293 results on '"Leenen, Frans H.H."'
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2. On-treatment blood pressures of older hypertensive patients in Canada: implications for Systolic blood PRessure INtervention Trial
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Fodor, Jiri George, Baker, Penelope, Chen, Li, and Leenen, Frans H.H.
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- 2017
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3. The Brain Renin-Angiotensin System And Salt-Sensitive Hypertension
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Veerasingham, Shereeni J., Leenen, Frans H.H., Dhalla, Naranjan S., editor, Zahradka, Peter, editor, Dixon, Ian M. C., editor, and Beamish, Robert E., editor
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- 1998
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4. Enhanced expression of epithelial sodium channels in the renal medulla of Dahl S rats
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Amin, Md. Shahrier, Reza, Erona, Shahat, Esraa El-, Wang, Hong-Wei, Tesson, Frederique, and Leenen, Frans H.H.
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Epithelium -- Chemical properties -- Genetic aspects -- Physiological aspects ,Sodium in the body -- Physiological aspects -- Chemical properties -- Genetic aspects ,Kidneys -- Chemical properties -- Genetic aspects -- Physiological aspects ,Rats -- Physiological aspects -- Genetic aspects -- Chemical properties ,Rattus -- Physiological aspects -- Genetic aspects -- Chemical properties ,Biological sciences - Abstract
Inner medullary collecting duct (IMCD) cells from salt-sensitive (S) Dahl rats transport twice as much [Na.sup.+] as cells from salt-resistant (R) rats, possibly related to dysregulation of the renal epithelial sodium channel (ENaC). The effect of a high-salt diet on ENaC expression in the inner medulla of S versus R rats has not yet been studied. Young, male S and R rats were placed on a regular-salt (0.3%) or high-salt (8%) diet for 2 or 4 weeks. mRNA and protein expression of ENaC subunits were studied by real-time PCR and immunoblotting. Intracellular distribution of the subunits in the IMCD was evaluated by immunohistochemistry. On regular salt, the abundance of the mRNA of β and γENaC was higher in the medulla of S rats than R rats. This was associated with a greater protein abundance of 90 kDa γENaC and higher immunoreactivity for both α and γ ENaC. High salt did not affect mRNA abundance in either strain and decreased apical staining of βENaC in IMCD of R rats. In contrast, high salt did not affect the higher apical localization of αENaC and increased the apical membrane staining for β and γENaC in the IMCD of S rats. Expression of ENaC subunits is enhanced in the medulla of S vs. R rats on regular salt, and further increased on high salt. The persistent high expression of αENaC and increase in apical localization of β and γENaC may contribute to greater retention of sodium in S rats on a high-salt diet. Key words: kidney, salt, ENaC, real-time PCR, immunohistochemistry. Les cellules du tube collecteur medullaire interne (TCMI) des rats Dahl sensibles au sel (S) transportent deux fois plus de [Na.sup.+] que celles des rats resistants au sel (R), probablement en raison d'un dysfonctionnement du canal sodique epithelial renal (ENaC). L'effet d'une diete hypersodee sur l'expression du canal ENaC dans la partie medullaire interne des rats S versus R n'a a ce jour fait l'objet d'aucune etude. Nous avons soumis de jeunes rats S et R males a une diete contenant une quantite normale (0,3%) ou elevee (8%) de sel pendant 2 ou 4 semaines. Nous avons examinee l'expression de l'ARNm et des proteines des sous-unites de ENaC par PCR en temps reel et immunobuvardage, et nous avons evalue par immunohistochimie la distribution intracellulaire des sous-unites dans le TCMI. En condition normosodee, l'expression de l'ARNm des sous-unites β et γENaC a ete plus elevee dans la partie medullaire des rats S que des rats R. Cet effet a ete associe a un taux plus eelevee des proteeines des sous-unites γENaC de 90 kDA et a une plus forte immunoreactivitee tant pour ce qui est de β que de γENaC. La diete hypersodee n'a pas modifiee la teneur en ARNm des rats S et R, et a diminue la coloration apicale de βENaC dans le TCMI des rats R. A l'opposee, la dose eleveee de sel n'a pas influee sur la plus forte localisation apicale de γENaC, et a elle augmented la coloration apicale de β et γENaC dans le TCMI des rats S. L'expression des sous-unites ENaC est stimulee dans la partie medullaire des rats S versus R soumis a une diete normosodee, et elle augmente davantage avec une diete hypersodee. L'expression elevee persistante de αENaC et l'augmentation de la localisation apicale de β et γENaC pourraient contribuer a la plus forte retention de sodium chez les rats S soumis a une diete hypersodeee. Mots-cles: rein, sel, ENaC, PCR en temps reel, immunohistochimie. [Traduit par la Redaction], Introduction Blood pressure sensitivity to salt is seen in 40%-60% of patients with essential hypertension and in ~20%-30% of the general population (Franco and Oparil 2006). Genetic analyses of human [...]
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- 2011
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5. 2006 Ontario Survey on the Prevalence and Control of Hypertension (ON-BP): Rationale and design of a community-based cross-sectional survey
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Fodor, J. George, Leenen, Frans H.H., Helis, Eftyhia, and Turton, Penelope
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- 2008
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6. Central neuronal activation and pressor responses induced by circulating ANG II: role of the brain aldosterone-'ouabain' pathway
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Huang, Bing S., Ahmadi, Sara, Ahmad, Monir, White, Roselyn A., and Leenen, Frans H.H.
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Angiotensin -- Physiological aspects ,Angiotensin -- Genetic aspects ,Neurons -- Physiological aspects ,Neurons -- Genetic aspects ,Neurons -- Research ,Aldosterone -- Health aspects ,Biological sciences - Abstract
An increase in plasma ANG II causes neuronal activation in hypothalamic nuclei and a slow pressor response, presumably by increasing sympathetic drive. We evaluated whether the activation of a neuromodulatory pathway, involving aldosterone and 'ouabain,' is involved in these responses. In Wistar rats, the subcutaneous infusion of ANG II at 150 and 500 ng x [kg.sup.-1] x [min.sup.-1] gradually increased blood pressure up to 60 mmHg at the highest dose. ANG II at 500 ng x [kg.sup.-1] x min increased plasma ANG II by 4-fold, plasma aldosterone by 25-fold, and hypothalamic aldosterone by 3-fold. The intracerebroventricular infusion of an aldosterone synthase (AS) inhibitor prevented the ANG II-induced increase in hypothalamic aldosterone without affecting the increase in plasma aldosterone. Neuronal activity, as assessed by Fra-like immunoreactivity, increased transiently in the subfornical organ (SFO) but progressively in the paraventricular nucleus (PVN) and supraoptic nucleus (SON). The central infusion of the AS inhibitor or a mineralocorticoid receptor blocker markedly attenuated the ANG II-induced neuronal activation in the PVN but not in the SON. Pressor responses to ANG II at 150 ng x [kg-] x [min.sup.-1] were abolished by an intracerebroventricular infusion of the AS inhibitor. Pressor responses to ANG II at 500 ng x [kg.sup.-1] x [min.sup.-1 were attenuated by the central infusion of the AS inhibitor or the mineralocorticoid receptor blocker by 70-80% and by Digibind (to bind 'ouabain') by 50%. These results suggest a novel central nervous system mechanism for the ANG II-induced slow pressor response, i.e., circulating ANG II activates the SFO, leading to the direct activation of the PVN and SON, and, in addition, via aldosterone-dependent amplifying mechanisms, causes sustained activation of the PVN and thereby hypertension. Fra-like immunoreactivity; aldosterone synthase inhibitor; eplerenone; telemetry; angiotensin II doi: 10.1152/ajpheart.00256.2010.
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- 2010
7. Effects of central sodium on epithelial sodium channels in rat brain
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Wang, Hong-Wei, Amin, Md Shahrier, El-Shahat, Esraa, Huang, Bing S., Tuana, Balwant S., and Leenen, Frans H.H.
