Biomedical subjects

Fatimunnisa Qadri

Publications and source records attributed to Fatimunnisa Qadri.

15 recordsLinked to original sources

PubMed2006

Non-hypoxic induction of HIF-3alpha by 2-deoxy-D-glucose and insulin.

Hypoxia-inducible factors (HIFs) are key mediators of cellular adaptation to hypoxia, but also respond to non-hypoxic stimuli. To clarify involvement in metabolic disturbances, HIFs were characterised in rats subjected to insulin-induced hypoglycaemia or cellular glucoprivation provoked by 2-deoxy-D-glucose (2-DG). Using real-time qPCR, organ-specific expression of HIF-1alpha, -2alpha, -3alpha, -1beta, and of the target gene GLUT-1 was determined. Distribution of HIF-3alpha proteins was examined by immunohistochemistry. Both, insulin and 2-DG resulted in a widespread increase in HIF-3alpha mRNA. HIF-2alpha mRNA increased in lung and heart after 2-DG only, whereas other HIFs remained unaffected. A pronounced increase of protein levels in cerebral cortex was observed for HIF-3alpha. Functional significance of HIF induction was reflected in enhancement of GLUT-1 mRNA. Transcriptional up-regulation of HIF-3alpha represents a typical response to in vivo hypoglycaemia and glucoprivation. These data suggest an involvement of the HIF system in metabolic derangements as for instance caused by diabetes.

Animals↗

PubMed2006

Adrenal expression of orexin receptor subtypes is differentially regulated in experimental streptozotocin induced type-1 diabetes.

Orexins (hypocretins) are involved in the regulation of energy homeostasis and sleeping behavior. Orexins were also implicated in the regulation of neuroendocrine and autonomic functions. Recent data show the expression of orexin receptors within the hypothalamic-pituitary-adrenal (HPA) axis and suggest specific actions of orexins at the pituitary and adrenal glands. To further evaluate the role of orexin in the HPA axis, we investigated the mRNA expression of prepro-orexin (PPO) and orexin receptors within the HPA axis of streptozotocin-injected (STZ) rats showing type-1 like diabetes. PPO, as well as OX(1) and OX(2) receptor levels were analyzed by quantitative real-time PCR (qPCR). STZ rats were characterized by decreased body weight, plasma insulin, and leptin levels and by increased plasma glucose. Hypothalamic PPO mRNA levels were significantly reduced in STZ compared to non-diabetic control rats. No differences were found in the mRNA levels of hypothalamic or pituitary OX(1) and OX(2) receptors between control and STZ rats. In adrenals, OX(1) receptor mRNA levels were significantly elevated in STZ rats while OX(2) receptors were significantly reduced. Our results imply distinct functions of adrenal orexin receptor subtypes during type-1 like diabetes.

Adrenal Glands↗

PubMed2005

Expression of nitric oxide synthase isoforms in hypothalamo-pituitary-adrenal axis during the development of spontaneous hypertension in rats.

This study was performed to investigate the expression of the major isoforms of nitric oxide synthase mRNA and protein in the hypothalamo-pituitary-adrenal axis (HPA axis) of spontaneously hypertensive rats (SHR) at two different postnatal ages corresponding to the development of genetic hypertension. Using RT-PCR and Western blot techniques, the mRNA and protein levels of neuronal (nNOS), endothelial (eNOS) and inducible (iNOS) isoforms were measured in 3- to 4-week-old (prehypertensive phase) and 12- to 13-week-old (established hypertension phase) SHR and age-matched normotensive Wistar-Kyoto (WKY) rats. nNOS but not eNOS mRNA levels were increased at prehypertensive and hypertensive phases in SHR HPA axis. Compared to age-matched WKY rats, significantly higher levels of nNOS protein were found in the hypothalamus, lower levels in the adrenal glands and no changes were observed in the pituitary gland. At both ages tested, there was no significant change in eNOS protein expression in SHR HPA axis. The expression of iNOS mRNA and protein was under detection limit. In the HPA axis, the expression of nNOS isoform appears to be differentially controlled at the transcriptional and translational levels in SHR. Increased mRNA levels and differential nNOS protein expression from birth in SHR HPA axis may contribute in the pathogenesis of genetic hypertension.

Animals↗

PubMed2005

Deferoxamine induces prolonged cardiac preconditioning via accumulation of oxygen radicals.

