Neural Control Of Blood Pressure Research Articles

Sympathetic Neural Regulation of Blood Pressure: Influences of Sex and Aging

Sex and age have important influences on sympathetic neural control of blood pressure in humans. Young women are relatively protected against risk of hypertension due to greater peripheral vasodilator influences compared with young men and older people. This protective effect is lost at menopause. Older men and women have higher sympathetic nerve activity and tighter coupling between SNA and blood pressure, contributing to the increased risk of hypertension with aging.

Abstract 293: Brain Gai2 Proteins Mediate Acute Neural Blood Pressure Responses to Centrally and Peripherally Administered NaCl

Aim: We have demonstrated hypertension mediated by failure to upregulate PVN Gαi 2 proteins in rats fed a chronic high salt diet, but the role of this mechanism is unknown in acute settings. We examined the effect of central Gαi 2 proteins in the neural control of blood pressure in response to an acute physiological (IV and ICV) and pharmacological challenge. Methods: Twenty-four hour (24-h) ICV Gαi 2 or SCR oligodeoxynucleotide (ODN; 25μg/5μl)-pretreated conscious Sprague-Dawley rats were continuously monitored for changes in HR and MAP in response to peripherally-administered NaCl (3M IV bolus; 0.14 ml/100g) or centrally-administered NaCl (1M ICV; 5μL)(N=4/gp). To determine the cardiac baroreflex MAP was slowly raised to ~175 mmHg using phenylephrine and lowered to ~50 mmHg using sodium nitroprusside in separate group of pre-treated rats (N=8/gp). Results: In response to IV sodium, peak changes in HR were significantly greater in SCR vs. Gαi 2 treated rats (IV 3M NaCl ΔHR [bpm]; SCR -79±15 vs . Gαi 2 -59±12, P<0.05), but no difference was observed in peak changes in MAP (IV 3M NaCl ΔMAP [mmHg] SCR 147±4 mmHg vs . Gαi 2 149±3). In SCR rats, MAP returned to baseline by 100 min whereas Gαi 2 rats remained significantly elevated for 120 min (P<0.05). In response to ICV sodium, we observed no difference between groups in peak HR changes (ICV 1M NaCl ΔHR [bpm] -23±8 bpm vs . Gαi 2 -22±8) or peak MAP changes (ICV 1M NaCl ΔMAP [mmHg] 16±3 mmHg vs . Gαi 2 9±3). In SCR rats, MAP returned to baseline by 50 min whereas Gαi 2 rats remained elevated for 90 min. The 24h Gαi 2 ODN pretreatment significantly altered the high-, but not low-pressure gain of the baroreflex in response to pharmacological challenge (MAP=180 mmHg, SCR HR=270 bpm, Gαi 2 HR=307 bpm, P<0.05). Conclusion: Downregulation of Gαi 2 proteins resulted in altered cardiac baroreflex function by impairing reflex decreases in HR and mediating significantly prolonged elevated MAP in response to peripherally administered sodium. This highlights a previously undiscovered role of brain Gαi 2 proteins in the baroreflex control of HR at elevated blood pressures—a factor that may contribute to elevated MAP in neurogenic models of hypertension.

A role for Gαi2 proteins in the acute neural control of blood pressure.

AimWe have demonstrated hypertension mediated by failure to upregulate hypothalamic paraventricular nucleus Gαi2 proteins in rats fed a high salt diet, but the role of this mechanism is unknown in acute settings. We examined the effect of central Gαi2 proteins in the neural control of blood pressure in response to an acute pharmacological and physiological challenge.MethodsNaïve and 24hr ICV Gαi2 oligodeoxynucleotide (ODN; 25μg/5μl)‐pretreated conscious Sprague‐Dawley rats were continuously monitored for changes in HR and MAP in response to intravenous (IV) infusion of phenylephrine and sodium nitroprusside or 3M NaCl IV bolus (0.14 ml/100g). To determine cardiac baroreflex relationships, MAP was slowly raised to ~175 mmHg using phenylephrine and lowered to ~50 mmHg using sodium nitroprusside (N=8/gp).Results24h Gαi2 ODN pretreatment did not affect the cardiac baroreflex response. In response to IV sodium, peak changes in HR were significantly greater in naïve animals vs. Gαi2 treated animals (Naïve + 3M NaCl ΔHR=−79±15 bpm vs. Gαi2 + 3M NaCl ΔHR=−59±12 bpm; P<0.05). We observed no difference in peak MAP post‐IV NaCl between groups (Naïve + 3M NaCl MAP 147±4 mmHg vs. Gαi2 + 3M NaCl MAP 149±3 mmHg). In naïve rats, MAP returned to baseline by 100 min whereas Gαi2 animals remained significantly elevated for 120 min (P<0.05).ConclusionEndogenous Gαi2 proteins are involved in neural control of HR and MAP during an acute sodium challenge. These data suggest brain Gαi2 signal transduction is required to mediate sodium‐sensitive neural responses to maintain physiologically appropriate blood pressure regulation.

