scholarly journals Activation of the (pro)renin receptor in the paraventricular nucleus increases sympathetic outflow in anesthetized rats

2015 ◽  
Vol 309 (5) ◽  
pp. H880-H887 ◽  
Author(s):  
Michael J. Huber ◽  
Rupsa Basu ◽  
Cassie Cecchettini ◽  
Adolfo E. Cuadra ◽  
Qing-Hui Chen ◽  
...  
Keyword(s):  
Paraventricular Nucleus ◽  
Mrna Levels ◽  
Ros Production ◽  
Activator Protein 1 ◽  
Sprague Dawley ◽  
Neurogenic Hypertension ◽  
Napdh Oxidase ◽  
Arterial Blood ◽  
Sd Rats ◽  
Oxide Synthase

Previous studies have indicated that hyperactivity of brain prorenin receptors (PRR) is implicated in neurogenic hypertension. However, the role of brain PRR in regulating arterial blood pressure (ABP) is not well understood. Here, we test the hypothesis that PRR activation in the hypothalamic paraventricular nucleus (PVN) contributes to increased sympathetic nerve activity (SNA). In anaesthetized adult Sprague-Dawley (SD) rats, bilateral PVN microinjection of human prorenin (2 pmol/side) significantly increased splanchnic SNA (SSNA; 71 ± 15%, n = 7). Preinjection of either prorenin handle region peptide, the PRR binding blocker (PRRB), or tiron (2 nmol/side), the scavenger of reactive oxygen species (ROS), significantly attenuated the increase in SSNA (PRRB: 32 ± 5% vs. control, n = 6; tiron: 8 ± 10% vs. control, n = 5; P < 0.05) evoked by prorenin injection. We further investigated the effects of PRR activation on ROS production as well as downstream gene expression using cultured hypothalamus neurons from newborn SD rats. Incubation of brain neurons with human prorenin (100 nM) dramatically enhanced ROS production and induced a time-dependent increase in mRNA levels of inducible nitric oxide synthase (iNOS), NAPDH oxidase 2 subunit cybb, and FOS-like antigen 1 (fosl1), a marker for neuronal activation and a component of transcription factor activator protein-1 (AP-1). The maximum mRNA increase in these genes occurred 6 h following incubation (iNOS: 201-fold; cybb: 2 -fold; Ffosl1: 11-fold). The increases in iNOS and cybb mRNA were not attenuated by the AT1 receptor antagonist losartan but abolished by the AP-1 blocker curcumin. Our results suggest that PVN PRR activation induces sympathoexcitation possibly through stimulation of an ANG II-independent, ROS-AP-1-iNOS signaling pathway.

Abstract P327: Increased Brain iNOS Contributes to Hypertension in Dahl Salt Sensitive Rats

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Michael J Huber ◽  
Fengli Zhu ◽  
Robert A Larson ◽  
Qing-Hui Chen ◽  
Zhiying Shan
Keyword(s):  
Hypertonic Saline ◽  
Neural Mechanism ◽  
Neuronal Cultures ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
Inos Activity ◽  
Arterial Blood ◽  
Sd Rats ◽  
Inos Inhibitor ◽  
Salt Sensitive Hypertension

