Acetylcholine↗
PubMed1995

Structural predictions of the binding site architecture for monoclonal antibody NC6.8 using computer-aided molecular modeling, ligand binding, and spectroscopy.

Monoclonal antibody NC6.8 binds the superpotent sweetener ligand N-(p-cyanophenyl)-N'-(diphenylmethyl) guanidineacetic acid with high affinity (Kd = 53 nM). Using computer-aided molecular modeling and several experimental techniques, such as competitive ligand binding, absorbance spectroscopy, and fluorescence spectroscopy, we have predicted the structure of the variable domain fragment (Fv) and identified the key residues in the combining site of the antibody. We have identified nine specific amino acids as being involved in ligand recognition and complexation. Most notable are H:33W, which is responsible for ligand-induced tryptophan fluorescence quenching, H:56R, which forms a salt bridge with the carboxylate moiety of the ligand, and L:34H, which, deep in the binding site, interacts with the cyanophenyl portion of the ligand. Two residues located deep in the putative binding pocket, H:35E and H:50E, provide the negatively charged potential for interaction with the protonated aryl nitrogen and the positive guanidinium group. These modeling predictions were made before the solution of high-resolution structures of the native Fab (2.6 A) and the Fab-ligand complex (2.2 A). Comparisons between the theoretical model and experimental native and liganded Fab structures are made.

Acetates↗
PubMed1994

Seripauperins of Saccharomyces cerevisiae: a new multigene family encoding serine-poor relatives of serine-rich proteins.

A gene, PAU1, has been cloned from Saccharomyces cerevisiae and sequenced. It is located in a telomeric region, probably on chromosome IV, and contains an open reading frame encoding a protein of 120 amino acids (aa) (approx. 13 kDa). The deduced sequence is nearly identical to two other genes found in GenBank (named PAU2 and PAU3 by us), which are located close to the ends of chromosomes V and III, respectively. Blotting of separated chromosomes with a PAU1 probe at high stringency revealed that at least six chromosomes in addition to III, IV and V possessed related sequences, suggesting a large gene family. Probing of an ordered array of phage lambda clones containing yeast genomic DNA inserts ('Olson filters') revealed ten additional hybridizing sequences, located close to the ends of the left and/or right arms of chromosomes I, II, VII, VIII, X, XII, XIV and XV. Transcription of these sequences could not be demonstrated, however, under a wide variety of growth and culture conditions. The deduced PAU1, PAU2 and PAU3 aa sequences are all highly homologous with the SRP1 aa sequences, which contains eight serine-rich tandem repeats of 12 aa each, at its C terminus. This homology is limited, however, to the N-terminal half of SRP1, and does not include the repeats. In fact, PAU1 is quite serine-poor (5.8%), leading to the suggested name of seripauperins for this family of genes.

Amino Acid Sequence↗
PubMed1994

Expression of a novel non-angiotensin II [125I]CGP 42112 binding site in healing wounds of the rat brain.

We characterized a novel non-angiotensin II binding site that is recognized by the angiotensin II AT2 receptor ligand [125I]CGP 42112, in healing brain wounds of adult rats. The binding, which was highest at 3 days after injury, appears to be localized to activated microglia surrounding the wound. The novel CGP 42112 binding site may have a role in the function of microglia and in mechanisms of tissue repair in the brain.

Angiotensin II↗
PubMed1994

Specific, non-angiotensin, [125I]CGP 42112 binding sites in rat spleen macrophages.

We report the novel expression of a high affinity non-angiotensin II binding site to [125I]CGP 42112, predominantly localized to the red pulp of the rat spleen and to isolated rat spleen macrophages. Binding is not inhibited by angiotensin II, related peptides or AT1 or AT2 receptor ligands, and is not affected by several growth factors and cytokines involved in macrophage function. Thus, CGP 42112 recognizes binding sites other than angiotensin II AT2 sites in rat macrophages. CGP 42112 and related peptides might influence the regulation of macrophage function.

Amino Acid Sequence↗
PubMed1994

Family studies of non-insulin-dependent diabetes mellitus in South Indians.

Though a genetic basis for non-insulin-dependent diabetes mellitus (NIDDM) is clear, the likely mode of inheritance is not known. The segregation of NIDDM was studied in 64 nuclear South Indian pedigrees (449 individuals) ascertained through an affected proband having both parents and more than 1 sibling alive and available for oral glucose tolerance testing. A high proportion of parents were found to be of abnormal glucose tolerance [89 of 128 (70%) diabetic and 11 of 128 (9%) impaired]. Complex segregation analysis was performed using (1) POINTER which implements the mixed model and distinguishes major gene, multifactorial and non-transmitted environmental contributions to affection and (2) COMDS which implements an oligogenic model with major gene, modifier gene and environmental contributions to a) affection and b) diathesis (an ordered polychotomy amongst non-affected family members, based on 2-h plasma glucose level). Using POINTER, there was no formal support for a major gene and the most parsimonious solutions were achieved with multifactorial models. Using COMDS, we found i) significant improvements in models when information on glucose levels in nondiabetic family members (diathesis) was included, ii) support for segregation of a diallelic gene as well as background familial resemblance, and iii) under the best-supported model, this diallelic locus featured incomplete dominance (d = 0.8) and a disease-predisposing allele frequency of 14%. In South Indians, segregation of NIDDM is inadequately described by simple major gene models: more complex models provide more satisfactory descriptions. This finding, if applicable in other populations, has important implications for the search for diabetes-susceptibility genes.

Blood Glucose↗
PubMed1994

[125I]CGP 42112 reveals a non-angiotensin II binding site in 1-methyl-4-phenylpyridine (MPP+)-induced brain injury.

1. Intracerebral injection of the oxidative metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 1-methyl-4-phenylpyridine (MPP+), into the substantia nigra of adult rats resulted in a lesion at the injection site. 2. Using autoradiography, we localized specific [125I]CGP 42112 binding that was not recognized by angiotensin II or angiotensin II AT1 or AT2 receptor-selective ligands. 3. Our results suggest that [125I]CGP 42112 may be binding to activated microglia that appear at the lesion site.

1-Methyl-4-phenylpyridinium↗
PubMed1994

Delayed onset of diabetes in children of low economic stratum--a study from southern India.

Influence of the socioeconomic status on the age at onset of insulin-dependent diabetes mellitus (IDDM) was analysed in 614 patients who developed diabetes < or = 20 years. The peak occurrence was seen at 11 years in girls (n = 293). The boys (n = 321) showed multiple peaks between 11 and 18 years. In the urban patients (n = 463), the peak was at 11 years in contrast to a delayed peak at 18 years in the rural group (n = 151). When analysed with respect to the family income, the higher income group (HIG) (Rs > 2000/month) showed a sharp peak at 11 years whereas the lower income group (LIG) showed a peak at 18 years (chi 2 = 7.2, P = 0.007). The median body weight of the LIG was lower compared to the HIG. Although the exact cause for the delayed age at onset of IDDM in the rural or LIG is not known, it is likely to be a consequence of the lower socioeconomic and nutritional status (indicated by low body weight) and probably indicates the influence of environmental factors in the pathogenesis of the disease.

Adolescent↗
PubMed1994

Height at onset of insulin-dependent diabetes in children in southern India.

A total of 250 children with insulin-dependent diabetes mellitus (IDDM), having age at onset of diabetes < or = 18 years were studied. Their height at onset of diabetes was compared with that of the normal age- and sex-matched control population. No differences were observed in the heights of the two groups of children. Therefore, our results were similar to that found in Japan and differed from the reports in European children with IDDM in whom an increased growth velocity was noted before the onset of IDDM.

Adolescent↗