Iron chelation by deferoxamine (DFO) blocks the Fenton reaction, but also inhibits prolyl hydroxylases and thereby activates certain hypoxia-inducible transcription factors (HIFs) that trigger cellular adaptation to hypoxia. Because both mechanisms may alleviate tissue damage in ischemia and reperfusion, we tried to differentiate their contribution to DFO-induced cardioprotection. Myocardial ischemia and reperfusion were induced in anesthetized Wistar rats. Infarct size was related to the ischemic area. Myocardial mRNA expression was determined by real-time PCR. Radical reactivity was probed in myocardial tissue slices with the redox-sensitive dye CM-H(2)DCFDA. Single ip applications of DFO (200 mg/kg) administered 2 h to 3 days before infarction reduced infarct size from 55 +/- 7% to 22-26%. Protection was abolished by the radical scavenger N-(2-mercaptopropionyl)glycine and the protein kinase C inhibitor chelerythrine when either was given 30 min before DFO, whereas subsequent application was ineffective. DFO did not alter the expression of various HIF target genes, whereas mRNAs of HIF-independent genes, aldose reductase and glucose transporter-4, were increased in infarcted myocardium 2 days after DFO treatment. Enhancement of superoxide activity by DFO could be demonstrated in vitro. Acute and prolonged myocardial preconditioning is triggered by DFO in response to accumulation of oxygen radicals and activation of protein kinase C.

Aldehyde Reductase↗

PubMed2004

Neuronal electrical high frequency stimulation modulates presynaptic GABAergic physiology.

Electrical high frequency deep brain stimulation (DBS) of the globus pallidus internus (GPi) or the subthalamic nucleus (STN) has dramatic beneficial motor effects in advanced Parkinson's disease (PD). However, the mechanisms underlying these clinical results remain unclear. It is proposed that the gamma-aminobutyric acid (GABA) system is involved in the effectiveness of DBS. To prove this hypothesis, rat striatal slices were stimulated electrically (130 Hz) in vitro; GABA and glutamate (GLU) outflow from striatal slices of normal or kainic acid-lesioned rats were measured after o-phthaldialdehyde sulphite derivatization using HPLC with electrochemical detection. Our results could demonstrate that high frequency stimulation (HFS) did not modulate basal GABA outflow in the perfusate. In the presence of submaximal concentrations of the voltage-gated sodium channel opener veratridine, HFS significantly enhanced GABA outflow. When the GABA transporter inhibitor, nipecotic acid, was added to the incubation medium, the HFS effects decreased to nearly control values. Destruction of striatal GABAergic neurons by kainic acid completely reversed the effects of HFS on GABA outflow. In the present study no effect of HFS on glutamate outflow was observed under any condition. These results suggest that HFS has a specific effect on GABAergic neuronal terminals resulting in an enhancement of extracellular GABA in the caudate nucleus. This effect is probably due to an inhibitory effect of HFS on the GABA uptake system rather than to stimulation of vesicular GABA release from GABAergic neurons, which are both associated with the presynaptic GABAergic physiology.

Animals↗

PubMed2004

Expression of kinin receptor mRNA in the HPA axis of type 1 and type 2 diabetic rats.

mRNA levels of kinin B1 and B2 receptors were determined in HPA axis of type 1 (STZ-induced) and type 2 diabetic rats (ZDF and obese Zucker rats). B2 mRNA levels were elevated in hypothalamus of STZ-induced diabetic (STZ-D) and ZDF rats. Pituitary B2 mRNA levels were elevated in ZDF and obese rats. Adrenal B2 mRNA level was attenuated in STZ-D rats. Kinin B1 receptor may not play a role in HPA axis in diabetes since its expression was unchanged. Enhanced mRNA expression of B2 receptors in hypothalamus of STZ-D and ZDF rats parallels a rise in plasma glucose and reflect a functional relationship. Enhanced pituitary B2 mRNA in type 2 and reduced adrenal in type 1 diabetes account for a differential pattern in release of transmitters.

Animals↗

PubMed2003

Modulation of striatal serotonin and opioid receptor mRNA expression following systemic N-methyl-norsalsolinol administration.