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Brain -- Research ,Rats -- Physiological aspects ,Rattus -- Physiological aspects ,Sodium channels -- Research ,Cerebrospinal fluid -- Research ,Epithelium -- Research ,Biological sciences - Abstract
We evaluated the effects of intracerebroventricular (icv) infusion of [Na.sup.+]-rich artificial cerebrospinal fluid (aCSF), with or without the mineralocorticoid receptor (MR) blocker spironolactone, on epithelial [Na.sup.+] channel (ENaC) subunits and regulators, such as MR, serum/glucocorticoid-inducible kinase 1, neural precursor cells expressed developmentally downregulated 4-like gene, 11[beta]-hydroxylase, and aldosterone synthase, in brain regions of Wistar rats. The effects of icv infusion of the amiloride analog benzamil on brain tissue and CSF [Na.sup.+] concentration ([[Na.sup.+]]) were also assessed. In the choroid plexus and ependyma of the anteroventral third ventricle, ENaC subunits are present in apical and basal membranes. [Na.sup.+]-rich aCSF increased [beta]-ENaC mRNA and immunoreactivity in the choroid plexus and increased [alpha]- and [beta]-ENaC immunoreactivities in the ependyma. [Na.sup.+]-rich aCSF increased [alpha]- and [beta]-ENaC-gold-labeled particles in the microvilli of the choroid plexus and in basolateral membranes of the ependyma. Spironolactone only prevented the increase in [beta]-ENaC immunoreactivity in the choroid plexus and ependyma. In the supraoptic nucleus, paraventricular nucleus, and subfornical organ, [Na.sup.+]-rich aCSF did not affect mRNA expression levels of the studied genes. Benzamil significantly increased CSF [[Na.sup.+]] in the control, but not [Na.sup.+]-rich, aCSF group. In contrast, benzamil prevented the increase in hypothalamic tissue [[Na.sup.+]] by [Na.sup.+]-rich aCSF. These results suggest that CSF [Na.sup.+] upregulates ENaC expression in the brain epithelia, but not in the neurons of hypothalamic nuclei. ENaC in the choroid plexus and ependyma appear to contribute to regulation of [Na.sup.+] homeostasis in the brain. sodium-rich artificial cerebrospinal fluid; benzamil; cerebrospinal fluid sodium concentration doi: 10.1152/ajpregu.00834.2009.
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- 2010
8. Brain renin-angiotensin-aldosterone system and ventricular remodeling after myocardial infarct: a review
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Westcott, Katherine V., Huang, Bing S., and Leenen, Frans H.H.
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Renin-angiotensin system -- Health aspects -- Research ,Cardiotonic agents -- Health aspects -- Research ,Cardiac glycosides -- Health aspects -- Research ,Ouabain -- Research ,Heart failure -- Risk factors -- Care and treatment ,Biological sciences ,Care and treatment ,Research ,Risk factors ,Health aspects - Abstract
After a myocardial infarct (MI), a variety of mechanisms contribute to progressive cardiac remodeling and dysfunction. Progressive activation of central sympathoexcitatory pathways appears to depend on a neuromodulatory pathway, involving local production of aldosterone and release of endogenous ouabain-like compounds ('ouabain') possibly from magnocellular neurons in the supraoptic and paraventricular nuclei. 'Ouabain' may lower the membrane potential of neurons and thereby enhance activity of angiotensinergic pathways. These central pathways appear to coordinate progressive activation of several peripheral mechanisms such as sympathetic tone and circulating and cardiac renin-angiotensin-aldosterone system (RAAS). Central blockade of aldosterone production, mineralocorticoid receptors, 'ouabain' activity, or [AT.sub.1] receptors similarly prevents activation of these peripheral mechanisms. Cardiac remodeling after MI involves progressive left ventricular dilation, fibrosis, and decrease in contractile performance. Central blockade of this neuromodulatory pathway causes a marked attenuation of the remodeling and dysfunction, presumably by inhibiting increases in (cardiac) sympathetic activity and RAAS. At the cellular level, these systems may contribute to the cardiac remodeling by activating proinflammatory cytokines and cardiac myocyte apoptosis. New therapeutic approaches, specifically preventing activation of this brain neuromodulatory pathway, may lead to more optimal and specific approaches to the prevention of heart failure after MI. Key words: brain RAAS, myocardial infarction, central nervous system, inflammation, apoptosis, sympathetic hyperactivity, ventricular remodeling. Apres un infarctus du myocarde (IM), divers mecanismes contribuent au remodelage et au dysfonctionnement progressifs du coeur. L'activation progressive des voies sympathoexcitatrices centrales semble dependre d'une voie neuromodulatrice impliquant la production d'aldosterone et la liberation de substances endogenes de type ouabalne (<< ouabalne >>) probablement des neurones magnocellulaires situes dans les noyaux supraoptiques et paraventriculaires. Les substances ouabalne pourraient diminuer le potentiel membranaire des neurones et ainsi stimuler l'activite des voies angiotensinergiques. Ces voies centrales semblent coordonner l'activation progressive de plusieurs mecanismes peeripheeriques tels que le tonus sympathique et le systeme renine-angiotensine-aldosterone (SRAA) cardiaque circulant. Le blocage central de la production d'aldosterone, des recepteurs mineeralocorticoides, de l'activite; des substances ouabalne ou des recepteurs [AT.sub.1] empeche aussi l'activation de ces mecanismes peripheriques. Le remodelage cardiaque apres l'lM implique une dilatation progressive du ventricule gauche, une fibrose et une diminution de la performance contractile . Le blocage central de cette voie neuromodulatrice entraine une attenuation marquee du remodelage et du dysfonctionnement, vraisemblablement en inhibant les augmentations de l'activite; sympathique et du SRAA (cardiaques). Au niveau cellulaire, ces systemes pourraient contribuer au remodelage cardiaque en activant des cytokines proinflammatoires et l'apoptose des myocytes cardiaques. De nouvelles approches theerapeutiques prevenant specifiquement l'activation de cette voie neuromodulatrice ceerebrale pourraient mener au developpement d'approches optimales permettant de prevenir l'insuffisance cardiaque apres un IM. Mots-cles: SRAA cerebral, infarctus du myocarde, systeme nerveux central, inflammation, apoptose, hyperactivite; sympathique, remodelage ventriculaire. [Traduit par la Redaction], Introduction The concept that after a myocardial infarct (MI), activation of pathways in the central nervous system (CNS) contributes to progressive cardiac remodeling and dysfunction has drawn increasing attention in [...]
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- 2009
9. Chronic central versus systemic blockade of [AT.sub.1] receptors and cardiac dysfunction in rats post-myocardial infarction
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Huang, Bing S., Ahmad, Monir, Tan, Junhui, and Leenen, Frans H.H.
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Heart attack -- Care and treatment ,Heart attack -- Patient outcomes ,Heart attack -- Research ,Losartan -- Dosage and administration ,Losartan -- Research ,Heart ventricle, Left -- Physiological aspects ,Heart ventricle, Left -- Research ,Animal models in research -- Physiological aspects ,Biological sciences - Abstract
In rats, both central and systemic ANG II type 1 ([AT.sub.1]) receptor blockade attenuate sympathetic hyperactivity, but central blockade more effectively attenuates left ventricular (LV) dysfunction post-myocardial infarction (MI). In protocol 1, we examined whether functional effects on cardiac load may play a role and different cardiac effects disappear after withdrawal of the blockade. Wistar rats were infused for 4 wk post-MI intracerebroventricularly (1 mg x [kg.sup.-1] x [day.sup.-1]) or injected subcutaneously daily (100 mg x [kg.sup.-1] x [day.sup.-1]) with losartan. LV dimensions and function were assessed at 4 wk and at 6 wk post-MI, i.e., 2 wk after discontinuing treatments. At 4 and 6 wk post-MI, LV dimensions were increased and ejection fraction was decreased. Intracerebroventricular but not subcutaneous losartan significantly improved these parameters. At 6 wk, LV peak systolic pressure (LVPSP) and maximal or minimal first derivative of change in pressure over time (dP/[dt.sub.max/min]) were decreased and LV end-diastolic pressure (LVEDP) was increased. All four indexes were improved by previous intracerebroventricular losartan, whereas subcutaneous losartan improved LVEDP only. In protocol H, we evaluated effects of oral instead of subcutaneous administration of losartan for 4 wk post-MI. Losartan (~200 mg x [kg.sup.-1] x [day.sup.-1]) either via drinking water or by gavage similarly decreased [AT.sub.1] receptor binding densities in brain nuclei and improved LVEDP but further decreased LVPSP and dP/[dt.sub.max]. These results indicate that effects on cardiac load by peripheral [AT.sub.1] receptor blockade or the pharmacokinetic profile of subcutaneous versus oral dosing do not contribute to the different cardiac effects of central versus systemic [AT.sub.1] receptor blockade post-MI. losartan; cardiac remodeling; echocardiography; Millar catheter; brain; ANG II type 1
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- 2009
10. Role of central nervous system aldosterone synthase and mineralocorticoid receptors in salt-induced hypertension in Dahl salt-sensitive rats
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Huang, Bing S., White, Roselyn A., Jeng, Arco Y., and Leenen, Frans H.H.
