Shereeni Veerasingham - Academia.edu (original) (raw)

Papers by Shereeni Veerasingham

Journal of Pharmaceutical Sciences

Brain Research, Sep 8, 2000

In normotensive Wistar rats, systemic administration of exogenous ouabain for 10 days or more ind... more In normotensive Wistar rats, systemic administration of exogenous ouabain for 10 days or more induces hypertension, presumably through central mechanisms. To identify which neuronal populations may be involved, we assessed Fos-like immunoreactivity (FLI) using an antibody that recognizes the protein products of the fos family comprising Fos, Fos B, Fra 1 and Fra 2, thus enabling detection of chronic neuronal activation. Young Wistar rats received s.c. infusions of either ouabain (50 microg/day) or saline for 7 or 14 days. At the end of the experimental period, mean arterial pressure (MAP) was assessed. In a separate set of rats FLI was detected immunohistochemically and quantified in cardiovascular and osmo-regulating centers. Resting MAP in ouabain-treated rats was significantly higher than in control rats at 14 but not at 7 days (125+/-4 vs. 101+/-6, P&amp;amp;amp;lt;0.05 and 102+/-4 vs. 98+/-6 (not significant), respectively). Within the supraoptic nucleus, ouabain induced significant increases in FLI compared with control rats at 14 days (9+/-2 vs. 2+/-2, P&amp;amp;amp;lt;0.05) but not at 7 days. Within the locus ceruleus, FLI was only detectable in rats that received ouabain infusions for 14 days but not in other groups of rats. Ouabain treatment did not induce significant changes in FLI within other areas. These results demonstrate that chronic s.c. ouabain infusion only increases neuronal FLI in the supraoptic nucleus and locus ceruleus where increases in FLI parallel the increase in blood pressure.

Progress in Experimental Cardiology, 1998

American journal of physiology. Heart and circulatory physiology, 2003

To assess effects of dietary salt on brain AT1 receptor densities, 4-wk-old Dahl salt-sensitive (... more To assess effects of dietary salt on brain AT1 receptor densities, 4-wk-old Dahl salt-sensitive (Dahl S) and salt-resistant (Dahl R) rats were fed a regular (101 mumol Na/g) or high (1,370 mumol Na/g)-salt diet for 1, 2, or 4 wk. AT1 receptors were assessed by quantitative in vitro autoradiography. AT1 receptor densities did not differ significantly between strains on the regular salt diet. The high-salt diet for 1 or 2 wk increased AT1 receptor binding by 21-64% in the Dahl S rats in the subfornical organ, median preoptic nucleus, paraventricular nucleus, and suprachiasmatic nucleus. No changes were noted in the Dahl R rats. After 4 wk on a high-salt diet, increases in AT1 receptor binding persisted in Dahl S rats but were now also noted in the paraventricular nucleus, median preoptic nucleus, and suprachiasmatic nucleus of Dahl R rats. At 4 wk on the diet, intracerebroventricular captopril caused clear decreases in blood pressure only in the Dahl S on the high-salt diet but caused...

The American journal of physiology, 1999

To examine the role of the ventral anteroventral third ventricle (vAV3V) in the hypertension indu... more To examine the role of the ventral anteroventral third ventricle (vAV3V) in the hypertension induced by chronic subcutaneous ouabain and intracerebroventricular hypertonic saline, neurons in this area were destroyed by microinjection of an excitotoxin, ibotenic acid. Sham-operated or lesioned Wistar rats were administered ouabain (50 microgram/day) or placebo for 3 wk from subcutaneously implanted controlled release pellets or artificial cerebrospinal fluid (CSF) or CSF containing 0.8 mol/l NaCl (5 microliter/h) infused intracerebroventricularly for 2 wk. At the end of the experiment, mean arterial pressure (MAP) and heart rate at rest and in response to ganglionic blockade by intravenous hexamethonium (30 mg/kg) were assessed. In rats infused with hypertonic saline, responses to air jet stress were also assessed. Baseline MAP in sham-operated rats receiving intracerebroventricular hypertonic saline or subcutaneous ouabain was significantly higher than in control rats (115 +/- 1 vs....