The hypothalamic paraventricular nucleus (PVN) is one of the key central nuclei to play an important role in regulating arterial blood pressure (ABP) of salt-sensitive hypertension (SSH). However, the detailed molecular mechanism(s) whereby the PVN increases ABP are not well understood. Here, we tested the hypothesis that high salt (HS) loading increases expression of iNOS in the PVN which contributes to SSH. Six-week-old male Dahl salt sensitive (Dahl S) rats and age matched Sprague Dawley (SD) rats were fed either a HS (4% NaCI) or a normal salt (NS, 0.4% NaCl) diet (n=4~7/group). Mean arterial pressure (MAP) was measured via tail cuff method. Five weeks following diet treatment, HS diet induced hypertension in Dahl S rats (HS: 153±9; vs. NS: 122±2 mmHg, P<0.05), but not in SD rats (HS: 107±3; vs. NS: 107±2 mmHg). Rats were then euthanized and PVN tissues were punched out for real time PCR. The HS diet induced dramatic increases in mRNA levels of iNOS (25-fold), and Fra1 (3.6-fold), a chronic neuronal activation marker, in Dahl S rat but not in SD rats. Next, we investigated the effect of intracerebroventricular (ICV) administration of hypertonic saline on PVN iNOS and Fra1 expression in SD rats. Anesthetized adult male SD rats received ICV infusion of isotonic NaCI (0.15 M, 2μl, as control) or hypertonic NaCI (2M, 2μl) (n=7~8/group). Three hours following ICV infusion, rats were euthanized and PVN mRNA levels of iNOS and Fra1 were assayed. ICV hypertonic saline increased mRNA levels of iNOS (9.5-fold) and Fra1 (4.1-fold). We further tested whether these increases in iNOS and Fra1 expression occurred in neurons. Incubation of hypertonic saline (10 mM NaCI) for 3 hours increased iNOS (6-fold) and Fra1 (2.8-fold) mRNA levels in neuronal cultures from the hypothalamus containing the PVN. Finally, we tested whether increased iNOS activity contributes to ABP elevation in Dahl SSH. In anaesthetized Dahl S rats, bilateral PVN microinjection of the iNOS inhibitor, aminoguanidine (250 pmol) significantly decreased MAP in HS treated animals compared to rats with a NS diet (HS: -13±3; vs. NS: -2±2 mmHg, P<0.05) (n=5/group). These observations suggest that HS intake increases iNOS expression in PVN neurons, which may contribute to the central neural mechanism of Dahl SSH.

scholarly journals Systemic hypotensive effects of testosterone are androgen structure-specific and neuronal nitric oxide synthase-dependent

2015 ◽  
Vol 309 (2) ◽  
pp. R189-R195 ◽  
Author(s):  
Mercedes Perusquía ◽  
Clayton D. Greenway ◽  
Lisa M. Perkins ◽  
John N. Stallone
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Neuronal Nitric Oxide Synthase ◽  
Sprague Dawley ◽  
Peripheral Vasculature ◽  
Similar Reduction ◽  
Arterial Blood ◽  
Sd Rats ◽  
Oxide Synthase

Testosterone (TES) and other androgens exert a direct vasorelaxing action on the vasculature in vitro that is structurally specific and independent of cytosolic androgen receptor (AR). The effects of intravenous androgen infusions on mean arterial blood pressure (BP) and heart rate (HR) were determined in conscious, unrestrained, chronically catheterized, ganglionically blocked (hexamethonium, HEX; 30 mg/kg ip) male Sprague-Dawley (SD) and testicular-feminized male (Tfm; AR-deficient) rats, 16–20 wk of age. BP and HR were recorded at baseline and with increasing doses of androgens (0.375–6.00 μmol·kg−1·min−1 iv; 10 min/dose). Data are expressed as means ± SE ( n = 5–8 rats/group). In SD rats, baseline BP and HR averaged 103 ± 4 mmHg and 353 ± 12 beats/min (bpm). TES produced a dose-dependent reduction in BP to a low of 87 ± 4 mmHg (Δ16%), while HR was unchanged (354 ± 14 bpm). Neither BP (109 ± 3 mmHg) nor HR (395 ± 13 bpm) were altered by vehicle (10% EtOH in 0.9% saline; 0.15 ml·kg−1·min−1, iv). In Tfm, TES produced a similar reduction in BP (99 ± 3 to 86 ± 3 mmHg, Δ13%); HR was unchanged (369 ± 18 bpm). In SD, 5β-dihydrotestosterone (genomically inactive metabolite) produced a greater reduction in BP than TES (102 ± 2 to 79 ± 2 mmHg, Δ23%); HR was unchanged (361 ± 9). A 20-μg iv bolus of sodium nitroprusside in both SD and Tfm rats reduced BP 30–40 mmHg, while HR was unchanged, confirming blockade by HEX. Pretreatment of SD rats with neuronal nitric oxide synthase (nNOS) inhibitor (S-methyl-thiocitrulline, SMTC; 20 μg·kg−1·min−1 × 30 min) abolished the hypotensive effects of TES infusion on BP (104 ± 2 vs. 101 ± 2 mmHg) and HR (326 ± 11 vs. 324 ± 8 bpm). These data suggest the systemic hypotensive effect of TES and other androgens involves a direct vasodilatory action on the peripheral vasculature which, like the effect observed in isolated arteries, is structurally specific and AR-independent, and involves activation of nNOS.