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Cerebrospinal fluid -- Physiological aspects ,Cerebrospinal fluid -- Research ,Corticosterone -- Health aspects ,Corticosterone -- Research ,Hypertension -- Risk factors ,Hypertension -- Care and treatment ,Hypertension -- Research ,Biological sciences - Abstract
In Dahl salt-sensitive (S) rats, high salt intake increases cerebrospinal fluid (CSF) [Na.sup.+] concentration ([[Na.sup.+]]) and blood pressure (BP). Intracerebroventricular (ICV) infusion of a mineralocorticoid receptor (MR) blocker prevents the hypertension. To assess the role of aldosterone locally produced in the brain, we evaluated the effects of chronic central blockade with the aldosterone synthase inhibitor FAD286 and the MR blocker spironolactone on changes in aldosterone and corticosterone content in the hypothalamus and the increase in CSF [[Na.sup.+]] and hypertension induced by high salt intake in Dahl S rats. After 4 wk of high salt intake, plasma aldosterone and corticosterone were not changed, but hypothalamic aldosterone increased by ~35% and corticosterone tended to increase in Dahl S rats, whereas both steroids decreased by ~65% in Dahl salt-resistant rats. In Dahl S rats fed the high-salt diet, ICV infusion of FAD286 or spironolactone did not affect the increase in CSF [[Na.sup.+]]. ICV infusion of FAD286 prevented the increase in hypothalamic aldosterone and 30 mmHg of the 50-mmHg BP increase induced by high salt intake. ICV infusion of spironolactone fully prevented the salt-induced hypertension. These results suggest that, in Dalai S rats, high salt intake increases aldosterone synthesis in the hypothalamus and aldosterone acts as the main MR agonist activating central pathways contributing to salt-induced hypertension. brain; corticosterone; high-salt diet
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- 2009
11. Mechanisms in the PVN mediating local and central sodium-induced hypertension in Wistar rats
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Gabor, Alexander and Leenen, Frans H.H.
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Ouabain -- Properties ,Aldosterone -- Properties ,Hypertension -- Development and progression ,Blood pressure -- Measurement ,Angiotensin -- Receptors ,Angiotensin -- Properties ,Biological sciences - Abstract
Sympathoexcitatory and hypertensive responses to central infusion of [Na.sup.+]-rich artificial cerebrospinal fluid (aCSF) are enhanced by aldosterone and mediated by mineralocorticoid receptors (MRs) and benzamil-blockable [Na.sup.+] influx, leading to 'ouabain' release and ANG II type 1 ([AT.sub.1]) receptor stimulation. The present study evaluated the functional role of these mechanisms in the paraventricular nucleus (PVN). In conscious Wistar rats, [Na.sub.+] -rich aCSF was infused either directly into the PVN or intracerebroventricularly preceded by aldosterone and blockers. Infusion of [Na.sup.+] -rich aCSF in the PVN caused gradual increases in blood pressure (BP) and heart rate (HR). Aldosterone and a subpressor dose of ouabain in the PVN alone did not affect BP and HR but enhanced responses to [Nasup.+]. Eplerenone, benzamil, and 'ouabain' binding Fab fragments only blocked the enhancement by aldosterone, whereas losartan blocked all responses to [Na.sup.+] -rich aCSF in the PVN. Increases in BP and HR by intracerebroventricular infusion of [Na.sup.+] rich aCSF were enhanced by aldosterone infused intracerebroventricularly, but not in the PVN. Telmisartan in the PVN again blocked all responses. In contrast, both eplerenone and benzamil in the PVN did not change the pressor responses to intracerebroventricular infusion of aldosterone and [Na.sup.+] -rich aCSF. These findings indicate that ATI receptors in the PVN mediate the responses to [Na.sup.+] -rich aCSF and their enhancement by aldosterone, both locally in the PVN or in the general CSF. MRs, benzamil-blockable [Na.sup.+] channels or transporters, and 'ouabain' can be functionally active in the PVN, but in Wistar rats appear not to contribute to the pressor responses to short-term increases in CSF [[Na.sup.+]]. brain; aldosterone; ouabain; angiotensin II type l receptors; blood pressure; paraventricular nucleus
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- 2009
12. Central infusion of aldosterone synthase inhibitor prevents sympathetic hyperactivity and hypertension by central [Na.sup.+] in Wistar rats
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Huang, Bing S., White, Roselyn A., Ahmad, Monir, Jeng, Arco Y., and Leenen, Frans H.H.
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Enzyme inhibitors -- Dosage and administration ,Enzyme inhibitors -- Research ,Hypertension -- Drug therapy ,Hypertension -- Prevention ,Hypertension -- Research ,Biological sciences - Abstract
In Wistar rats, increasing cerebrospinal fluid (CSF) [Na.sup.+] concentration ([[Na.sup.+]]) by intracerebroventricular (ICV) infusion of hypertonic saline causes sympathetic hyperactivity and hypertension that can be prevented by blockade of brain mineralocorticoid receptors (MR). To assess the role of aldosterone produced locally in the brain in the activation of MR in the central nervous system (CNS), Wistar rats were infused ICV with artificial CSF (aCSF), [Na.sup.+]-rich (800 mmol/1) aCSF, aCSF plus the aldosterone synthase inhibitor FAD286 (100 [micro]g*[kg.sup.-1] * [day.sup.-1]), or [Na.sup.+]-rich aCSF plus FAD286. After 2 wk of infusion, rats treated with [Na.sup.+]-rich aCSF exhibited significant increases in aldosterone and corticosterone content in the hypothalamus but not in the hippocampus, as well as increases in resting blood pressure (BP) and sympathoexcitatory responses to air stress, and impairment of arterial baroreflex function. Concomitant ICV infusion of FAD286 prevented the [Na.sup.+]-induced increase in hypothalamic aldosterone but not corticosterone and prevented most of the increases in resting BP and sympathoexcitatory and pressor responses to air stress and the baroreflex impairment. FAD286 had no effects in rats infused with ICV aCSF. In another set of rats, 24-h BP and heart rate were recorded via telemetry before and during a 14-day ICV infusion of [Na.sup.+]-rich aCSF with or without FAD286. [Na.sup.+]-rich aCSF without FAD286 caused sustained increases (~10 mmHg) in resting mean arterial pressure that were absent in the rats treated with FAD286. These data suggest that in Wistar rats, an increase in CSF [[Na.sup.+]] may increase the biosynthesis of corticosterone and aldosterone in the hypothalamus, and mainly aldosterone activates MR in the CNS leading to sympathetic hyperactivity and hypertension. brain sodium; brain steroids; mineralocorticoid receptor; cytochrome P-450 aldosterone synthase; hypothalamus; sympathoexcitation; diurnal variation
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- 2008
13. Effects of hypertension on cardiovascular responses to epinephrine in humans
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Leenen, Frans H.H., Fourney, Anne, Coletta, Elizabeth, and White, Roselyn
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Aging -- Physiological aspects ,Hypertension -- Physiological aspects ,Epinephrine -- Evaluation ,Epinephrine -- Dosage and administration ,Biological sciences - Abstract
Cardiac [beta]-receptor responsiveness is diminished by both aging and hypertension. However, concomitant decreases in the activity of counterregulatory mechanisms, such as the arterial baroreflex and neuronal catecholamine uptake, influence the ultimate cardiac responses to adrenergic agents in vivo. In the present study, we evaluated by echocardiography cardiac responses to intravenous infusion of epinephrine in 14 young and 18 older normotensive men and women and in 10 young and 17 older hypertensive men and women. To assess the relative contribution of intrinsic cardiac and counterregulatory components to the overall response, infusions were repeated combined with a ganglionic blocker in the young groups. Epinephrine-induced increases in heart rate were similar in the four groups. Increases in stroke volume, ejection fraction, and cardiac index were similar in the two hypertensive and two young normotensive groups. In contrast, they were attenuated in the older normotensive group, resulting in higher left ventricular responses in older hypertensive than in normotensive subjects. Heart rate and left ventricular responses to epinephrine in the presence of ganglionic blockade did not differ between the two young groups. Increases in plasma norepinephrine due to epinephrine infusion were larger in hypertensive than in normotensive subjects. One may conclude that compared with young normotensive subjects, in hypertensive subjects mechanisms increasing versus decreasing cardiac responses to epinephrine may remain in balance, and, compared with older normotensive subjects, older hypertensive subjects exhibit enhanced cardiac responses to sympathetic stimulation. aging; arterial baroflex; neuronal uptake; B-receptor responsiveness; heart doi:10.1152/ajpheart.01200.2006.
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- 2007
14. Prevention of Renal Dysfunction and Hypertension by Amlodipine After Heart Transplant
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Leenen, Frans H.H., Coletta, Elizabeth, and Davies, Ross A.