The dihydroxylated tetrahydroisoquinoline derivative, 2(N)-methyl-norsalsolinol (NMNorsal), was identified in L-DOPA-treated patients with Parkinson's disease and proposed to be responsible for behavioral changes. In the present study, we investigated the effect of NMNorsal on serotonin and opioid receptors gene expression in caudate nucleus of Wistar rats. Using RT-PCR, serotonin 5-HT2A, micro- and delta-opioid receptor mRNA levels were determined after NMNorsal administration (40 mg/kg, i.p.). There was a marked increase of 5-HT2A and delta-opioid receptor mRNA levels with a maximum after 48 h. In contrast, micro-opioid receptor mRNA levels were significantly decreased to 10% after 24 h and 21% after 48 h, respectively. Our present results demonstrate for the first time that the atypical heterocylic L-DOPA/dopamine metabolite NMNorsal is able to modify long-term regulation of serotonin and opioid receptor expression in striatum. Since the occurrence of hallucinosis or psychosis following L-DOPA treatment is related to the serotonergic system, these results probably reflect a link between NMNorsal and L-DOPA side effects in Parkinson's disease. However, further experiments are needed.

Animals↗

PubMed2003

Hypoxia rapidly activates HIF-3alpha mRNA expression.

The role of the hypoxia-inducible factor (HIF) subunits 1alpha and 1beta in cellular response to hypoxia is well established, whereas little is known about HIF-2alpha and HIF-3alpha with respect to organ distribution and transcriptional regulation by hypoxia. We investigated mRNA levels of all HIF subunits and of their target genes erythropoietin (EPO) and glucose-transporter 1 (GLUT1) in rats undergoing systemic hypoxia for 30 or 120 min by quantitative real-time RT-PCR. In normoxia, persistently high mRNA levels of all HIF subunits were detected in cerebral cortex, hippocampus, and lung; the heart contained the lowest amounts. Hypoxia did not affect mRNA levels of HIF-1alpha, -1beta, and -2alpha. HIF-3alpha mRNA levels increased in all organs examined after 2 h of hypoxia. A significant rise of EPO and GLUT1 mRNA levels occurred in cortex, heart, liver, and kidney after 2 h of hypoxia, indicating activation of the HIF system. Protein levels of all HIF subunits, determined in brain and lung by immunoblotting, showed a marked increase corresponding to the duration of hypoxia. Our results suggest that induction at the transcriptional level is a unique feature of HIF-3alpha, which therefore may represent a rapidly reacting component of the HIF system in protection against hypoxic damage.

Animals↗

PubMed2003

Deep brain stimulation: response to neuronal high frequency stimulation is mediated through GABA(A) receptor activation in rats.

High frequency stimulation (HFS) of deep brain regions such as globus pallidus internus or subthalamic nucleus can reverse Parkinson's symptoms probably through activation of gamma-aminobutyric acid (GABA)ergic neurotransmission. To prove the hypothesis, rat striatal slices were stimulated electrically (130 Hz) in vitro and dopamine (DA) outflow was measured using high performance liquid chromatography. HFS induced an attenuation in basal DA release in perfusate. Veratridine-induced DA outflow was blocked by the simultaneous application of HFS. Addition of bicuculline, a GABA(A) receptor antagonist, reversed the effect of HFS on DA outflow. In addition, destruction of striatal GABAergic neurons with kainic acid also reversed the effect of HFS. In conclusion, our present data provide strong evidence that HFS does not only need presynaptic GABA(A) receptors but also intact GABAergic nerve terminals coupled to GABA(A) receptors to exert an inhibitory effect and give a rationale of HFS effectiveness in the treatment of Parkinson's disease.

Animals↗

PubMed2003

Differential expression of AT1 receptors in the pituitary and adrenal gland of SHR and WKY.

The renin-angiotensin (ANG) system has been implicated in the development of hypertension in spontaneously hypertensive rats (SHR). Because SHR are more susceptible to stress than normotensive Wistar-Kyoto rats (WKY), we measured the mRNA expression of AT1A, AT1B, and AT2 receptors in the hypothalamo-pituitary-adrenal (stress) axis of male SHR in comparison to age-matched WKY at prehypertensive (3 to 4 weeks), developing (7 to 8 weeks), and established (12 to 13 weeks) stages of hypertension. AT1A receptor mRNA was mainly expressed in the hypothalamus and adrenal gland. AT1B receptor mRNA was detected in the pituitary and adrenal gland. AT2 receptor mRNA was prominent only in the adrenal gland. When compared with WKY, SHR showed increased AT1A receptor mRNA levels in the pituitary gland at all ages in contrast to reduced pituitary AT1B receptor mRNA levels. In the adrenal gland of SHR, AT1B receptor mRNA levels were decreased at the hypertensive stages when compared with WKY. The reduced expression of adrenal AT1B receptor mRNA was localized selectively in the zona glomerulosa by in situ hybridization. No differences were observed between WKY and SHR in the expression of hypothalamic ANG receptors. ANG significantly increased plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone in dexamethasone-treated SHR but not in WKY. The aldosterone response to ANG was similar in SHR and WKY. Our results suggest a differential gene expression of AT1A and AT1B receptors in the hypothalamo-pituitary-adrenal axis of SHR and normotensive WKY and imply the participation of AT1 receptors in an exaggerated endocrine stress response of SHR to ANG.

