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1.  Angiotensin II-Superoxide Signaling and Arterial Baroreceptor Function in Type-1 Diabetes Mellitus 
Journal of diabetes & metabolism  2013;Suppl 12:1-6.
Diabetes is a major world health problem. Growing evidence from both clinical trials and animal experiments has clearly confirmed that arterial baroreflex dysfunction is a feature of type 1 diabetes, which links to prognosis and mortality of the type 1 diabetic patients. The arterial baroreflex normally regulates the blood pressure and heart rate through sensing changes of arterial vascular tension by the arterial baroreceptors in the aortic arch and carotid sinus. The aortic baroreceptor neuron located in the nodose ganglia is a primary afferent component of the arterial baroreflex. The functional changes of these neurons are involved in the arterial baroreflex dysfunction in the type 1 diabetes. Type 1 diabetes causes the overexpression and hyperactivation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels and further reduces cell excitability of the aortic baroreceptor neurons. The alterations of the HCN channels are regulated by angiotensin II-NADPH oxidase-superoxide signaling in the aortic baroreceptor neurons. From the present review, we can understand the possible mechanisms responsible for the attenuated arterial baroreflex in the type 1 diabetes. These findings are beneficial for improving quality of life and prognosis in patients with the type 1 diabetes mellitus.
doi:10.4172/2155-6156.S12-001
PMCID: PMC3932051  PMID: 24567847
Baroreflex; Baroreceptor; Ion channels; Angiotensin II; Superoxide; Diabetes
2.  The Brain Renin-Angiotensin System and Mitochondrial Function: Influence on Blood Pressure and Baroreflex in Transgenic Rat Strains 
Mitochondrial dysfunction is implicated in many cardiovascular diseases, including hypertension, and may be associated with an overactive renin-angiotensin system (RAS). Angiotensin (Ang) II, a potent vasoconstrictor hormone of the RAS, also impairs baroreflex and mitochondrial function. Most deleterious cardiovascular actions of Ang II are thought to be mediated by NADPH-oxidase- (NOX-) derived reactive oxygen species (ROS) that may also stimulate mitochondrial oxidant release and alter redox-sensitive signaling pathways in the brain. Within the RAS, the actions of Ang II are counterbalanced by Ang-(1–7), a vasodilatory peptide known to mitigate against increased oxidant stress. A balance between Ang II and Ang-(1–7) within the brain dorsal medulla contributes to maintenance of normal blood pressure and proper functioning of the arterial baroreceptor reflex for control of heart rate. We propose that Ang-(1–7) may negatively regulate the redox signaling pathways activated by Ang II to maintain normal blood pressure, baroreflex, and mitochondrial function through attenuating ROS (NOX-generated and/or mitochondrial).
doi:10.1155/2013/136028
PMCID: PMC3564433  PMID: 23401750
3.  CENTRAL ANGIOTENSIN-(1-7) IMPROVES VAGAL FUNCTION INDEPENDENT OF BLOOD PRESSURE IN HYPERTENSIVE (MREN2)27 RATS 
Hypertension  2012;60(5):1257-1265.
Hypertensive transgenic (mRen2)27 rats with overexpression of the mRen2 gene have impaired baroreflex sensitivity (BRS) for heart rate control and high NADPH oxidase and kinase-to-phosphatase signaling activity in medullary tissue compared to normotensive Hannover Sprague-Dawley control rats. They also exhibit insulin resistance at a young age. To determine whether blocking angiotensin (Ang) II actions, supplementing Ang-(1-7) or scavenging reactive oxygen species (ROS) in brain differentially alters mean arterial pressure (MAP), BRS or metabolic function, while altering medullary signaling pathways in these animals, we compared intracerebroventricular (ICV) infusions of the AT1 receptor antagonist candesartan (CAN; 4μg/5μL/hr), Ang-(1-7) [0.1μg/5μL/hr], a ROS scavenger tempol (25μg/5μL/hr) or artificial cerebrospinal fluid (aCSF; 5 μL/hr) for 2 weeks. MAP was reduced in CAN treated rats without significantly improving the vagal components of baroreflex function or heart rate variability. In contrast, Ang-(1-7) treatment significantly improved the vagal components of baroreflex function and heart rate variability at a dose that did not significantly lower MAP. Tempol significantly reduced NADPH oxidase activity in brain dorsal medullary tissue, but had no effect on MAP or autonomic function. CAN tended to reduce fat mass, but none of the treatments significantly altered indices of metabolic function or mitogen-activated protein kinase (MAPK) signaling pathways in dorsal medulla. While additional dose response studies are necessary to determine the potential maximal effectiveness of each treatment, the current findings demonstrate that blood pressure and baroreflex function can be essentially normalized independently of medullary NADPH oxidase or MAPK in hypertensive (mRen2)27 rats.
doi:10.1161/HYPERTENSIONAHA.112.196782
PMCID: PMC3491885  PMID: 23045456
Hypertension; baroreflex function; angiotensin peptides; oxidative stress; brain
4.  Coronary Constriction to Angiotensin II Is Enhanced by Endothelial Superoxide Production in Sheep Programmed by Dexamethasone 
Pediatric research  2008;63(4):370-374.