scholarly journals Increased activity of the orexin system in the paraventricular nucleus contributes to salt-sensitive hypertension

2017 ◽  
Vol 313 (6) ◽  
pp. H1075-H1086 ◽  
Author(s):  
Michael J. Huber ◽  
Yuanyuan Fan ◽  
Enshe Jiang ◽  
Fengli Zhu ◽  
Robert A. Larson ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Paraventricular Nucleus ◽  
Mrna Levels ◽  
Nacl Solution ◽  
Sprague Dawley ◽  
Orexin A ◽  
Intracerebroventricular Infusion ◽  
Sd Rats ◽  
Salt Sensitive Hypertension ◽  
Increased Activity

The orexin system is involved in arginine vasopressin (AVP) regulation, and its overactivation has been implicated in hypertension. However, its role in salt-sensitive hypertension (SSHTN) is unknown. Here, we tested the hypothesis that hyperactivity of the orexin system in the paraventricular nucleus (PVN) contributes to SSHTN via enhancing AVP signaling. Eight-week-old male Dahl salt-sensitive (Dahl S) and age- and sex-matched Sprague-Dawley (SD) rats were placed on a high-salt (HS; 8% NaCl) or normal-salt (NS; 0.4% NaCl) diet for 4 wk. HS intake did not alter mean arterial pressure (MAP), PVN mRNA levels of orexin receptor 1 (OX1R), or OX2R but slightly increased PVN AVP mRNA expression in SD rats. HS diet induced significant increases in MAP and PVN mRNA levels of OX1R, OX2R, and AVP in Dahl S rats. Intracerebroventricular infusion of orexin A (0.2 nmol) dramatically increased AVP mRNA levels and immunoreactivity in the PVN of SD rats. Incubation of cultured hypothalamus neurons from newborn SD rats with orexin A increased AVP mRNA expression, which was attenuated by OX1R blockade. In addition, increased cerebrospinal fluid Na+ concentration through intracerebroventricular infusion of NaCl solution (4 µmol) increased PVN OX1R and AVP mRNA levels and immunoreactivity in SD rats. Furthermore, bilateral PVN microinjection of the OX1R antagonist SB-408124 resulted in a greater reduction in MAP in HS intake (−16 ± 5 mmHg) compared with NS-fed (−4 ± 4 mmHg) anesthetized Dahl S rats. These results suggest that elevated PVN OX1R activation may contribute to SSHTN by enhancing AVP signaling. NEW & NOTEWORTHY To our best knowledge, this study is the first to investigate the involvement of the orexin system in salt-sensitive hypertension. Our results suggest that the orexin system may contribute to the Dahl model of salt-sensitive hypertension by enhancing vasopressin signaling in the hypothalamic paraventricular nucleus.

scholarly journals Differential Effects of Refeeding on Melanocortin-Responsive Neurons in the Hypothalamic Paraventricular Nucleus

Endocrinology ◽  
2008 ◽  
Vol 149 (9) ◽  
pp. 4329-4335 ◽  
Author(s):  
Edith Sánchez ◽  
Praful S. Singru ◽  
Runa Acharya ◽  
Monica Bodria ◽  
Csaba Fekete ◽  
...  
Keyword(s):  
Gene Expression ◽  
Paraventricular Nucleus ◽  
Hypothalamic Paraventricular Nucleus ◽  
Mrna Levels ◽  
Sprague Dawley ◽  
Early Action ◽  
Sprague Dawley Rats ◽  
Melanocortin Signaling ◽  
Agouti Related Protein ◽  
Serum Tsh