Adrenal Glands↗

PubMed2003

Kinin B2 receptor localization and expression in the hypothalamo-pituitary-adrenal axis of spontaneously hypertensive rats.

OBJECTIVE: An enhanced hypothalamo-pituitary-adrenocortical (HPA) activity has been demonstrated during onset of high blood pressure in spontaneously hypertensive rats (SHR). Furthermore, compared to normotensive Wistar-Kyoto (WKY) rats, SHR show hypersensitivity to bradykinin (BK)-induced pressor responses which may be caused by an upregulation of B(2) receptor expression in the brain. METHODS: We performed an immunohistochemical localization and measured gene expression of B(2) receptors in the hypothalamus, pituitary and adrenal glands of SHR at three ages corresponding to the development of hypertension, i.e. prehypertensive phase, onset of hypertension and established hypertension. Using reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot technique, B(2) receptor mRNA and protein levels, respectively, were measured. RESULTS: A specific immunostaining for B(2) receptors was observed in the hypothalamic nuclei paraventricularis (PVN) and supraopticus (SON). In the pituitary and adrenal glands, a strong immunostaining was observed in neurohypophysis (NH) and adrenal medulla, respectively. At all ages tested, B(2) receptor mRNA and protein levels were higher in the hypothalamus and adrenal glands of SHR compared to age-matched WKY rats. Among SHR, the mRNA level was increased in neurohypophysis with age, and no difference was found in the adenohypophysis (AH) between SHR and WKY rats. CONCLUSION: The data demonstrate a specific localization and an upregulation of B(2) receptor expression in the hypothalamus and adrenal glands of SHR, providing an anatomical and molecular basis for a possible contributory role to bradykinin-induced hypersensitivity of cardiovascular responses. The increased B(2) receptor expression in the hypothalamus and adrenal glands may also play a role in the abnormalities of the HPA axis in SHR during the development of hypertension.

Aging↗

PubMed2003

N-methyl-norsalsolinol modulates serotonin metabolism in the rat caudate nucleus: correlation with behavioural changes.

In earlier studies the dihydroxylated tetrahydroisoquinoline derivative 2(N)-methyl-norsalsolinol (NMNorsal) was identified in patients with Parkinson's disease. In the present study, NMNorsal (20 or 40 mg/kg) was given intraperitoneally to rats kept under normal light-dark cycles. Using brain microdialysis technique, serotonin (5-HT), 5-hydroxyindolacetic acid (HIAA), dopamine (DA), and 3,4-dihydroxyphenylacetic acid (DOPAC) were determined in the dialysate from caudate nucleus in vivo and from tissue in vitro at various times following NMNorsal administration. Even after high-dose NMNorsal administration (40 mg/kg) and measurements up to 48 h after administration, levels of DA and its metabolite DOPAC were not modified. In contrast to the DA metabolism, 5-HT levels in the dialysate increased to approx. 2-fold during the 48 h following administration of a single high-dose of NMNorsal while HIAA decreased to approx. 50%. These changes of 5-HT and HIAA were nearly identical in the homogenate preparation of the caudate nucleus when compared to the amounts present in the dialysate. During assessment controls and low-dose-treated animals were almost always sleeping. Only high-dose NMNorsal-treated rats were active, with maximum activity after 48 h, however, behavioural activity was clearly different to the classical 5-HT behavioural syndrome. Taken together, increased 5-HT levels in the striatum found in our studies seem to be linked to the behavioural activity induced by high-dose NMNorsal, and NMNorsal appeared to perturb normal diurnal rhythms of spontaneous locomotor activity. The precise mechanism by which NMNorsal acts on 5-HT metabolism and behaviour is, however, unclear and further investigation is required.

Animals↗

PubMed2003

Brain nitric oxide synthase activity in spontaneously hypertensive rats during the development of hypertension.