Early gestation dexamethasone (dex) administration is an ovine model of fetal programming associated with increased coronary reactivity to angiotensin II (Ang II). NADPH oxidase-dependent superoxide production plays an important role in both Ang II signaling and coronary disease. We sought to determine whether early gestation dex-exposure increases coronary reactivity to Ang II by enhancing endothelial NADPH oxidase-dependent superoxide production. Dex (0.28 mg/kg/d for 48 h) was administered to pregnant ewes at 27–28 d gestation. Dex-exposed and control offspring were studied at 4 mo of age. Coronary superoxide production was measured by lucigenin-enhanced chemiluminescence and dihydroethidium fluorescence. Coronary arteries from dex-exposed sheep had significantly enhanced vasoconstriction to Ang II, an effect abolished by either endothelial removal or preincubation with membrane-permeable superoxide dismutase and catalase. Ang II significantly increased endothelial superoxide production and NADPH oxidase activity in coronaries from dex-exposed offspring, but not controls. This programmed alteration in superoxide production was accentuated by PD123319 (AT2 antagonist), but abolished by losartan (AT1 antagonist). In conclusion, early gestation dex-exposure programs coronary reactivity to Ang II by enhancing Ang II-stimulated endothelial superoxide production. This programming effect may predispose to progressive coronary endothelial dysfunction and coronary artery disease.
doi:10.1203/PDR.0b013e3181659bfa
PMCID: PMC3663587  PMID: 18356741
5.  Exercise Training Prevents Arterial Baroreflex Dysfunction in Rats Treated With Central Angiotensin II 
Hypertension  2007;49(3):519-527.
Angiotensin II (Ang II)–induced arterial baroreflex dysfunction is associated with superoxide generation in the brain. Exercise training (EX) improves baroreflex function and decreases oxidative stress in cardiovascular diseases linked to elevated central Ang II. The aim of this study was to determine whether previous EX prevents baroreflex impairment caused by central administration of exogenous Ang II via an Ang II–superoxide mechanism. Four groups of rats were used: non-EX artificial cerebrospinal fluid infused, non-EX Ang II infused, EX artificial cerebrospinal fluid infused, and EX Ang II infused. Rats were treadmill trained for 3 to 4 weeks and subjected to intracerebroventricular infusion of Ang II over the last 3 days of EX. Twenty-four hours after the end of EX, the arterial baroreflex was assessed in anesthetized rats. Compared with non-EX artificial cerebrospinal fluid–infused rats, Ang II significantly decreased baroreflex sensitivity (maximum gain: 3.0 ± 0.2% of maximum per millimeter of mercury versus 1.6 ± 0.1% of maximum per millimeter of mercury; P < 0.01), which was abolished by acute intracerebroventricular infusion of the Ang II type 1 receptor antagonist losartan and the reduced nicotinamide-adenine dinucleotide phosphate oxidase inhibitor apocynin. EX prevented the decrease in baroreflex sensitivity and downregulated Ang II type 1 receptor and NADPH oxidase subunit protein expression in the paraventricular nucleus of Ang II–infused rats. Finally, EX decreased superoxide production in the paraventricular nucleus of Ang II–infused rats. These results indicate that EX improves arterial baroreflex function in conditions of high brain Ang II, which is mediated by the central Ang II type 1 receptor and associated with a reduction in central oxidative stress.
doi:10.1161/01.HYP.0000256955.74461.93
PMCID: PMC1904508  PMID: 17224469
exercise; baroreflex; sympathetic nerve activity; reactive oxygen species; AT1 receptor
6.  Additive Role of the Vestibular End Organ and Baroreceptors on the Regulation of Blood Pressure in Rats 
Contribution of the vestibular end organ to regulation of arterial pressure was quantitatively compared with the role of baroreceptors in terms of baroreflex sensitivity and c-Fos protein expression in the rostral ventrolateral medulla (RVLM). Baroreflex sensitivity and c-Fos protein expression in the RVLM were measured in conscious rats that had undergone bilateral labyrinthectomy (BL) and/or baroreceptor unloading. BL attenuated baroreflex sensitivity during intravenous infusion of sodium nitroprusside (SNP), but did not significantly affect the sensitivity following infusion of phenylephrine (PE). Baroreflex sensitivity became positive following sinoaortic denervation (SAD) during infusion of PE and attenuated sensitivity during infusion of SNP. Baroreflex sensitivity also became positive following double ablation (BL+SAD) during infusion of PE, and attenuated sensitivity during infusion of SNP. c-Fos protein expression increased significantly in the RVLM in the sham group after SNP administration. However, the BL, SAD, and SAD+BL groups showed significant decreases in c-Fos protein expression compared with that in the sham group. The SAD group showed more reduced c-Fos protein expression than that in the BL group, and the SAD+BL group showed less expression than that in the SAD group. These results suggest that the vestibular system cooperates with baroreceptors to maintain arterial pressure during hypotension but that baroreceptors regulate arterial pressure during both hypotension and hypertension. Additionally, afferent signals for maintaining blood pressure from the vestibular end organs and the baroreceptors may be integrated in the RVLM.
doi:10.4196/kjpp.2013.17.4.367
PMCID: PMC3741494  PMID: 23946697
Baroreceptor; Blood pressure; c-Fos protein; Rostral ventrolateral medulla; Vestibular system
7.  Reduced expression and activation of voltage-gated sodium channels contributes to blunted baroreflex sensitivity in heart failure rats 
Journal of neuroscience research  2010;88(15):3337-3349.
Voltage-gated sodium (Nav) channels are responsible for initiation and propagation of action potential in the neurons. To explore the mechanisms for chronic heart failure (CHF)-induced baroreflex dysfunction, we measured the expression and current density of Nav channel subunits (Nav1.7, Nav1.8, and Nav1.9) in the aortic baroreceptor neurons and investigated the role of Nav channels on aortic baroreceptor neuron excitability and baroreflex sensitivity in sham and CHF rats. CHF was induced by left coronary artery ligation. The development of CHF (6–8 weeks after the coronary ligation) was confirmed by hemodynamic and morphological characteristics. Immunofluorescent data indicated that Nav1.7 was expressed in A-type (myelinated) and C-type (unmyelinated) nodose neurons but Nav1.8 and Nav1.9 were expressed only in C-type nodose neurons. Real-time RT-PCR and western blot data showed that CHF reduced mRNA and protein expression levels of Nav channels in nodose neurons. In addition, using the whole cell patch-clamp technique, we found that Nav current density and cell excitability of the aortic baroreceptor neurons were lower in CHF rats than that in sham rats. Aortic baroreflex sensitivity was blunted in anesthetized CHF rats, compared with that in sham rats. Furthermore, Nav channel activator (rATX II, 100 nM) significantly enhanced Nav current density and cell excitability of aortic baroreceptor neurons and improved aortic baroreflex sensitivity in CHF rats. These results suggest that reduced expression and activation of the Nav channels is involved in the attenuation of baroreceptor neuron excitability, which subsequently contributes to the impairment of baroreflex in CHF state.
doi:10.1002/jnr.22483
PMCID: PMC2953570  PMID: 20857502
Aortic baroreceptor neuron; Baroreflex; Heart failure; Sodium channel
8.  The Ion Channel ASIC2 is Required for Baroreceptor and Autonomic Control of the Circulation 
Neuron  2009;64(6):885-897.