To explore the effect of refeeding on recovery of TRH gene expression in the hypothalamic paraventricular nucleus (PVN) and its correlation with the feeding-related neuropeptides in the arcuate nucleus (ARC), c-fos immunoreactivity (IR) in the PVN and ARC 2 h after refeeding and hypothalamic TRH, neuropeptide Y (NPY) and agouti-related protein (AGRP) mRNA levels 4, 12, and 24 h after refeeding were studied in Sprague-Dawley rats subjected to prolonged fasting. Despite rapid reactivation of proopiomelanocortin neurons by refeeding as demonstrated by c-fos IR in ARC α-MSH-IR neurons and ventral parvocellular subdivision PVN neurons, c-fos IR was present in only 9.7 ± 1.1% hypophysiotropic TRH neurons. Serum TSH levels remained suppressed 4 and 12 h after the start of refeeding, returning to fed levels after 24 h. Fasting reduced TRH mRNA compared with fed animals, and similar to TSH, remained suppressed at 4 and 12 h after refeeding, returning toward normal at 24 h. AGRP and NPY gene expression in the ARC were markedly elevated in fasting rats, AGRP mRNA returning to baseline levels 12 h after refeeding and NPY mRNA remaining persistently elevated even at 24 h. These data raise the possibility that refeeding-induced activation of melanocortin signaling exerts differential actions on its target neurons in the PVN, an early action directed at neurons that may be involved in satiety, and a later action on hypophysiotropic TRH neurons involved in energy expenditure, potentially mediated by sustained elevations in AGRP and NPY. This response may be an important homeostatic mechanism to allow replenishment of depleted energy stores associated with fasting.

Differential sympathetic nerve responses to nitric oxide synthase inhibition in anesthetized rats

1995 ◽  
Vol 269 (4) ◽  
pp. R807-R813 ◽  
Author(s):  
T. Hirai ◽  
T. I. Musch ◽  
D. A. Morgan ◽  
K. C. Kregel ◽  
D. E. Claassen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Sympathetic Nerve ◽  
Sprague Dawley ◽  
Arterial Blood ◽  
Sprague Dawley Rats ◽  
Before And After ◽  
Important Means ◽  
Nos Inhibitor ◽  
Oxide Synthase ◽  
Tonic Excitation

Recent studies have suggested that the interaction between the sympathetic nervous system and nitric oxide (NO) or nitrosyl factors may be an important means by which arterial blood pressure is regulated. We investigated whether NO synthase (NOS) inhibition modulates basal sympathetic nerve discharge (SND) in baroreceptor-innervated and -denervated, chloralose-anesthetized Sprague-Dawley rats. We recorded mean arterial pressure (MAP), renal SND, and lumbar SND before and after administration of the NOS inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 20 mg/kg iv). Two minutes after L-NAME administration in baroreceptor-innervated rats, MAP increased (+23 +/- 3 mmHg), whereas renal (-45 +/- 6%, n = 7) and lumbar (-35 +/- 2%, n = 6) SND significantly decreased from control levels. These changes persisted for up to 20 min after L-NAME administration. In baroreceptor-denervated rats, L-NAME increased MAP (+40 +/- 6 mmHg) and decreased lumbar SND (n = 7) (-37 +/- 10% from control at 20 min post-L-NAME). In contrast, renal SND progressively increased (+33 +/- 8% at 20 min post-L-NAME) from control after L-NAME administration in baroreceptor-denervated rats (n = 7). These results demonstrate that NOS inhibition can produce nonuniform changes in SND in baroreceptor-denervated rats and suggest that endogenous nitrosyl factors provide tonic excitation to lumbar SND, whereas they provide a tonic restraint to renal SND.

scholarly journals Reno-Protective Effect of GLP-1 Receptor Agonists in Type1 Diabetes: Dual Action on TRPC6 and NADPH Oxidases

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1360
Author(s):  
Natalie Youssef ◽  
Mohamed Noureldein ◽  
Rachel Njeim ◽  
Hilda E. Ghadieh ◽  
Frederic Harb ◽  
...  
Keyword(s):  
Protective Effect ◽  
Diabetic Complication ◽  
Trpc Channels ◽  
Mrna Levels ◽  
Ros Production ◽  
Sprague Dawley ◽  
Nadph Oxidases ◽  
Type1 Diabetes ◽  
Sprague Dawley Rats ◽  
Dual Action