OBJECTIVES: Blockade of neuronal nitric oxide synthase (nNOS) in the brain induced an increase in mean arterial pressure of spontaneously hypertensive rats (SHR). We hypothesize that increased nitric oxide (NO) synthesis in the brain compensates for hypertension. Therefore, we measured NOS activity in different brain regions in SHR at prehypertensive, onset and established hypertension, and compared with age-matched Wistar-Kyoto (WKY) rats. METHOD: NOS activity was measured by the ability of tissue homogenate to convert [3H]l-arginine to [3H]l-citrulline in a Ca2+- and NADPH-dependent manner. RESULTS: NOS activity was impaired in the cerebral cortex and brainstem of prehypertensive SHR. At established hypertension, SHR showed an augmentation in NOS activity in hypothalamus and brainstem. Chronic treatment of SHR with the angiotensin-1 converting enzyme (ACE)-inhibitor, enalapril, and the AT(1) receptor antagonist, losartan, normalized NOS activity in the hypothalamus but not in the brainstem. Treatment with a peripheral vasodilator, hydralazine, did not affect NOS activity. CONCLUSION: Attenuated NOS activity in the cortex and brainstem of prehypertensive SHR may play a role in the pathogenesis of hypertension. The upregulated NOS activity in the hypothalamus and brainstem of SHR possibly serves to compensate for hypertension. Hypothalamic, but not brainstem, NO is involved in antihypertensive effects of ACE inhibition and AT(1) receptor blockade. Since a blood pressure decrease per se had no effect on NOS activity, it appears that central sympathetic activity influenced by endogenous angiotensin II, rather than blood pressure, represents the stimulus for the increased NOS activity in the hypothalamus of SHR.

Age Factors↗

PubMed2002

N-methyl-norsalsolinol, a putative dopaminergic neurotoxin, passes through the blood-brain barrier in vivo.

In earlier studies the dihydroxylated tetrahydroisoquinoline derivatives salsolinol and 2(N)-methyl-norsalsolinol (NMNorsal), a 2(N)-analogue of salsolinol, were identified as putative endogenous neurotoxins in patients with Parkinson's disease. Since a prominent blood-brain barrier (BBB) was described to exist for salsolinol, in the present study microdialysis experiments were performed to investigate the penetration of NMNorsal through the BBB into the caudate nucleus of the rat brain. After i.p. administration of NMNorsal (20 mg/kg), it could be detected in the dialysate of the caudate nucleus with a mean maximum after 40 min. There was no alteration in extracellular dopamine or 3,4-dihydroxyphenylacetic acid levels. Addition of the monoamine oxidase inhibitor pargyline (10 microM) to the perfusate did not modify NMNorsal levels in the caudate nucleus. To corroborate the microdialysis results, homogenates of the contralateral caudate nucleus were prepared and NMNorsal could also be detected. These findings indicate that NMNorsal is indeed able to pass through the blood-brain barrier of the rat brain.

Animals↗

PubMed2002

Agmatine, an endogenous ligand at imidazoline binding sites, does not antagonize the clonidine-mediated blood pressure reaction.

Since agmatine has been identified as a clonidine displacing substance (CDS), the aim of this study was to investigate whether agmatine can mimic CDS-induced cardiovascular reactions in organ bath experiments, pithed spontaneously hypertensive rats (SHR) and anaesthetized SHR. Intravenously-administered agmatine significantly reduced the blood pressure and heart rate of anaesthetized SHR at doses higher than 1 and 3 mg kg(-1), respectively. These effects are probably mediated via central mechanisms, since there was an approximate 8 fold rightward shift of the dose-response curve in the pithed SHR (indicating a weakened cardiovascular effect). Moreover, in organ bath experiments, agmatine failed to alter the contractility of intact or endothelium-denuded aortal rings. When agmatine was administered i.c.v. to anaesthetized SHR, blood pressure was increased without any alteration of heart rate, whereas blood pressure was unchanged and heart rate was increased after injection into the 4th brain ventricle. This suggests that haemodynamic reaction patterns after central application are related to distinct influences on central cardiovascular mechanisms. Agmatine reduces noradrenaline release in pithed SHR while alpha(2)-adrenoceptors are irreversibly blocked with phenoxybenzamine, but not while I(1)-binding sites are selectively blocked with AGN192403. This suggests that agmatine may modulate noradrenaline release in the same way that clonidine does, i.e. via imidazoline binding sites; this involves a reduction in sympathetic tone which in turn reduces blood pressure and heart rate. Finally, CDS-like cardiovascular activity appears not to be due to agmatine, since (i) blood pressure in anaesthetized SHR is decreased by agmatine and clonidine, and (ii) agmatine did not antagonize the blood pressure reaction to clonidine in pithed or anaesthetized SHR.

Adrenergic alpha-Agonists↗