The American journal of physiology, 1998

Both brain ouabain-like activity ("ouabain") and brain angiotensin II (ANG II) contribu... more Both brain ouabain-like activity ("ouabain") and brain angiotensin II (ANG II) contribute to the sympathoexcitatory and pressor responses to high sodium intake in spontaneously hypertensive (SHR) and Dahl salt-sensitive (Dahl S) rats. To assess whether increases in cerebrospinal fluid (CSF) sodium can mimic this pattern of changes, Wistar rats were chronically infused with artificial CSF (aCSF) or sodium-rich aCSF (0.8 or 1.2 M sodium) intracerebroventricularly through osmotic minipumps for 14 days. Sodium-rich aCSF (0.8 M) was also infused intracerebroventricularly for 2 wk concomitantly with either antibody Fab fragments that bind ouabain and related steroids with high affinity, gamma-globulins as control (200 micrograms/day for both), or the AT1 blocker losartan (1 mg.kg-1.day-1). Sodium-rich aCSF increased CSF sodium from 146 +/- 2 to 152 +/- 2 (0.8 M) and 160 +/- 3 (1.2 M) mmol/l, and increased brain "ouabain" in the hypothalamus, pituitary, and pons. In con...

Progress in Biophysics and Molecular Biology, 2004

Centrally mediated increases in sympathetic nerve activity and attenuated arterial baroreflexes c... more Centrally mediated increases in sympathetic nerve activity and attenuated arterial baroreflexes contribute to the pathogenesis of hypertension. Despite the characterization of cellular and physiological mechanisms that regulate blood pressure and alterations that contribute to hypertension, the genetic and molecular basis of this pathophysiology remains poorly understood. Strategies to identify genes that contribute to central pathophysiologic mechanisms in hypertension include integrative biochemistry and physiology as well as functional genomics. This article summarizes recent progress in applying functional genomics to elucidate the genetic basis of altered central blood pressure regulatory mechanisms in hypertension. We describe approaches others and we have undertaken to investigate gene expression profiles in hypertensive models in order to identify genes that contribute to the pathogenesis of hypertension. Finally, we provide the readers a roadmap for negotiating the route from experimental findings of gene expression profiling to translating their therapeutic potential. The combination of gene expression profiling and the phenotypic characterization of in vitro and in vivo loss or gain of function experiments for candidate genes have the potential to identify genes involved in the pathogenesis of hypertension and may present novel targets for therapy.

Circulation Research, 2005

Existing evidence led us to hypothesize that increases in p85␣, a regulatory subunit of PI3-kinas... more Existing evidence led us to hypothesize that increases in p85␣, a regulatory subunit of PI3-kinase, in presympathetic brain areas contribute to hypertension. PI3-kinase p85␣, p110␣, and p110␦ mRNA was 1.5-to 2-fold higher in the paraventricular nucleus (PVN) of spontaneously hypertensive rats (SHR) compared with their controls, Wistar Kyoto rats (WKY). The increase in p85␣/p110␦ was attenuated in SHR treated with captopril, an angiotensin (Ang)converting enzyme inhibitor, from in utero to 6 months of age. In the rostral ventrolateral medulla (RVLM), p110␦ mRNA was Ϸ2-fold higher in SHR than in WKY. Moreover, the increases in mRNA were associated with higher PI3-kinase activity in both nuclei. The functional relevance was studied in neuronal cultures because SHR neurons reflect the augmented p85␣ mRNA and PI3-kinase activity. Expression of a p85 dominant-negative mutant decreased norepinephrine (NE) transporter mRNA and [ 3 H]NE uptake by Ϸ60% selectively in SHR neurons. In summary, increased p85␣/p110␦ expression in the PVN and RVLM is associated with increased PI3-kinase activity in the SHR. Furthermore, normalized PI3-kinase p85␣/p110␦ expression within the PVN might contribute to the overall effect of captopril, perhaps attributable to a consequent decrease in NE availability.