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- 2007
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15. Activation of brain renin-angiotensin-aldosterone system by central sodium in Wistar rats
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Huang, Bing S., Cheung, Warren J., Wang, Hao, Tan, Junhui, White, Roselyn A., and Leenen, Frans H.H.
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Angiotensin converting enzyme -- Research ,Mineralocorticoids -- Research ,Ouabain -- Research ,Biological sciences - Abstract
Functional studies indicate that the sympathoexcitatory and pressor responses to an increase in cerebrospinal fluid (CSF) [[Na.sup.+]] by central infusion of [Na.sup.+]-rich artificial cerebrospinal fluid (aCSF) in Wistar rats are mediated in the brain by mineralocorticoid receptor (MR) activation, ouabain-like compounds (OLC), and A[T.sub.1]receptor stimulation. In the present study, we examined whether increasing CSF [[Na.sup.+]] by intracerebroventricular infusion of [Na.sup.+]-rich aCSF activates MR and thereby increases OLC and components of the renin-angiotensin system in the brain. Male Wistar rats received via osmotic minipump an intracerebroventricular infusion of aCSF or [Na.sup.+]-rich aCSF, in some groups combined with intracerebroventricular infusion of spironolactone (100 ng/h), antibody Fab fragments (to bind OLC), or as control [gamma]-globulins. After 2 wk of infusion, resting blood pressure and heart rate were recorded, OLC and aldosterone content in the hypothalamus were assessed by a specific ELISA or radioimmunoassay, and angiotensin-converting enzyme (ACE) and A[T.sub.1]-receptor binding densities in various brain nuclei were measured by autoradiography using [sup.125]I-labeled 351 A and [sup.125]I-labeled ANG II. When compared with intracerebroventricular aCSF, intracerebroventricular [Na.sup.+]-rich aCSF increased CSF [[Na.sup.+]] by ~5 mmol/l, mean arterial pressure by ~20 mmHg, heart rate by ~65 beats/min, and hypothalamic content of OLC by 50% and of aldosterone by 33%. Intracerebroventricular spironolactone did not affect CSF [[Na.sup.+]] but blocked the [Na.sup.+]-rich aCSF-induced increases in blood pressure and heart rate and OLC content. Intracerebroventricular [Na.sup.+]-rich aCSF increased ACE and A[T.sub.1]-receptor-binding densities in several brain nuclei, and Fab fragments blocked these increases. These data indicate that in Wistar rats, a chronic increase in CSF [[Na.sup.+]] may increase hypothalamic aldosterone and activate CNS pathways involving MR, and OLC, leading to increases in A[T.sub.1]-receptor and ACE densities in brain areas involved in cardiovascular regulation and hypertension. brain mineralocorticoid receptor; ouabain; angiotensin-converting enzyme; A[T.sub.1]-receptor doi:10.1152/ajpheart.00024.2006
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- 2006
16. Regulation of components of the brain and cardiac renin-angiotensin systems by 17[beta]-estradiol after myocardial infarction in female rats
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Dean, Stephanie A., Tan, Junhui, White, Roselyn, O'Brien, Edward R., and Leenen, Frans H.H.
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Angiotensin converting enzyme -- Research ,Heart attack -- Research ,Rats as laboratory animals -- Research ,Ovariectomy -- Research ,Biological sciences - Abstract
The present study tested the hypothesis that 17[beta]-estradiol ([E.sub.2]) inhibits increases in angiotensin-converting enzyme (ACE) and ANG II type 1 receptor (A[T.sub.1]R) in the brain and heart after myocardial infarction (MI) and, thereby, inhibits development of left ventricular (LV) dysfunction after MI. Agematched female Wistar rats were treated as follows: 1) no surgery (ovary intact), 2) ovariectomy + subcutaneous vehicle treatment (OVX + Veh), or 3) OVX + subcutaneous administration of a high dose of [E.sub.2] (OVX + high-[E.sub.2]). After 2 wk, rats were randomly assigned to coronary artery ligation (MI) and sham operation groups and studied after 3 wk. [E.sub.2] status did not affect LV function in sham rats. At 2-3 wk after MI, impairment of LV function was similar across MI groups, as measured by echocardiography and direct LV catheterization. LV ACE mRNA abundance and activity were increased severalfold in all MI groups compared with respective sham animals and to similar levels across MI groups. In most brain nuclei, ACE and A[T.sub.1]R densities increased after MI. Unexpectedly, compared with the respective sham groups the relative increase was clearest (20-40%) in OVX + high-[E.sub.2] MI rats, somewhat less (10-15%) in ovary-intact MI rats, and least (< 10-15%) in OVX + Veh MI rats. However, because in the sham group brain ACE and A[T.sub.1]R densities increased in the OVX + Veh rats and decreased in the OVX + high-[E.sub.2] rats compared with the ovary-intact rats, actual ACE and A[T.sub.1]R densities in most brain nuclei were modestly higher ( ovariectomy; heart failure; estrogens
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- 2006
17. Distribution of epithelial sodium channels and mineralocorticoid receptors in cardiovascular regulatory centers in rat brain
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Amin, Md Shahrier, Wang, Hong-Wei, Reza, Erona, Whitman, Stewart C., Tuana, Balwant S., and Leenen, Frans H.H.
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Polymerase chain reaction -- Research ,Mineralocorticoids -- Health aspects ,Sodium channels -- Research ,Biological sciences - Abstract
Epithelial sodium channels (ENaC) are important for regulating sodium transport across epithelia. Functional studies indicate that neural mechanisms acting through mineralocorticoid receptors (MR) and sodium channels (presumably ENaC) are crucial to the development of sympathoexcitation and hypertension in experimental models of salt-sensitive hypertension. However, expression and localization of the ENaC in cardiovascular regulatory centers of the brain have not yet been studied. RT-PCR and immunohistochemistry were performed to study ENaC and MR expression at the mRNA and protein levels, respectively. Both mRNA and protein for [alpha]-, [beta]-, and [gamma]-ENaC subunits and MR were found to be expressed in the rat brain. All three ENaC subunits and MR were present in the supraoptic nucleus, magnocellular paraventricular nucleus, hippocampus, choroid plexus, ependyma, and brain blood vessels, suggesting the presence of multimeric channels and possible regulation by mineralocorticoids. In most cortical areas, thalamus, amygdala, and suprachiasmatic nucleus, notable expression of [gamma]-ENaC was undetectable, whereas [alpha]- and [beta]-ENaC were abundantly expressed pointing to the possibility of a heterogeneous population of channels. The findings suggest that stoichiometrically different populations of ENaC may be present in both epithelial and neural components in the brain, which may contribute to regulation of cerebrospinal fluid and interstitial [Na.sup.+] concentration as well as neuronal excitation. reverse transcriptase polymerase chain reaction; immunohistochemistry
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- 2005
18. Blockade of brain mineralocorticoid receptors or [Na.sup.+] channels prevents sympathetic hyperactivity and improves cardiac function in rats post-MI
- Author
-
Huang, Bing S. and Leenen, Frans H.H.