SUMMARY
Arterial baroreceptors provide a neural sensory input that reflexly regulates the autonomic drive of the circulation. Our goal was to test the hypothesis that a member of the acid sensing ion channel (ASIC) subfamily of the DEG/ENaC superfamily is an important determinant of the arterial baroreceptor reflex. We found that aortic baroreceptor neurons in the nodose ganglia and their terminals express ASIC2. Conscious ASIC2 null mice developed hypertension, had exaggerated sympathetic and depressed parasympathetic control of the circulation, and a decreased gain of the baroreflex, all indicative of an impaired baroreceptor reflex. Multiple measures of baroreceptor activity each suggests that mechanosensitivity is diminished in ASIC2- null mice. The results define ASIC2 as an important determinant of autonomic circulatory control and of baroreceptor sensitivity. The genetic disruption of ASIC2 recapitulates the pathological dysautonomia seen in heart failure and hypertension and defines a molecular defect that may be relevant to its development.
doi:10.1016/j.neuron.2009.11.007
PMCID: PMC2807410  PMID: 20064394
9.  Shift to an Involvement of PI3-Kinase in Angiotensin II Actions on Nucleus Tractus Solitarii Neurons of the Spontaneously Hypertensive Rat 
Circulation research  2009;105(12):1248-1255.
Rationale
Central Ang II inhibits baroreflex and plays an important role in the pathogenesis of hypertension. However, the underlying molecular mechanisms are still not fully understood.
Objective
Our objective in the present study was to characterize the signal transduction mechanism of PI3-kinase involvement in Ang II-induced stimulation of central neuronal activity in cultured neurons and Ang II-induced inhibition of baroreflex in SHR versus WKY rats.
Methods and Results
Application of Ang II to neurons produced a 42% greater increase in neuronal firing in cells from the SHR than the WKY rat. Whilst in the WKY the Ang II-mediated increase in firing rate was abolished entirely by the PKC inhibitor GF109230, it was necessary to block both PKC and PI3K activity in the SHR. This was associated with an increased ability of Ang II to stimulate NADPH-oxidase-ROS mediated signaling involving phosphorylation of the p47phox subunit of the NADPH oxidase and was dependent on the activation of PI3 Kinase in the SHR. Inhibition of PI3 Kinase resulted in the reduction of levels of p47phox phosphorylation, NADPH oxidase activity, ROS levels and ultimately neuronal activity in cells from the SHR but not the WKY rat. In addition, in working heart-brainstem preparations, inhibition of PKC activity in the NTS in situ abolished the Ang II-mediated depression of cardiac and sympathetic baroreceptor reflex gain in the WKY. In contrast, PKC inhibition in the NTS of SHR only partially reduced the effect of Ang II on the baroreceptor reflex gain.
Conclusions
These observations demonstrate that PI3-Kinase in the cardiovascular brainstem regions of the SHR may be selectively involved in Ang II-mediated signaling that includes a reduction in baroreceptor reflex function, presumably via a NADPH-ROS mediated pathway.
doi:10.1161/CIRCRESAHA.109.208926
PMCID: PMC2810537  PMID: 19850939
Hypertension; angiotensin II; PI3 kinase; reactive oxygen species; NADPH oxidase
10.  Human Investigations into the Arterial and Cardiopulmonary Baroreflexes during Exercise 
Experimental Physiology  2011;97(1):39-50.
After considerable debate and key experimental evidence, the importance of the arterial baroreflex in contributing to and maintaining the appropriate neural cardiovascular adjustments to exercise is now well accepted. Indeed, the arterial baroreflex resets during exercise in an intensity-dependent manner to continue to regulate blood pressure as effectively as at rest. Studies have indicated that the exercise resetting of the arterial baroreflex is mediated by both the feed-forward mechanism of central command and the feed-back mechanism associated with skeletal muscle afferents (the exercise pressor reflex). Another perhaps less appreciated neural mechanism involved in evoking and maintaining neural cardiovascular responses to exercise is the cardiopulmonary baroreflex. The limited information available regarding the cardiopulmonary baroreflex during exercise provides evidence for a role in mediating sympathetic nerve activity and blood pressure responses. In addition, recent investigations have demonstrated an interaction between cardiopulmonary baroreceptors and the arterial baroreflex during dynamic exercise, which contributes to the magnitude of exercise-induced increases in blood pressure as well as the resetting of the arterial baroreflex. Furthermore, neural inputs from the cardiopulmonary baroreceptors appear to play an important role in establishing the operating point of the arterial baroreflex. This symposium review will highlight recent studies in these important areas indicating that the interactions of four neural mechanisms (central command, the exercise pressor reflex, the arterial baroreflex and cardiopulmonary baroreflex) are integral in mediating the neural cardiovascular adjustments to exercise.
doi:10.1113/expphysiol.2011.057554
PMCID: PMC3253263  PMID: 22002871
arterial blood pressure; baroreceptors; central blood volume; baroreflex resetting; muscle sympathetic nerve activity
11.  CENTRAL ANG-(1–7) ENHANCES BAROREFLEX GAIN IN CONSCIOUS RABBITS WITH HEART FAILURE 
Hypertension  2011;58(4):627-634.