Diabetic kidney disease (DKD), a serious diabetic complication, results in podocyte loss and proteinuria through NADPH oxidases (NOX)-mediated ROS production. DUOX1 and 2 are NOX enzymes that require calcium for their activation which enters renal cells through the pivotal TRPC channels. Hypoglycemic drugs such as liraglutide can interfere with this deleterious mechanism imparting reno-protection. Herein, we aim to investigate the reno-protective effect of GLP1 receptor agonist (GLP1-RA), via its effect on TRPC6 and NADPH oxidases. To achieve our aim, control or STZ-induced T1DM Sprague–Dawley rats were used. Rats were treated with liraglutide, metformin, or their combination. Functional, histological, and molecular parameters of the kidneys were assessed. Our results show that treatment with liraglutide, metformin or their combination ameliorates DKD by rectifying renal function tests and protecting against fibrosis paralleled by restored mRNA levels of nephrin, DUOX1 and 2, and reduced ROS production. Treatment with liraglutide reduces TRPC6 expression, while metformin treatment shows no effect. Furthermore, TRPC6 was found to be directly interacting with nephrin, and indirectly interacting with DUOX1, DUOX2 and GLP1-R. Our findings suggest that treatment with liraglutide may prevent the progression of diabetic nephropathy by modulating the crosstalk between TRPC6 and NADPH oxidases.

scholarly journals Glutamate receptors in the hypothalamic paraventricular nucleus contribute to insulin-induced sympathoexcitation

2015 ◽  
Vol 113 (5) ◽  
pp. 1302-1309 ◽  
Author(s):  
Sean D. Stocker ◽  
Kathryn W. Gordon
Keyword(s):  
Paraventricular Nucleus ◽  
Excitatory Amino Acid ◽  
Isotonic Saline ◽  
Nmda Antagonist ◽  
Receptor Activation ◽  
Hypothalamic Paraventricular Nucleus ◽  
Sprague Dawley ◽  
Arterial Blood ◽  
Drug Treatments ◽  
Change In Mean

The sympathoexcitatory response to insulin is mediated by neurons in the arcuate nucleus (ARC) and hypothalamic paraventricular nucleus (PVH). Previous studies have reported that stimulation of ARC neurons increases sympathetic nerve activity (SNA) and arterial blood pressure (ABP) through glutamate receptor activation in the PVH. Therefore, the purpose of the present study was to determine whether glutamatergic neurotransmission in the PVH contributes to insulin-induced sympathoexcitation. Male Sprague-Dawley rats (275–400 g) were infused with isotonic saline or insulin (3.75 mU·kg−1·min−1) plus 50% dextrose to maintain euglycemia. Intravenous infusion of insulin significantly increased lumbar SNA without a significant change in mean ABP, renal SNA, heart rate, or blood glucose. Bilateral PVH injection of the excitatory amino acid antagonist kynurenic acid (KYN) lowered lumbar SNA and ABP of animals infused with insulin. Similarly, a cocktail of the NMDA antagonist dl-2-amino-5-phosphonopentanoic acid (AP5) and non-NMDA antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) reduced lumbar SNA and mean ABP during infusion of insulin. In a final experiment, bilateral PVH injection of AP5 only, but not CNQX, lowered lumbar SNA and mean ABP of animals infused with insulin. The peak changes in lumbar SNA and mean ABP of insulin-treated animals were not different between KYN, AP5 plus CNQX, or AP5 alone. These drug treatments did not alter any variable in animals infused with saline. Altogether, these findings suggest that glutamatergic NMDA neurotransmission in the PVH contributes to insulin-induced sympathoexcitation.

scholarly journals Role of central AT1 and V1 receptors in cardiovascular adaptation to hemorrhage in SD and renin TGR rats