- Subjects
Aldosterone -- Research ,Heart attack -- Research ,Brain -- Research ,Biological sciences - Abstract
In rats post-myocardial infarction (MI), sympathetic hyperactivity can be prevented by blockade of brain mineralocorticoid receptors (MR). Stimulatory responses to central infusion of aldosterone can be blocked by benzamil and therefore appear to be mediated via [Na.sup.+] channels, presumably epithelial [Na.sup.+] channels (ENaC), in the brain. To evaluate this concept of endogenous mineralocorticoids in Wistar rats post-MI, we examined effects of blockade of MR and [Na.sup.+] channels in the brain. At 3 days after coronary artery ligation, intracerebroventricular infusions were started with spironolactone (400 ng x [kg.sup.-1] x [h.sup.-1]) or its vehicle, or with benzamil (4 [micro]g x [kg.sup.-1] x [h.sup.-1]) or its vehicle, using osmotic minipumps. Rats with sham ligation served as control. After 4 wk, in conscious rats, mean arterial pressure, heart rate, and renal sympathetic nerve activity were recorded at rest and in response to air-jet stress, intracerebroventricular injection of the [[alpha].sub.2]-adrenoceptor agonist guanabenz, and intravenous infusion of phenylephrine and nitroprusside for baroreflex function. MI size was similar among the four groups of rats (~31%). In rats treated post-MI with vehicles, cardiac function was decreased, sympathetic reactivity was enhanced, and baroreflex function was impaired. Blockade of brain [Na.sup.+] channels or brain MR similarly prevented sympathetic hyperactivity and impairment of baroreflex function and improved cardiac function. These findings suggest that in rats post-MI, increased binding of endogenous agonists to MR increases ENaC activity in the brain and thereby leads to sympathetic hyperactivity and progressive left ventricular dysfunction. myocardial infarction; cardiac dysfunction; aldosterone
- Published
- 2005
19. Aging and cardiac responses to epinephrine in humans: role of neuronal uptake
- Author
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Leenen, Frans H.H., Coletta, Elizabeth, Fourney, Anne, and White, Roselyn
- Subjects
Heart -- Research ,Aging -- Research ,Biological sciences - Abstract
In healthy humans, ganglionic blockade unmasks a clear age-related decrease in cardiac responses to isoproterenol but not to epinephrine. We postulated that an age-related decrease in neuronal uptake (which affects epinephrine but not isoproterenol) may offset a parallel decrease in [beta]-receptor-mediated responses. To test this concept, nine young (mean 29 [+ or -] 2 yr) and eight older (mean 61 [+ or -] 2 yr) healthy subjects were infused on three different study mornings with epinephrine at increasing rates either alone or combined with desipramine to eliminate differences in neuronal uptake or with desipramine and trimetaphan to induce ganglionic blockade and thereby also eliminate differences in arterial baroreflex activity. Epinephrine caused the expected rate-related increases in systolic blood pressure, heart rate, stroke volume, ejection fraction, and cardiac index. Except for the systolic blood pressure, the extent of the changes was similar in young and older subjects. After desipramine, cardiac responsiveness to epinephrine was markedly enhanced, although more (P < 0.01) in young vs. older subjects for heart rate and cardiac index (+ 14 vs. 7 beats/min and + 1.6 vs. 1.1 1 x [min.sup.-1] x [m.sup.-2] respectively, at 20 ng x [kg.sup.-1] x [min.sup.-1]). Combined with desipramine and trimetaphan, cardiac responses to epinephrine were further enhanced, again more (P < 0.01) in young subjects, resulting in large differences in heart rate and ejection fraction increases (+29 vs. 17 beats/min and + 14 vs. 7%, respectively, at 20 ng x [kg.sup.-1] x [min.sup.-1]). Here, we show that 'healthy aging' in humans is associated with decreased cardiac responsiveness to the [beta]-agonist epinephrine: however, this decrease can be balanced by concomitant decreases in buffering of these responses by neuronal uptake and the arterial baroreflex. age; baroreflex; [beta]-receptors; desipramine; trimetaphan
- Published
- 2005
20. Chronic central infusion of aldosterone leads to sympathetic hyperreactivity and hypertension in Dahl S but not Dahl R rats
- Author
-
Huang, Bing S., Wang Hao, and Leenen, Frans H.H.
- Subjects
Rats -- Research ,Rattus -- Research ,Hypertension -- Research ,Cookery for hypertensives -- Research ,Cerebrospinal fluid ,Body fluids ,Biological sciences - Abstract
Six-week-old Dahl salt-sensitive (S) and -resistant (R) rats received for 2 wk an intracerebroventricular infusion of aldosterone (Aldo) (22.5 ng/h) or vehicle containing artificial cerebrospinal fluid (aCSF) with 0.15 M [Na.sup.+]. At 8 wk, mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were recorded in conscious rats at rest, in response to air stress, and to an intracerebroventricular injection of the [[alpha].sub.2]-adrenoceptor agonists guanabenz or ouabain. Baroreflex control of RSNA and HR was estimated by using intravenous phenylephrine and nitropmsside. In Dahl S but not Dahl R rats, Aldo raised resting MAP by 20-25 mmHg, doubled sympathoexcitatory and pressor responses to air stress and sympathoinhibitory and depressor responses to guanabenz, and impaired baroreflex function. In Dahl S but not Dahl R rats, Aldo significantly increased content of ouabain-like compounds (OLC) in the hypothalamus and attenuated excitatory responses to ouabain. Aldo did not affect water intake, plasma electrolytes, or OLC in plasma and adrenal glands. In another set of three groups of Dahl S rats, Aldo dissolved in aCSF containing 0.16, 0.15, or 0.14 M [Na.sup.+] was infused intracerebroventrcularly for 2 wk. CSF [Na.sup.+] concentration ([[Na.sup.+]]) showed only a nonsignificant increase, but resting MAP increased from 111 [+ or -] 3 mmHg in rats with Aldo in 0.14 M [Na.sup.+] to 131 [+ or -] 3 and 147 [+ or -] 3 mmHg with Aldo in 0.15 and 0.16 M [Na.sup.+], respectively (P < 0.05 for both). These findings indicate that in Dahl S rats, intracerebroventricular infusion of Aldo causes similar central responses as high salt intake, i.e., increases in brain OLC content, sympathetic hyperreactivity, and hypertension. The extent of the increase in blood pressure (BP) by intracerebroventricular Aldo depends on the [[Na.sup.+]] in the vehicle. In Dahl R rats, intracerebroventricular Aldo did not increase brain OLC, sympathetic reactivity, and BP, suggesting that in this rat strain, a decrease in central responsiveness to mineralocorticoids may contribute to its salt-resistant nature. ouabain-like compounds; cerebrospinal fluid [Na.sup.+] concentration
- Published
- 2005
21. Increases in CSF [[Na.sup.+]] precede the increases in blood pressure in Dahl S rats and SHR on a high-salt diet
- Author
-
Huang, Bing S., Van Vliet, Bruce N., and Leenen, Frans H.H.
- Subjects
Salt -- Research ,Salt -- Physiological aspects ,Hypertension -- Research ,Hypertension -- Causes of ,Cookery for hypertensives -- Research ,Cookery for hypertensives -- Causes of ,Rats -- Research ,Rats -- Physiological aspects ,Rattus -- Research ,Rattus -- Physiological aspects ,Biological sciences - Abstract
In Dahl salt-sensitive (S) and salt-resistant (R) rats, and spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, at 5-6 wk of age, a cannula was placed in the cisterna magna, and cerebrospinal fluid (CSF) was withdrawn continuously at 75 [micro]l/12 h. CSF was collected as day- and nighttime samples from rats on a regular salt intake (0.6% [Na.sup.+]; R-Na) and then on a high salt intake (8% [Na.sup.+]; H-Na). In separate groups of rats, the abdominal aorta was cannulated and blood pressure (BP) and heart rate (HR) measured at 10 AM and 10 PM, with rats first on R-Na and then on H-Na. On H-Na, CSF [[Na.sup.+]] started to increase in the daytime of day 2 in Dahl S rats and of day 3 in SHR. BP and HR did not rise until day 3 in Dahl S rats and day 4 in SHR. In Dahl R and WKY rats, high salt did not change CSF [Na.sup.+], BP, or HR. In a third set of Dahl S rats, sampling of both CSF and BP was performed in each individual rat. Again, significant increases in CSF [Na.sup.+] were observed 1-2 days earlier than the increases in BP and HR. In a fourth set of Dahl S rats, BP and HR were recorded continuously by means of radiotelemetry for 5 days on R-Na and 8 days on H-Na. On H-Na, BP (but not HR) increased first in the nighttime of day 2. In another set of Dahl S rats, intracerebroventricular infusion of antibody Fab fragments binding ouabain-like compounds (OLC) with high affinity prevented the increase in BP and HR by H-Na but further increased CSF [[Na.sup.+]]. Finally, in Wistar rats on H-Na, intracerebroventricular infusion of ouabain increased BP and HR but decreased CSF [[Na.sup.+]]. Thus, in both Dahl S and SHR on H-Na, increases in CSF [[Na.sup.+]] preceded the increases in BP and HR, consistent with a primary role of increased CSF [[Na.sup.+]] in the salt-induced hypertension. An increase in brain OLC in response to the initial increase in CSF [[Na.sup.+]] appears to attenuate further increases in CSF [[Na.sup.+]] but at the 'expense' of sympathoexcitation and hypertension. cerebrospinal fluid withdrawal; cisterna magna; [Na.sup.+]-[K.sup.+]-ATPase isoforms; ouabain-like compounds; telemetry
- Published
- 2004
22. Increases in brain and cardiac A[T.sub.1] receptor and ACE densities after myocardial infarct in rats
- Author
-
Tan, Junhui, Wang Hao, and Leenen, Frans H.H.