In chronic heart failure (CHF), arterial baroreflex function is impaired, in part, by activation of the central renin-angiotensin system. A metabolite of Angiotensin II (Ang II), Ang-(1–7), has been shown to exhibit cardiovascular effects that are in opposition to that of Ang II. However, the action of Ang-(1–7) on sympathetic outflow and baroreflex function is not well understood, especially in CHF. The aim of this study was to determine the effect of intracerebroventricular infusion of Ang-(1–7) on baroreflex control of heart rate (HR) and renal sympathetic nerve activity (RSNA) in conscious rabbits with CHF. We hypothesized that central Ang-(1–7) would improve baroreflex function in CHF. Ang-(1–7) (2 nmol/1 μl/hour) or artificial cerebrospinal fluid (1 μl/hour) was infused by an osmotic mini-pump for 4 days in sham and pacing-induced CHF rabbits (n=3–6/group). Ang-(1–7) treatment had no effects in sham rabbits but reduced HR and increased baroreflex gain (7.4±1.5 bpm/mm Hg vs. 2.5±0.4 bpm/mm Hg, P<0.05) in CHF rabbits. The Ang-(1–7) antagonist A779 (8 nmol/1 μl/hr) blocked the improvement in baroreflex gain in CHF. Baroreflex gain increased in CHF+Ang-(1–7) animals when only the vagus was allowed to modulate baroreflex control by acute treatment with the β-1 antagonist metoprolol, indicating increased vagal tone. Baseline RSNA was significantly lower and baroreflex control of RSNA was enhanced in CHF rabbits receiving Ang-(1–7). These data suggest that augmentation of central Ang-(1–7) inhibits sympathetic outflow and increases vagal outflow in CHF thus contributing to enhanced baroreflex gain in this disease state.
doi:10.1161/HYPERTENSIONAHA.111.177600
PMCID: PMC3187859  PMID: 21844487
angiotensin-(1–7); heart failure; sympathetic nervous system; baroreflex; vagus nerve; blood pressure; heart rate
12.  Angiotensin Signaling in Cardio-Renal Disease 
Current opinion in pharmacology  2011;11(2):131-137.
Aging, hypertension and fetal programmed cardiovascular disease are associated with a functional deficiency of angiotensin (Ang)-(1–7) in the brain dorsomedial medulla. The resulting unrestrained activity of Ang II in brainstem regions negatively impacts resting mean arterial pressure, sympathovagal balance and baroreflex sensitivity for control of heart rate. The differential effects of Ang II and Ang-(1–7) may be related to the cellular sources of these peptides as well as different precursor pathways. Long-term alterations of the brain renin-angiotensin system may influence signaling pathways including phosphoinositol-3-kinase and mitogen-activated protein kinase and their downstream mediators, and as a consequence may influence metabolic function. Differential regulation of signaling pathways in aging and hypertension by Ang II versus Ang-(1–7) may contribute to the autonomic dysfunction accompanying these states.
doi:10.1016/j.coph.2011.02.001
PMCID: PMC3120135  PMID: 21367658
13.  Protective effect of the daming capsule on impaired baroreflexes in STZ-induced diabetic rats with hyperlipoidemia 
Background
The Daming capsule (DMC) is a traditional Chinese medicine used to treat hyperlipoidemia. Both clinic trials and studies on animal models have demonstrated that DMC is beneficial against diabetic symptoms. Impairment of the baroreflex can cause life-threatening arrhythmias and sudden cardiac death in patients with diabetes mellitus (DM). This study was designed to elucidate the effects of DMC on baroreflexes in streptozocin (STZ)-induced diabetic rats with hyperlipoidemia.
Methods
Wistar rats were randomly divided into three groups: untreated controls, rats pretreated STZ and high lipids (a diabetes model or DM rats), and DM rats treated with DMC. The baroreflex sensitivity was examined during intravenous injection of phenylephrine (PE) or sodium nitroprusside (SNP) and quantified by the change in heart rate over the change in mean arterial blood pressure (ΔHR/ΔMABP). Morphological remodeling of baroreceptors was analyzed by transmission electron microscopy (TEM). The mRNA levels and expression of GluR2 and a GABAA receptor subunit were measured by quantitative RT-PCR and Western blotting.
Results
Compared to untreated DM rats, DMC significantly elevated the ratio of ΔHR/ΔMABP by enhancing the compensatory reduction in HR (-ΔHR) in response to PE-induced hypertension (+ΔMABP) (P < 0.05). In the presence of SNP, DMC increased the ΔMABP (P < 0.05). In addition, DMC markedly shortened the duration of blood pressure changes elicited by PE or SNP in DM rats compared to the untreated DM group (P < 0.05). Electron microscopy revealed disrupted myelin sheaths, swollen ER, and lysed mitochondria in the nucleus ambiguous (NAm) DM rats. These signs of neuropathology were largely prevented by treatment with DMC for 30 days. Treatment with DMC elevated both mRNA and protein level of GluR2 in the NAm of DM rats, but had no effect on GABAA receptor expression.
Conclusion
The Daming capsule partially reversed the parasympathetic baroreflex impairment observed in STZ-induced diabetic rats with hyperlipoidemia. Treatment with DMC also prevented the degeneration of neurons and myelinated axons in the brain stem NAm and reversed the down-regulation of GluR2 mRNA. Rescue of NAm function may contribute to the medicinal properties of DMC in diabetic rats.
doi:10.1186/1472-6882-10-80
PMCID: PMC3022895  PMID: 21176164
14.  TARGETED DELETION OF NEUROKININ-1 RECEPTOR EXPRESSING NUCLEUS TRACTUS SOLITARII NEURONS PRECLUDES SOMATOSENSORY DEPRESSION OF ARTERIAL BARORECEPTOR–HEART RATE REFLEX 
Neuroscience  2007;145(3):1168-1181.