British Journal of Pharmacology, 2003

This review focuses on the dysfunction of the intrinsic brain renin-angiotensin system (RAS) in t... more This review focuses on the dysfunction of the intrinsic brain renin-angiotensin system (RAS) in the pathogenesis of hypertension. Hyperactivity of the brain RAS plays a critical role in mediating hypertension in both humans and animal models of hypertension, including the spontaneously hypertensive rat (SHR). The specific mechanisms by which increased brain RAS activity results in hypertension are not well understood but include increases in sympathetic vasomotor tone and impaired arterial baroreflex function. We discuss the contribution of endogenous angiotensin (Ang) II actions on presympathetic vasomotor rostral ventrolateral medulla neurons to enhance sympathetic activity and maintain hypertension. In addition, we discuss Ang II-induced attenuation of afferent baroreceptor feedback within the nucleus tractus solitarius and its relevance to the development of hypertension. We also outline the cellular and molecular mechanisms of Ang II signal transduction that may be critical for the initiation and establishment of hypertension. In particular, we present evidence for a phosphoinositide-3-kinase-dependent signaling pathway that appears to contribute to hypertension in the SHR, possibly via augmented Ang II-induced increases in neuronal firing rate and enhanced transcriptional noradrenaline neuromodulation. Finally, we outline future directions in utilizing our understanding of the brain RAS dysfunction in hypertension for the development of improved therapeutic intervention in hypertension.

Brain Research, 1997

To clarify the role of neurones in the anteroventral third ventricle (AV3V) area in cardiovascula... more To clarify the role of neurones in the anteroventral third ventricle (AV3V) area in cardiovascular responses to CSF sodium, ouabain and angiotensin II (ANG II), we employed excitotoxic lesions of the ventral AV3V (vAV3V). In conscious lesioned Wistar rats with systemic vasopressin blockade, pressor and tachycardiac responses to intracerebroventricular (i.c.v.) artificial CSF containing 0.3 M NaCl or ouabain were significantly attenuated by 26-32% whereas responses to ANG II were not affected. Thus, in rats with systemic blockade of vasopressin mechanisms, the vAV3V region partially mediates acute pressor responses to i.c.v. sodium and ouabain but not to ANG II.

Brain Research, 2000

Hypertension, Apr 1, 2005

Despite intensive investigation, the molecular mechanism by which the angiotensin II type 2 (AT 2... more Despite intensive investigation, the molecular mechanism by which the angiotensin II type 2 (AT 2) receptor exerts its cellular and physiological actions remains elusive. In the present study, we have used microarray expression analysis to identify genes whose expression was regulated by this receptor and to determine its cellular consequences. Lentiviral vector was used to express the AT 2 receptor in human coronary artery endothelial cells (HCAECs), followed by analysis of expression profiles. We observed Ϸ5224 genes regulated in an AT 2 receptor ligand-independent manner in HCAECs expressing the AT 2 receptor. In addition, 1235 genes were differentially expressed in response to the AT 2 receptor-specific ligand, CGP42112A. Validity of the expression profiles was demonstrated by real-time reversetranscriptase polymerase chain reaction quantitation of 5 genes. Because some of these genes could be linked to the regulation of extracellular matrix association, we studied the effect of the AT 2 receptor on cell migration. Expression of the AT 2 receptor resulted in a 2-fold inhibition of HCAEC migration. Taken together, these observations demonstrate that the AT 2 receptor regulates expression of genes relevant to cell migration, protein processing, intracellular signaling, and DNA repair in both ligand-dependent and ligand-independent manners. (Hypertension. 2005;45[part 2]:692-697.