- Subjects
Angiotensin -- Research ,Biological sciences - Abstract
In the brain, ouabain-like compounds (OLC) and the reninangiotensin system (RAS) contribute to sympathetic hyperactivity in rats after myocardial infarction (MI). This study aimed to evaluate changes in components of the central vs. the peripheral RAS. Angiotensin-converting enzyme (ACE) and angiotensin type 1 (A[T.sub.1]) receptor binding densities were determined by measuring [sup.125]I-labeled 351A and [sup.125]I-labeled ANG II binding 4 and 8 wk after MI. In the brain, ACE and A[T.sub.1] receptor binding increased 8-15% in the subfornical organ, 14-22% in the organum vasculosum laminae terminalis, 20-34% in the paraventricular nucleus, and 13-15% in the median preoptic nucleus. In the heart, the greatest increase in ACE and A[T.sub.1] receptor binding occurred at the infarct scar (~10-fold) and the least in the right ventricle (2-fold). In kidneys, ACE and A[T.sub.1] receptor binding decreased 10-15%. After intracerebroventricular infusion of Fab fragments to block brain OLC from 0.5 to 4 wk after MI, increases in ACE and A[T.sub.1] receptors in the subfornical organ, organum vasculosum laminae terminalis, paraventricular nucleus, and medial preoptic nucleus were markedly inhibited, and ACE and A[T.sub.1] receptor densities in the heart increased less (6-fold in the infarct scar). In kidneys, decreases in ACE and A[T.sub.1] receptor binding were absent after treatment with Fab fragments. These results demonstrate that ACE and A[T.sub.1] receptor binding densities increase not only in the heart but also in relevant areas of the brain of rats after MI. Brain OLC appears to play a major role in activation of brain RAS in rats after MI and, to a modest degree, in activation of the cardiac RAS. renin-angiotensin system; autoradiography; heart failure
- Published
- 2004
23. Inhibition of brain angiotensin III attenuates sympathetic hyperactivity and cardiac dysfunction in rats post-myocardial infarction
- Author
-
Huang, Bing S., Ahmad, Monir, White, Roselyn A., Marc, Yannick, Llorens-Cortes, Catherine, and Leenen, Frans H.H.
- Published
- 2013
- Full Text
- View/download PDF
24. Brain sodium channels and ouabainlike compounds mediate central aldosterone-induced hypertension
- Author
-
Wang Hao, Huang, Bing S., and Leenen, Frans H.H.
- Subjects
Sodium channels -- Research ,Biological sciences - Abstract
Central nervous system (CNS) effects of mineralocorticoids participate in the development of salt-sensitive hypertension. In the brain, mineralocorticoids activate amiloride-sensitive sodium channels, and we hypothesized that this would lead to increased release of ouabainlike compounds (OLC) and thereby sympathetic hyperactivity and hypertension. In conscious Wistar rats, intracerebroventricular infusion of aldosterone at 300 or 900 ng/h in artificial cerebrospinal fluid (aCSF) with 0.145 M [Na.sup.+] for 2 h did not change baseline mean arterial pressure (MAP), renal sympathetic nerve activity (RSNA), of heart rate (HR). Intracerebroventricular infusion of aCSF containing 0.16 M [Na.sup.+] (versus 0.145 M [Na.sup.+] in regular aCSF) did not change MAP or RSNA, but significant increases in MAP, RSNA, and HR were observed after intracerebroventricular infusion of aldosterone at 300 ng/h for 2 h. Intracerebroventricular infusion of aCSF containing 0.3 M [Na.sup.+] increased MAP, RSNA, and HR significantly more after intracerebroventricular infusion of aldosterone versus vehicle. After intracerebroventricular infusion of aldosterone, the MAP, RSNA, and HR responses to intracerebroventricular infusion of aCSF containing 0.16 M [Na.sup.+] were blocked by blockade of brain OLC with intracerebroventricular infusion of Fab fragments or of brain sodium channels with intracerebroventricular benzamil. Chronic intracerebroventricular infusion of aldosterone at 25 ng/h in aCSF with 0.15 M [Na.sup.+] for 2 wk increased MAP by 15-20 mmHg and increased hypothalamic OLC by 30% and pituitary OLC by 60%. Benzamil blocked all these responses to aldosterone. These findings indicate that in the brain, mineralocorticoids activate brain sodium channels, with small increases in CSF [Na.sup.+] leading to increases in brain OLC, sympathetic outflow, and blood pressure. benzamil; blood pressure
- Published
- 2003
25. Stimulation of brain [Na.sup.+] channels by FMRFamide in Dahl SS and SR rats
- Author
-
Wang Hao, White, Roselyn, and Leenen, Frans H.H.
- Subjects
Brain -- Research ,Biological sciences - Abstract
Wang, Hao, Roselyn White, and Frans H.H. Leenen. Stimulation of brain [Na.sup.+] channels by FMRFamide in Dahl SS and SR rats. Am J Physiol Heart Circ Physiol 285: H2013-H2018, 2003. First published July 10, 2003; 10.1152/ajpheart.00453.2003.--Stimulation of brain [Na.sup.+] channels by Phe-Met-Arg-Phe-N[H.sup.2] (FMRFamide) increases sympathetic nerve activity and blood pressure (BP) in Wistar rats. Blockade of brain ouabain-like compounds (OLC) by specific antibody Fab fragments prevents these responses to intracerebroventricular FMRFamide. In the present study, we evaluated the effects of high-salt intake on brain FMRFamide levels and the responses of BP and brain OLC to intracerebroventricular infusion of FMRFamide in Dahl salt-sensitive (SS) and salt-resistant (SR) rats. FMRFamide and OLC content was measured with the use of RIA and ELISA, respectively. A high-salt diet (1,370 [micro]mol [Na.sup.+]/g) for 2 wk significantly increased BP in Dahl SS but not in SR rats. On a regular salt diet, Dahl SS and SR rats showed similar FMRFamide levels in the whole hypothalamus, pons and medulla, and spinal cord. A high-salt diet for 2 wk did not affect FMRFamide levels in these tissues in both Dahl SS and SR rats. In Dahl SS but not in SR rats, chronic intracerebroventricular infusion of FMRFamide (200 nmol * [kg.sup.-1] * [day.sup.-1]) for 2 wk significantly increased BP (mean arterial pressure: 116 [+ or -] 5 vs. 100 [+ or -] 2 mmHg; P < 0.01). Chronic intracerebroventricular infusion of FMRFamide significantly increased hypothalamic and pituitary OLC in Dahl SS but not SR rats. These results indicate that Dahl SS rats exhibit enhanced central responses to FMRFamide. In Dahl SS but not in SR rats on a high-salt diet, enhanced [Na.sup.+] entry through FMRFamide-activated brain [Na.sup.+] channels may increase brain OLC release, thereby leading to hypertension. ouabain-like compounds; blood pressure; salt-sensitive and salt-resistant rats
- Published
- 2003
26. Effects of high salt intake on brain A[T.sub.1] receptor densities in Dahl rats
- Author
-
Wang, Jun Ming, Veerasingham, Shereeni J., Tan, Junhui, and Leenen, Frans H.H.
- Subjects
Brain -- Research ,Biological sciences - Abstract
Wang, Jun Ming, Shereeni J. Veerasingham, Junhui Tan, and Frans H.H. Leenen. Effects of high salt intake on brain A[T.sub.1] receptor densities in Dahl rats. Am J Physiol Heart Circ Physiol 285: H1949-H1955, 2003. First published July 3, 2003; 10.1152/ajpheart.00744.2002.--To assess effects of dietary salt on brain A[T.sub.1] receptor densities, 4-wk-old Dahl salt-sensitive (Dahl S) and salt-resistant (Dahl R) rats were fed a regular (101 [micro]mol Na/g) or high (1,370 [micro]mol Na/g)-salt diet for 1, 2, or 4 wk. A[T.sub.1] receptors were assessed by quantitative in vitro autoradiography. A[T.sub.1] receptor densities did not differ significantly between strains on the regular salt diet. The high-salt diet for 1 or 2 wk increased A[T.sub.1] 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 A[T.sub.1] 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 highsalt diet but caused largely similar relative increases in brain A[T.sub.1] receptor densities in Dahl S and R on the high-salt diet versus regular salt diet. These data demonstrate that high salt intake rapidly (within 1 wk) increases A[T.sub.1] receptor densities in specific brain nuclei in Dahl S and later (by 4 wk) also in Dahl R rats. Because the brain renin-angiotensin system only contributes to salt-induced hypertension in Dahl S rats, further studies are needed to determine which of the salt-induced increases in brain A[T.sub.1] receptor densities contribute to the hypertension and which to other aspects of body homeostasis. brain renin-angiotensin system; salt-induced hypertension; angiotensin II; autoradiography
- Published
- 2003
27. Presence of cellular renin-angiotensin system in chromaffin cells of bovine adrenal medulla
- Author
-
Wang, Jun Ming, Slembrouck, Dirk, Tan, Junhui, Arckens, Lut, Leenen, Frans H.H., Courtoy, Pierre J., and De Potter, Werner P.