Neurokinin-1 receptor (NK1-R) expressing neurons are densely distributed throughout the nucleus tractus solitarii (NTS). However, their fundamental role in arterial baroreflex function remains debated. Previously, our group has shown that activation of contraction-sensitive somatic afferents evoke substance P (SP) release in the NTS and resets the arterial baroreflex via activation of a GABAergic NTS circuit. Based on these findings, we hypothesized that modulation of arterial baroreflex function by somatic afferents is mediated by NK1-R dependent inhibition of barosensitive NTS circuits. In the present study, SP-conjugated saporin toxin (SP-SAP) was used to ablate NK1-R expressing NTS neurons. Contraction-sensitive somatic afferents were activated by electrically-evoked muscle contraction and the arterial baroreceptor–heart rate reflex was assessed by constructing reflex curves using a decerebrate, arterially-perfused preparation. Baseline baroreflex sensitivity was significantly attenuated in SP-SAP-treated rats compared with control rats receiving either unconjugated SAP or vehicle. Muscle contraction significantly attenuated baroslope in SAP and vehicle-treated animals and shifted the baroreflex curves to higher systemic pressure. In contrast, somatic afferent stimulation failed to alter baroslope or shift the baroreflex curves in SP-SAP-treated animals. Moreover, when reflex sensitivity was partially restored in SP-SAP animals, somatic stimulation failed to attenuate baroreflex bradycardia. In contrast, SP-SAP and somatic stimulation failed to blunt the reflex bradycardia evoked by the peripheral chemoreflex. Immunohistochemistry revealed that pretreatment with SP-SAP significantly reduced the number of NK1-R expressing neurons in the caudal NTS, while sparing NK1-R expressing neurons rostral to the injection site. This was accompanied by a significant reduction in the number of glutamic acid decarboxylase (GAD67) expressing neurons at equivalent levels of the NTS. These findings indicate that immunolesioning of NK1-R expressing NTS neurons selectively abolishes the depressive effect of somatosensory input on arterial baroreceptor–heart rate reflex function.
doi:10.1016/j.neuroscience.2007.01.001
PMCID: PMC1905828  PMID: 17293052
nucleus tractus solitarii; neurokinin receptors; substance P; GABA; arterial baroreflex; exercise
15.  Genetic silencing of Nox2 and Nox4 reveals differential roles of these NADPH oxidase homologues in the vasopressor and dipsogenic effects of brain angiotensin-II 
Hypertension  2009;54(5):1106-1114.
The renin angiotensin system (RAS) exerts a tremendous influence over fluid balance and arterial pressure. Angiotensin II (Ang-II), the effector peptide of the RAS, acts in the CNS to regulate neurohumoral outflow and thirst. Dysregulation of Ang-II signaling in the CNS is implicated in cardiovascular diseases, however the mechanisms remain poorly understood. Recently we established that NADPH oxidase (Nox)-derived superoxide acting in the forebrain subfornical organ (SFO) is critical in the physiologic responses to central Ang-II. In addition, we have found that Nox2 and Nox4 are the most abundantly expressed Nox homologues within Ang-II-sensitive sites in the forebrain. To dissect out the functional importance and unique roles of these Nox enzymes in the pressor and dipsogenic effects of central Ang-II, we developed adenoviral vectors expressing siRNA to selectively silence Nox2 or Nox4 expression in the SFO. Our results demonstrate that both Nox2 and Nox4 are required for the full vasopressor effects of brain Ang-II, but that only Nox2 is coupled to the Ang-II-induced water intake response. These studies establish the importance of both Nox2- and Nox4-containing NADPH oxidases in the actions of Ang-II in the CNS, and are the first to reveal differential involvement of these Nox enzymes in the various physiologic effects of central Ang-II.
doi:10.1161/HYPERTENSIONAHA.109.140087
PMCID: PMC2773438  PMID: 19805637
hypertension; blood pressure; water intake; subfornical organ; adenovirus; siRNA
16.  Pregnancy increases baroreflex-independent GABAergic inhibition of the RVLM in rats 
During baroreceptor unloading, sympathoexcitation is attenuated in near-term pregnant compared with nonpregnant rats. Alterations in balance among different excitatory and inhibitory inputs within central autonomic pathways likely contribute to changes in regulation of sympathetic outflow in pregnancy. Both baroreflex-dependent and baroreflex-independent GABAergic inputs inhibit sympathoexcitatory neurons within rostral ventrolateral medulla (RVLM). The present experiments tested the hypothesis that influence of baroreflex-independent GABAergic inhibition of RVLM is greater in pregnant compared with nonpregnant rats. Afferent baroreceptor inputs were eliminated by bilateral sinoaortic denervation in inactin-anesthetized rats. In pregnant compared with nonpregnant rats, baseline mean arterial pressure (MAP) was lower (pregnant = 75 ± 6 mmHg, nonpregnant = 115 ± 7 mmHg) and heart rate was higher (pregnant = 381 ± 10 beats/min, nonpregnant = 308 ± 10 beats/min). Pressor and sympathoexcitatory [renal sympathetic nerve activity, (RSNA)] responses due to bilateral GABAA receptor blockade (bicuculline, 4 mM, 100 nl) of the RVLM were greater in pregnant rats (ΔMAP: pregnant = 101 ± 4 mmHg, nonpregnant = 80 ± 6 mmHg; ΔRSNA: pregnant = 182 ± 23% control, nonpregnant = 133 ± 10% control). Unexpected transient sympathoexcitatory effects of angiotensin AT1 receptor blockade in the RVLM were greater in pregnant rats. Although excitatory responses to bicuculline were attenuated by prior RVLM AT1 receptor blockade in both groups, pressor responses to disinhibition of the RVLM remained augmented in pregnant rats. Increased influence of baroreflex-independent GABAergic inhibition in RVLM could contribute to suppressed sympathoexcitation during withdrawal of arterial baroreceptor input in pregnant animals.
doi:10.1152/ajpregu.00365.2007
PMCID: PMC2841061  PMID: 17898121
sympathetic nerve activity; brain stem; cardiovascular regulation; angiotensin II
17.  CHBPR Proton Magnetic Resonance Spectroscopy Detection of Neurotransmitters in Dorsomedial Medulla Correlate with Spontaneous Baroreceptor Reflex Function 
Hypertension  2010;55(2):487-493.