1999 ◽  
Vol 276 (6) ◽  
pp. H1918-H1926 ◽  
Author(s):  
Piotr Paczwa ◽  
Ewa Szczepańska-Sadowska ◽  
Slawomir Łoń, Ursula Ganten ◽  
Detlev Ganten
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Cardiovascular Effects ◽  
Sprague Dawley ◽  
Arterial Blood ◽  
Sd Rats ◽  
Vasopressin Receptors ◽  
In Series ◽  
Regulation Of Blood Pressure

In acute experiments, intracranially applied angiotensin II and vasopressin elicit significant cardiovascular effects. The purpose of the present study was to find out whether chronic intrabrain elevation of these peptides, occurring in the renin transgenic TGR(mRen2)27 (TGR) rats, results in an alteration of the cardiovascular control. Mean arterial blood pressure (MAP) and heart rate responses to hypovolemia were examined in hypertensive TGR and normotensive Sprague-Dawley (SD) rats under control conditions and during blockade of central AT1 or V1 receptors. Both groups received cerebroventricular infusions of either 1) cerebrospinal fluid ( series 1), 2) AT1 receptors antagonist (AT1ANT, series 2), or 3) V1 receptors antagonist (V1ANT, series 3). Blockade of AT1 and V1 receptors decreased MAP in TGR but not in SD rats. In SD rats, bleeding elicited a similar decrease of MAP in each series and a transient increase of heart rate in series 3. In TGR, hemorrhage caused bradycardia and decrease of MAP, which was greater than in SD rats. Hemorrhagic hypotension in TGR was abolished by V1ANT and bradycardia by V1ANT or AT1ANT. The results demonstrate remarkable differences in cardiovascular adjustment to hemorrhage in SD and TGR rats and provide evidence for enhanced involvement of central V1 and AT1 receptors in the regulation of blood pressure during hypovolemia in TGR. Central V1 vasopressin receptors play a crucial role in eliciting posthemorrhagic hypotension and bradycardia in this strain.

scholarly journals The NOS Inhibitor, 7-Nitroindazole, Decreases Focal Infarct Volume but Not the Response to Topical Acetylcholine in Pial Vessels

1994 ◽  
Vol 14 (6) ◽  
pp. 924-929 ◽  
Author(s):  
Tazuka Yoshida ◽  
Volker Limmroth ◽  
Katsumi Irikura ◽  
Michael A. Moskowitz
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Infarct Volume ◽  
Ischemic Injury ◽  
Sprague Dawley ◽  
Arterial Blood ◽  
Mca Occlusion ◽  
Permanent Occlusion ◽  
Nos Inhibitor ◽  
Oxide Synthase

We examined whether 7-nitroindazole (7-NI), a putative inhibitor of neuronal nitric oxide synthase (nNOS), decreases cerebral infarction 24 h after proximal middle cerebral artery (MCA) occlusion. In preliminary experiments, we determined that 7-NI (25, 50, and 100 mg/kg i.p.) decreased nitric oxide synthase (NOS) activity within cerebral cortex by 40–60% when measured up to 120 min, but not 240 min after administration. At 25 or 50 mg/kg, 7-NI did not alter the systemic arterial blood pressure or the dilation of pial arterioles after topical acetylcholine (10 and 100 μ M). To examine the effect of 7-NI on infarct size, 55 Sprague–Dawley halothaneanesthetized rats were subjected to proximal MCA occlusion (modified Tamura method). Five minutes after occlusion, 7-NI (25 or 50 mg/kg i.p.) or vehicle was injected. Animals treated with 25 or 50 mg/kg showed 25 and 27% reductions in infarct volume, respectively. Coadministration of l-arginine (300 mg/kg i.p.) plus 7-NI (25 mg/kg i.p.) reversed the effect. If, indeed, the effects of 7-NI are mediated by inhibition of nNOS activity, these results suggest that enzymatic products of the neuronal isoform promote ischemic injury and that they do so at least within the first few hours after permanent occlusion. The results also emphasize the importance of developing strategies to selectively inhibit the neuronal isoform inasmuch as we observed previously that administering the less selective NOS inhibitor, Nω-nitro-l-arginine (L-NA), in the same model either caused no change or increased the volume of ischemic injury.

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