- Subjects
Immunocytochemistry -- Research ,Renin -- Physiological aspects ,Biological sciences - Abstract
The presence of a local renin-angiotensin system has been established in organs that serve as angiotensin targets. In this study, the expression of angiotensinogen mRNA and subcellular localization of renin, angiotensin-converting enzyme, and angiotensin II were investigated in bovine adrenal medullary cells in primary culture. By light microscopy, expression of angiotensinogen mRNA, immunoreactive renin, angiotensin-converting enzyme, and angiotensin II were readily detectable only in the chromaffin cells. The density distribution of renin and angiotensin II in sucrose gradients suggested a concentration in chromaffin granules, a localization directly confirmed by immunoelectron microscopy. Reverse transcriptase-polymerase chain reaction and sequencing confirmed the expression of angiotensinogen in bovine chromaffin cells and the adrenal medulla. In addition, in vitro autoradiography indicated that both angiotensin-converting enzyme and angiotensin type I receptors were present in the adrenal medulla. These results provide the first direct evidence that chromaffin cells in the adrenal medulla are not only the target for angiotensin but should also be considered as potential local angiotensin-generating and -storing cells. in situ hybridization; immunocytochemistry; radioligand autoradiography; angiotensinogen
- Published
- 2002
28. Relevance of Angiotensin II for Cardiac Hypertrophy and Failure Induced by Cardiac Volume Overload
- Author
-
Ruzicka, Marcel and Leenen, Frans H.H.
- Published
- 1999
- Full Text
- View/download PDF
29. Isoproterenol-induced cardiac hypertrophy: role of circulatory versus cardiac renin-angiotensin system
- Author
-
Leenen, Frans H.H., White, Roselyn, and Yuan, Baoxue
- Subjects
Isoproterenol -- Physiological aspects ,Heart enlargement -- Physiological aspects ,Renin-angiotensin system -- Physiological aspects ,Biological sciences - Abstract
Leenen, Frans H. H., Roselyn White, and Baoxue Yuan. Isoproterenol-induced cardiac hypertrophy: role of circulatory versus cardiac renin-angiotensin system. Am J Physiol Heart Circ Physiol 281: H2410-H2416, 2001.--To assess the possible contribution of the circulatory and cardiac renin-angiotensin system (RAS) to the cardiac hypertrophy induced by a [beta]-agonist, the present study evaluated the effects of isoproterenol, alone or combined with an angiotensin I-converting enzyme inhibitor or A[T.sub.1] receptor blocker, on plasma and LV renin activity, ANG I, and ANG II, as well as left ventricular (LV) and right ventricular (RV) weight. Male Wistar rats received isoproterenol by osmotic minipump subcutaneously and quinapril or losartan once daily by gavage. Plasma and LV ANGs were measured by radioimmunoassay after separation by HPLC. Isoproterenol alone decreased blood pressure, more markedly when combined with losartan or quinapril. Isoproterenol significantly increased LV and RV weight and total collagen. Neither losartan nor quinapril inhibited the increases in LV or RV weight. Losartan prevented the increase in RV collagen but enhanced the increase in LV collagen. Isoproterenol increased plasma renin, ANG I, and ANG II three- to fourfold. Isoproterenol combined with losartan or quinapril, caused marked further increases except for a significant decrease in plasma ANG II with quinapril. Isoproterenol alone did not increase LV ANG II and, combined with losartan or quinapril, actually decreased LV ANG II. These results indicate that isoproterenol-induced cardiac hypertrophy is associated with clear increases in plasma ANG II, but not in LV ANG II. Both losartan and quinapril lower LV ANG II below control levels, but do not prevent the isoproterenol-induced cardiac hypertrophy. These findings do not support a role for the circulatory or cardiac RAS in the cardiac trophic responses to [beta]-receptor stimulation. [beta]-agonist; angiotensin II; heart; angiotensin I-converting enzyeme inhibitor; A[T.sub.1]-receptor blocker Received 27 July 2000; accepted in final form 20 August 2001
- Published
- 2001
30. Changes in the rates of awareness, treatment and control of hypertension in Canada over the past two decades
- Author
-
McAlister, Finlay A., Wilkins, Kathryn, Joffres, Michel, Leenen, Frans H.H., Fodor, George, Gee, Marianne, Tremblay, Mark S., Walker, Robin, Johansen, Helen, and Campbell, Norm
- Published
- 2011
- Full Text
- View/download PDF
31. Effects of CPAP on Blood Pressure and Sympathetic Activity in Patients With Diabetes Mellitus, Chronic Kidney Disease, and Resistant Hypertension
- Author
-
Ruzicka, Marcel, primary, Knoll, Greg, additional, Leenen, Frans H.H., additional, Leech, Judith, additional, Aaron, Shawn D., additional, and Hiremath, Swapnil, additional
- Published
- 2020
- Full Text
- View/download PDF
32. Sodium pumps, ouabain and aldosterone in the brain: A neuromodulatory pathway underlying salt-sensitive hypertension and heart failure
- Author
-
Leenen, Frans H.H., primary, Wang, Hong-Wei, additional, and Hamlyn, John M., additional
- Published
- 2020
- Full Text
- View/download PDF
33. Angiotensin II modulates brain-derived neurotrophic factor expression in the brain and adrenal
- Author
-
Wang, Hong-Wei, primary, Lu, Jiao, additional, Liang, Wenbin, additional, and Leenen, Frans H.H., additional
- Published
- 2020
- Full Text
- View/download PDF
34. Blockade of AT1 receptors and Na+/H+ exchanger and LV dysfunction after myocardial infarction in rats
- Author
-
Ruzicka, Marcel, Yuan, Baoxue, and Leenen, Frans H.H.
- Subjects
Amiloride -- Physiological aspects ,Angiotensin -- Receptors ,Heart attack -- Research ,Heart cells -- Physiological aspects ,Heart ventricle, Left -- Research ,Biological sciences - Abstract
The hypothesis that activation of the Na+/H+ exchanger is involved in parallel with other signaling mechanisms for angiotensin II (ANG II) was evaluated. Left ventricular (LV) function was assessed from in vivo restingcardiac pressures, hemodynamic responses to cardiac volume and pressure load four weeks after coronary artery ligation. The combination of amiloride and losartan attenuated the shift of the pressure volume curve to the right while each drug alone improved LV responses to a minor extent. This showed that other mechanisms activated the Na+/H+ exchanger.
- Published
- 1999
35. Brain renin-angiotensin system and sympathetic hyperactivity in rats after myocardial infarction
- Author
-
Zhang, Weigo, Huang, Bing S., and Leenen, Frans H.H.
- Subjects
Rats -- Physiological aspects ,Nervous system, Sympathetic -- Research ,Congestive heart failure -- Research ,Guanabenz -- Research ,Stress (Physiology) -- Research ,Infarction -- Research ,Renin-angiotensin system -- Research ,Biological sciences - Abstract
Rats that were subjected to left coronary artery ligation are given intracerebroventricular losartan to investigate its effects on rats with congestive heart failure (CHF) postmyocardial infarction. It is found that chronic infusion of intracerebroventricular losartan normalizes the sympathetic hyperactivity and impairment of baroreflex function of the sample rats. Results also suggest that the increase in sympathoexcitation, decrease in sympathoinhibition and desensitization of the baroreflex function in CHF is dependent on the brain renin-angiotensin system.
- Published
- 1999
36. Ouabain- and central sodium-induced hypertension depend on the ventral anteroventral third ventricle region
- Author
-
Veerasingham, Shereeni J. and Leenen, Frans H.H.
- Subjects
Hypertension -- Research ,Heart ventricles -- Research ,Hypertonic solutions -- Physiological aspects ,Injections, Saline -- Physiological aspects ,Biological sciences - Abstract
The dependence of the hypertension stimulated by chronic intracerebroventricular application of ouabain in the ventral anteroventral third ventricle (vAV3V) is analyzed. This is ascertained by performing microinjections of the excitotoxin ibotenic acid to destroy neurons in the vAV3V. The results show that the vAV3V area is vital for hypertension stimulated by chronic intracerebroventricular hypertonic saline and subcutaneous application of ouabain.