Control of heart rate variability (HRV) via modulation of sympathovagal balance is a key function of nucleus tractus solitarii (nTS) and dorsal motor nucleus of the vagus localized in the dorsomedial medulla oblongata. Normal blood pressure regulation involves precise balance of glutamate-glutamine-GABA (Glu-Gln-GABA) transmitter systems, and angiotensin (Ang) II modulates these transmitters to produce tonic suppression of reflex function. It is not known, however, whether other brain transmitters/metabolites are indicators of baroreflex function. This study establishes the concept that comprehensive baseline transmitter/metabolite profiles obtained using in vivo 1H Magnetic Resonance Spectroscopy (1H MRS) in rats with well characterized differences in resting blood pressure and baroreflex function can be used as indices of autonomic balance or baroreflex sensitivity. Glu concentration in dorsal medulla is significantly higher in ASrAogen rats compared to either SD and (mRen2)27. Glu levels and the ratio of Glu/Gln correlated positively with indices of higher vagal tone consistent with the importance of these neurotransmitters in baroreflex function. Interestingly, the levels of choline containing metabolites showed a significant positive correlation with spontaneous baroreflex sensitivity and a negative correlation with sympathetic tone. Thus, we demonstrate the concept that non-invasive assessment of neurochemical biomarkers may be used as an index of baroreflex sensitivity.
doi:10.1161/HYPERTENSIONAHA.109.145722
PMCID: PMC2826127  PMID: 20065146
hypertension; baroreflex sensitivity; 1H MRS; brain; neurotransmitters
18.  Inhibition of Cardiac Sympathetic Afferent Reflex and Sympathetic Activity by Baroreceptor and Vagal Afferent Inputs in Chronic Heart Failure 
PLoS ONE  2011;6(10):e25784.
Background
Cardiac sympathetic afferent reflex (CSAR) contributes to sympathetic activation and angiotensin II (Ang II) in paraventricular nucleus (PVN) augments the CSAR in vagotomized (VT) and baroreceptor denervated (BD) rats with chronic heart failure (CHF). This study was designed to determine whether it is true in intact (INT) rats with CHF and to determine the effects of cardiac and baroreceptor afferents on the CSAR and sympathetic activity in CHF.
Methodology/Principal Findings
Sham-operated (Sham) or coronary ligation-induced CHF rats were respectively subjected to BD+VT, VT, cardiac sympathetic denervation (CSD) or INT. Under anesthesia, renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded, and the CSAR was evaluated by the RSNA and MAP responses to epicardial application of capsaicin. Either CSAR or the responses of RSNA, MAP and CSAR to Ang II in PVN were enhanced in CHF rats treated with BD+VT, VT or INT. Treatment with VT or BD+VT potentiated the CSAR and the CSAR responses to Ang II in both Sham and CHF rats. Treatment with CSD reversed the capsaicin-induced RSNA and MAP changes and the CSAR responses to Ang II in both Sham and CHF rats, and reduced the RSNA and MAP responses to Ang II only in CHF rats.
Conclusions
The CSAR and the CSAR responses to Ang II in PVN are enhanced in intact CHF rats. Baroreceptor and vagal afferent activities inhibit CSAR and the CSAR responses to Ang II in intact Sham and CHF rats.
doi:10.1371/journal.pone.0025784
PMCID: PMC3185007  PMID: 21991351
19.  Angiotensin-(1–7) prevents diabetes-induced attenuation in PPAR-γ and catalase activities 
European journal of pharmacology  2010;638(1-3):108-114.
The mechanisms by which angiotensin-(1–7) [Ang-(1–7)] exerts its beneficial effects on end-organ damage associated with diabetes and hypertension are not well understood. The purpose of this study was A) to compare the effects of apocynin with Ang-(1–7) on renal vascular dysfunction and NADPH oxidase activity in a combined model of diabetes and hypertension and B) to further determine whether chronic treatment with Ang-(1–7) can modulate renal catalase, and peroxisome proliferator activated receptor-γ (PPAR–γ) levels in streptozotocin induced-diabetes in both normotensive Wistar Kyoto rats (WKY) and in spontaneously hypertensive rats (SHR). Apocynin or Ang-(1–7) treatment for one month starting at the onset of diabetes similarly attenuated elevation of renal NADPH oxidase activity in the diabetic SHR kidney and reduced the degree of proteinuria and hyperglycemia, but had little or modest effect on reducing mean arterial pressure. Both drugs also attenuated the diabetes-induced increase in renal vascular responsiveness to endothelin-1. Induction of diabetes in WKY and SHR animals resulted in significantly reduced renal catalase activity and in PPAR–γ mRNA and protein levels. Treatment with Ang-(1–7) significantly prevented diabetes-induced reduction in catalase activity and the reduction in PPAR–γ mRNA and protein levels in both animal models. Taken together, these data suggest that activation of Ang-(1–7)-mediated signaling could be an effective way to prevent the elevation of NADPH oxidase activity and inhibition of PPAR–γ and catalase activities in diabetes and/or hypertension.
doi:10.1016/j.ejphar.2010.04.030
PMCID: PMC2907528  PMID: 20447391
Angiotensin; hypertension; diabetes; kidney
20.  Interaction of cardiopulmonary and carotid baroreflex control of vascular resistance in humans. 
Journal of Clinical Investigation  1985;76(4):1592-1598.
Previous studies in experimental animals indicate an important inhibitory interaction between cardiopulmonary and arterial baroreflexes. In the dog, for example, cardiopulmonary vagal afferents modulate carotid baroreflex control of vascular resistance. On the other hand, previous studies in human subjects have not produced convincing evidence of a specific interaction between these baroreceptor reflexes. The purpose of this study was to determine whether unloading of cardiopulmonary baroreceptors in humans with nonhypotensive lower body negative pressure selectively augments the reflex vasoconstrictor responses to simulated carotid hypotension produced by neck pressure. In nine healthy subjects, we measured forearm vascular responses with plethysmography during lower body negative pressure alone (cardiopulmonary baroreflex), during neck pressure alone (carotid baroreflex), and during concomitant lower body negative pressure and neck pressure (baroreflex interaction). Lower body negative pressure produced a greater than twofold augmentation of the forearm vasoconstrictor response to neck pressure. This increase in resistance was significantly greater (P less than 0.05) than the algebraic sum of the increase in resistance from lower body negative pressure alone plus that from neck pressure alone. In contrast, lower body negative pressure did not potentiate the forearm vasoconstrictor responses either to intra-arterial norepinephrine or to the cold pressor test. Thus, the potentiation of the vasoconstrictor response to neck pressure by lower body negative pressure cannot be explained by augmented reactivity to the neurotransmitter or to a nonspecific augmentation of responses to all reflex vasoconstrictor stimuli. In conclusion, nonhypotensive lower body negative pressure selectively augments carotid baroreflex control of forearm vascular resistance. These experiments demonstrate a specific inhibitory cardiopulmonary-carotid baroreflex interaction in humans.
PMCID: PMC424138  PMID: 4056042
21.  NADPH oxidase-derived superoxide anion mediates angiotensin II-enhanced carotid body chemoreceptor sensitivity in heart failure rabbits 
Cardiovascular research  2007;75(3):546-554.
Objective:
A previous study from this laboratory showed that elevation of endogenous angiotensin II (Ang II) and upregulation of the angiotensin II type 1 (AT1) receptor in the carotid body (CB) are involved in the enhanced peripheral chemoreceptor sensitivity in rabbits with chronic heart failure (CHF). NADPH oxidase-derived superoxide anion mediates the effects of Ang II in many organs. We investigated whether this signaling pathway may mediate the enhanced peripheral chemoreceptor sensitivity induced by Ang II in CHF rabbits.
Methods and results:
By recording single-unit activity from the carotid sinus nerve in isolated preparations, we found that phenylarsine oxide 2 μM (PAO, NADPH oxidase inhibitor) and TEMPOL 1 mM (superoxide dismutase mimetic) significantly decreased not only the Ang II-enhanced CB chemoreceptor responses to different levels of hypoxia in sham rabbits (Δ-12.5 ± 0.8 and Δ-12.8 ± 0.9 imp/s at 40.7 ± 2.3 mm Hg of PO2, and Δ-5.6 ± 0.5 and Δ-5.3 ± 0.4 imp/s at 60.2 ± 3.1 mm Hg of PO2, p<0.05, respectively) but also the CHF-induced elevation of CB chemoreceptor responses to different levels of hypoxia (Δ-13.6 ± 1.1 and Δ-13.7 ± 0.9 imp/s at 40.9 ± 3.1 mm Hg of PO2, and Δ-6.7 ± 1.2 and Δ-6.6 ± 0.8 imp/s at 59.8 ± 3.5 mm Hg of PO2, p<0.05). In addition, mRNA and protein expressions of NADPH oxidase components (gp91phox, p40phox and p47phox) were higher in the CB from CHF rabbits compared to sham rabbits. Furthermore, 100 pM Ang II induced an increase in superoxide production in CB homogenates from sham rabbits, which was similar to that in CB homogenate from CHF rabbits. PAO and Tempol inhibited the Ang II- and CHF-enhanced superoxide anion production.
Conclusions:
These results suggest that the enhanced peripheral chemoreceptor sensitivity mediated by Ang II in CHF rabbits occurs via a NADPH oxidase-superoxide signaling pathway.
doi:10.1016/j.cardiores.2007.04.006
PMCID: PMC2062532  PMID: 17499230
Angiotensin; Reactive oxygen species; autonomic nervous system; chemoreceptor; heart failure
22.  RELATIONSHIP BETWEEN SYMPATHETIC BAROREFLEX SENSITIVITY AND ARTERIAL STIFFNESS IN ELDERLY MEN AND WOMEN 
Hypertension  2011;59(1):98-104.
Previous human studies have shown that large-artery stiffness contributes to an age-related decrease in cardiovagal baroreflex sensitivity. Whether this is also true with sympathetic baroreflex sensitivity is unknown. We tested the hypothesis that sympathetic baroreflex sensitivity is associated with the stiffness of baroreceptor segments (the carotid artery and the aorta) in elderly individuals, and that sex affects this relationship. Sympathetic baroreflex sensitivity was assessed from the spontaneous changes in beat-by-beat diastolic pressure and corresponding muscle sympathetic nerve activity (microneurography) during supine rest in 30 men [69±1 (mean±SEM) years] and 31 women (68±1 years). Carotid artery stiffness (B-mode ultrasonography) and aortic stiffness (magnetic resonance imaging) were also determined. We found that elderly women had lower sympathetic baroreflex sensitivity than elderly men (–2.33±0.25 vs. –3.32±0.25 bursts·100 beats–1·mmHg–1; P=0.007). β-stiffness indices of the carotid artery and the aorta were greater in elderly women than in men (6.68±0.48 vs. 5.10±0.50 and 4.03±0.47 vs. 2.68±0.42; both P<0.050). Sympathetic baroreflex sensitivity was inversely correlated with carotid artery stiffness in both men and women (r=0.49 and 0.50, both P<0.05), while this relation was shifted in parallel upward (towards a reduced sensitivity) in women with no changes in the slope (0.26 vs. 0.24 a.u.). Sympathetic baroreflex sensitivity and aortic stiffness showed similar trends. Thus, barosensory artery stiffness seems to be one independent determinant of sympathetic baroreflex sensitivity in elderly men and women. The lower sympathetic baroreflex sensitivity in elderly women may predispose them to an increased prevalence of hypertension.
doi:10.1161/HYPERTENSIONAHA.111.176560
PMCID: PMC3241909  PMID: 22106403
baroreceptors; β-stiffness; muscle sympathetic nerve activity; aging; sex differences
23.  3′,4′-Dihydroxyflavonol Reduces Superoxide and Improves Nitric Oxide Function in Diabetic Rat Mesenteric Arteries 
PLoS ONE  2011;6(6):e20813.