- Published
- 1999
37. Changes in cardiac ANG II postmyocardial infarction in rats: effects of nephrectomy and ACE inhibitors
- Author
-
Leenen, Frans H.H., Skarda, Vaclav, Yuan, Baoxue, and White, Roselyn
- Subjects
Angiotensin converting enzyme -- Physiological aspects ,Heart attack -- Physiological aspects ,ACE inhibitors -- Physiological aspects ,Nephrectomy -- Physiological aspects ,Biological sciences - Abstract
The two-stage model described by Johnson and Schoemaker is used in measuring changes in angiotensin II (ANG II) in the left ventricle versus plasma of live rats after acute coronary ligation. The role of renal renin on changes in ANG II after myocardial infarction by bilateral nephrectomy has also been examined. The effects of angiotensin-converting enzyme inhibitors with low enalapril versus high quinapril affinity on early changes in cardiac and plasma ANG II has also been studied. Experimental results indicated a rapid but short-lived increase in cardiac tissue angiotensin II which does not depend on renal renin.
- Published
- 1999
38. Central infusion of aldosterone synthase inhibitor attenuates left ventricular dysfunction and remodelling in rats after myocardial infarction
- Author
-
Huang, Bing S., White, Roselyn A., Ahmad, Monir, Tan, Junhui, Jeng, Arco Y., and Leenen, Frans H.H.
- Published
- 2009
39. Inhibition of brain angiotensin-converting enzyme by peripheral administration of trandolapril versus lisinopril in Wistar rats
- Author
-
Tan, Junhui, Wang, Jun Ming, and Leenen, Frans H.H.
- Published
- 2005
- Full Text
- View/download PDF
40. Prevention of cardiac remodeling after myocardial infarction in transgenic rats deficient in brain angiotensinogen
- Author
-
Lal, Avtar, Veinot, John P., Ganten, Detlev, and Leenen, Frans H.H.
- Published
- 2005
- Full Text
- View/download PDF
41. Pattern of neuronal activation in rats with CHF after myocardial infarction
- Author
-
Vahid-Ansari, Faranak and Leenen, Frans H.H.
- Subjects
Rats -- Physiological aspects ,Hyperkinesia -- Physiological aspects ,Heart attack -- Physiological aspects ,Congestive heart failure -- Physiological aspects ,Biological sciences - Abstract
A study was conducted to analyze neuronal populations that may influence sympathetic hyperactivity in rats with congestive heart failure. Myocardial infarction, immunohistochemical detection of Fra-like immunoreactivity was utilized as a marker for long-term neuronal activation. An affinity-purified rabbit polyclonal antibody was used to detect Fra-like immunoreactivity. Results indicated an activation of neurons by Fra-like immunoreactivity in cardiovascular control centers.
- Published
- 1998
42. Results of the Ontario Survey on the Prevalence and Control of Hypertension
- Author
-
Leenen, Frans H.H., Dumais, Jean, McInnis, Natalie H., Turton, Penelope, Stratychuk, Lori, Nemeth, Kathleen, Moy Lum-Kwong, Margaret, and Fodor, George
- Published
- 2008
- Full Text
- View/download PDF
43. Chronic activation of brain areas by high-sodium diet in Dahl salt-sensitive rats
- Author
-
Budzikowski, Adam S., Vahid-Ansari, Faranak, and Leenen, Frans H.H.
- Subjects
Rats -- Physiological aspects ,Sodium in the body -- Physiological aspects ,Brain -- Physiological aspects ,Biological sciences - Abstract
Immunohistochemical detection of Fra-like proteins as an indicator for long-term neuronal activation was employed to map alterations in neuronal activity in the brains of Dahl salt-sensitive (Dahl S) vs salt-resistant (Dahl R) rats by high-sodium diet. Results showed that Dahl S rats have differential activation of brain areas contributing to the control of osmotic and cardiovascular homeostasis during development of sodium-sensitive hypertension.
- Published
- 1998
44. Brain 'ouabain,' ANG II, and sympathoexcitation by chronic central sodium loading in rats
- Author
-
Huang,bing S., Veerasingham, Shereeni J., and Leenen, Frans H.H.
- Subjects
Hypertension -- Causes of ,Sodium in the body -- Physiological aspects ,Biological sciences - Abstract
Artificial cerebrospinal fluid with high sodium content was infused into the ventricles of conscious rats to investigate if the elevation of central sodium concentration will lead to similar changes in sympathoexcitatory and pressor responses seen in spontaneously hypertensive rats on a high salt diet. Results reveal that increasing the central sodium load enhances sympathoexcitatory and pressor responses among test subjects through a mechanism that is similar to that seen among salt-sensitive rats.
- Published
- 1998
45. ACE inhibitors and cardiac ACE mRNA in volume overload-induced cardiac hypertrophy
- Author
-
Lear, William, Ruzicka, Marcel, and Leenen, Frans H.H.
- Subjects
Quinapril -- Research ,Angiotensin converting enzyme -- Research ,Hypertrophy -- Research ,Biological sciences - Abstract
The angiotensin-converting enzyme (ACE) inhibitors and cardiac ACE messenger RNA in volume overload-induced cardiac hypertrophy were investigated. The study aimed to prove the hypothesis that quinapril's high affinity for cardiac tissue ACE causes an increase in cardiac ACE mRNA in rats. Results revealed that both ACE inhibitors increased ACE mRNA in both heart ventricles. However, the increase was more observable with treatment of quinapril.
- Published
- 1997
46. Blockade of brain 'ouabain' prevents sympathoexcitatory and pressor responses to high sodium in SHR
- Author
-
Huang, Bing S. and Leenen, Frans H.H.
- Subjects
Hypertension -- Physiological aspects ,Rats -- Physiological aspects ,Sodium -- Physiological aspects ,Biological sciences - Abstract
Brain ouabain mediates the sympathoexcitatory and pressor responses to sodium. Central infusion of antibody Fab blocks the effects of ouabain. In a study of spontaneously hypertensive rats, increases in sodium intake were prevented by intracerebroventricular Fab fragments. However, Fab fragments had no effect on blood pressure, heart rate and renal sympathetic nerve activity. These results suggest that ouabain is involved in the development of hypertension.
- Published
- 1996
47. Sympathoexcitatory and pressor responses to increased brain sodium and ouabain are mediated via brain ANG II
- Author
-
Huang, Bing S. and Leenen, Frans H.H.
- Subjects
Nervous system, Sympathetic -- Research ,Angiotensin -- Physiological aspects ,Rats as laboratory animals -- Observations ,Sodium in the body -- Observations ,Biological sciences - Abstract
The increased concentration of sodium and ouabain in the brain leads to sympathoexcitatory and pressor effects in rats, in response to brain angiotensin II (ANG II). With the activation of brain renin-angiotensin system, ANG II is stimulated. The level of sodium concentration rises in the cerebrospinal fluid, increasing the brain ouabainlike activity (OLA). OLA is responsible for sympathoexcitation and the enhancement of mean arterial pressure via the activation of brain ANG II.
- Published
- 1996
48. ALLHAT: What has it taught us so far?
- Author
-
Leenen, Frans H.H.
- Published
- 2004
- Full Text
- View/download PDF
49. Dietary Na+ and cardiopulmonary baroreflex control of renal sympathetic nerve activity in SHR
- Author
-
Huang, Bing S. and Leenen, Frans H.H.
- Subjects
Cardiopulmonary system -- Research ,Sodium -- Physiological aspects ,Nervous system, Sympathetic -- Physiological aspects ,Biological sciences - Abstract
A study of the influence of low, high and regular dietary sodium intake on the regulation of heart rate (HR) and renal sympathetic nerve activity (RSNA) by cardiopulmonary baroreflex in conscious intact spontaneously hypertensive rats (SHR) versus Wistar-Kyoto rats (WKY) and in SHR versus WKY with chronic sinoaortic denervation (SAD) reveals that the cardiopulmonary baroreflex regulation of RSNA is desensitized by high sodium uptake in WKY and SHR, and that this effect is absent for the HR. While a prolonged sensitizing effect on arterial baroreflex control mediates desensitization in WKY, direct action of high sodium uptake leads to desensitization in SHR. SAD enhances the attenuation in SHR and weakens the same in WKY.
- Published
- 1995
50. Dietary sodium and central vs. peripheral ouabain-like activity in Dahl salt-sensitive vs. salt-resistant rats
- Author
-
Leenen, Frans H.H., Harmsen, Eef, and Yu, Huilian
- Subjects
Sodium -- Health aspects ,Nervous system, Sympathetic -- Research ,Biological sciences - Abstract
A comparative study of the influence of the central versus peripheral ouabain-like activity (OLA) on the pressor effects of high-sodium intake in Dahl salt-sensitive (Dahl S) rats and Dahl salt-resistant (Dahl R) rats reveals the involvement of central OLA in the high sodium-induced pressor response in Dahl S rats. Plasma OLA controls renal function to excrete excess the sodium in both groups and maintains the blood pressure in Dahl R rats or enhances the same in Dahl S rats during the intake of higher amounts of sodium.
- Published
- 1994
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