Background
3',4'-Dihydroxyflavonol (DiOHF) is an effective antioxidant that acutely preserves nitric oxide (NO) activity in the presence of elevated reactive oxygen species (ROS). We hypothesized that DiOHF treatment (7 days, 1 mg/kg per day s.c.) would improve relaxation in mesenteric arteries from diabetic rats where endothelial dysfunction is associated with elevated oxidant stress.
Methodology/Principal Findings
In mesenteric arteries from diabetic rats there was an increase in ROS, measured by L-012 and 2',7'-dichlorodihydrofluorescein diacetate fluorescence. NADPH oxidase-derived superoxide levels, assayed by lucigenin chemiluminescence, were also significantly increased in diabetic mesenteric arteries (diabetes, 4892±946 counts/mg versus normal 2486±344 counts/mg, n = 7–10, p<0.01) associated with an increase in Nox2 expression but DiOHF (2094±300 counts/mg, n = 10, p<0.001) reversed that effect. Acetylcholine (ACh)-induced relaxation of mesenteric arteries was assessed using wire myography (pEC50 = 7.94±0.13 n = 12). Diabetes significantly reduced the sensitivity to ACh and treatment with DiOHF prevented endothelial dysfunction (pEC50, diabetic 6.86±0.12 versus diabetic+DiOHF, 7.49±0.13, n = 11, p<0.01). The contribution of NO versus endothelium-derived hyperpolarizing factor (EDHF) to ACh-induced relaxation was assessed by evaluating responses in the presence of TRAM-34+apamin+iberiotoxin or N-nitro-L-arginine+ODQ respectively. Diabetes impaired the contribution of both NO (maximum relaxation, Rmax diabetic 24±7 versus normal, 68±10, n = 9–10, p<0.01) and EDHF (pEC50, diabetic 6.63±0.15 versus normal, 7.14±0.12, n = 10–11, p<0.01) to endothelium-dependent relaxation. DiOHF treatment did not significantly affect the EDHF contribution but enhanced NO-mediated relaxation (Rmax 69±6, n = 11, p<0.01). Western blotting demonstrated that diabetes also decreased expression and increased uncoupling of endothelial NO synthase (eNOS). Treatment of the diabetic rats with DiOHF significantly reduced vascular ROS and restored NO-mediated endothelium-dependent relaxation. Treatment of the diabetic rats with DiOHF also increased eNOS expression, both in total and as a dimer.
Conclusions/Significance
DiOHF improves NO activity in diabetes by reducing Nox2-dependent superoxide production and preventing eNOS uncoupling to improve endothelial function.
doi:10.1371/journal.pone.0020813
PMCID: PMC3108977  PMID: 21673968
24.  Clinical value of baroreflex sensitivity 
Netherlands Heart Journal  2012;21(2):61-63.
The arterial baroreflex is an important determinant of the neural regulation of the cardiovascular system. It has been recognised that baroreflex-mediated sympathoexcitation contributes to the development and progression of many cardiovascular disorders. Accordingly, the quantitative estimation of the arterial baroreceptor-heart rate reflex (baroreflex sensitivity, BRS), has been regarded as a synthetic index of neural regulation at the sinus atrial node. The evaluation of BRS has been shown to provide clinical and prognostic information in a variety of cardiovascular diseases, including myocardial infarction and heart failure that are reviewed in the present article.
doi:10.1007/s12471-012-0349-8
PMCID: PMC3547421  PMID: 23184601
Arterial baroreceptors; Baroreflex sensitivity; Autonomic nervous system; Prognosis; Myocardial infarction; Heart failure
25.  Effect of type 1 diabetes on the production and vasoactivity of hydrogen sulfide in rat middle cerebral arteries 
Physiological Reports  2013;1(5):e00111.
Hydrogen sulfide (H2S) is produced endogenously in vascular tissue and has both vasoregulation and antioxidant effects. This study examines the effect of diabetes-induced oxidative stress on H2S production and function in rat middle cerebral arteries. Diabetes was induced in rats with streptozotocin (50 mg/kg, i.v.). Middle cerebral artery function was examined using a small vessel myograph and superoxide anion generation measured using nicotinamide adenine dinucleotide phosphate (NADPH)-dependent lucigenin-enhanced chemiluminescence. Cystathionine-γ-lyase (CSE) mRNA expression was measured via RT-PCR. Diabetic rats had elevated blood glucose and significantly reduced cerebral artery endothelial function. Maximum vasorelaxation to the H2S donor NaHS was unaffected in diabetic cerebral arteries and was elicited via a combination of K+, Cl−, and Ca2+ channel modulation, although the contribution of Cl− channels was significantly less in the diabetic cerebral arteries. Vasorelaxation to the H2S precursor l-cysteine and CSE mRNA were significantly increased in diabetic cerebral arteries. Cerebral artery superoxide production was significantly increased in diabetes, but this increase was attenuated ex vivo by incubation with the H2S donor NaHS. These data confirm that cerebral artery endothelial dysfunction and oxidative stress occurs in diabetes. Endogenous H2S production and activity is upregulated in cerebral arteries in this model of diabetes. Vasorelaxation responses to exogenous H2S are preserved and exogenous H2S attenuates the enhanced cerebral artery generated superoxide observed in the diabetic group. These data suggest that upregulation of endogenous H2S in diabetes may play an antioxidant and vasoprotective role.
doi:10.1002/phy2.111
PMCID: PMC3841046  PMID: 24303182
Cerebral artery; diabetes; hydrogen sulfide; oxidative stress

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