Elderly Blacks Have a Blunted Sympathetic Neural Responsiveness But Greater Pressor Response to Orthostasis Than Elderly Whites

Neural control of blood pressure (BP) has been reported to differ between young blacks and whites. We hypothesized that elderly blacks have enhanced sympathetic neural responses during orthostasis compared with elderly whites. Muscle sympathetic nerve activity, arm-cuff BP, and heart rate were recorded continuously, and cardiac output, stroke volume, and total peripheral resistance were measured intermittently during supine and 5-minute 60° upright tilt in 10 blacks (65 [SD, 4] years; 4 women) and 20 whites (68 [6] years; 8 women). We found that muscle sympathetic nerve activity burst frequency was similar between blacks and whites in the supine position (44 [10] versus 42 [7] bursts per minute) and during upright tilt (59 [11] versus 60 [9] bursts per minute; P=0.846 for race, P<0.001 for posture, and P=0.622 for interaction). However, upright total muscle sympathetic nerve activity was smaller in blacks than in whites (162 [39] versus 243 [112]%; P=0.003). Systolic BP, heart rate, cardiac output, and stroke volume were not different between groups. Diastolic BP was similar in the supine position, increased in all of the subjects during tilting; upright diastolic BP was greater in blacks than in whites (80 [10] versus 71 [7] mmHg; P=0.008). Total peripheral resistance did not differ between blacks and whites in the supine position or during upright tilt (P=0.354 for race, P<0.001 for posture, P=0.825 for interaction). Thus, elderly blacks have a blunted sympathetic neural responsiveness but enhanced pressor response to orthostasis compared with elderly whites, which may be attributable to an augmented sympathetic vascular transduction and/or nonadrenergic vasoconstrictor mechanisms (ie, angiotensin II or the venoarteriolar response).

Sympathetic neural and hemodynamic responses to upright tilt in elderly African Americans versus Caucasians

It has been demonstrated that neural control of blood pressure (BP) is different in young African Americans (AA) and Caucasians (CAU). Whether this is also true in elderly people is unclear. We tested the hypothesis that elderly AA have enhanced sympathetic neural responses during orthostasis compared with elderly CAU. Muscle sympathetic nerve activity (MSNA), BP, and heart rate (HR) were recorded continuously, cardiac output (Qc, C2H2 rebreathing), stroke volume (SV=Qc/HR) and total peripheral resistance (TPR=mean BP/Qc) were measured intermittently supine and during 5‐min 60‐degree upright tilt in 10 AA [6 M, 4F; 65±4 (SD) yrs] and 15 CAU (9M, 6 F; 67±4 yrs). AA and CAU had similar supine (44±10 vs 42±8 bursts/min) and upright MSNA burst frequency (59±11 vs 60±11 bursts/min; P=0.98 for race, &lt;0.01 for posture, 0.58 for interaction). However, upright total MSNA was smaller in AA than CAU (162±39 vs 248±126%; P&lt;0.01). Systolic BP, HR, Qc and SV were not different between groups in the supine position and during upright tilt. Supine diastolic BP was similar between groups (66±7 vs 65±8 mmHg; P=0.76), but upright diastolic BP was greater in AA than CAU (80±10 vs 71±8 mmHg; P=0.02). TPR did not differ between AA and CAU in both supine (1536±295 vs 1741±401 dyn·s·cm−5) and upright postures (2490±555 vs 2522±886 dyn·s·cm−5; P=0.47 for race, &lt;0.01 for posture, 0.71 for interaction). These results suggest that elderly African Americans have a blunted sympathetic neural responsiveness but enhanced blood pressure reactivity during orthostasis compared with elderly Caucasians, which may be attributable to an augmented sympathetic vascular transduction.Supported by NIH R01 HL091078.

Microneurographic research in women

This article reviews microneurographic research on sympathetic neural control in women under both physiological and pathophysiological conditions across the lifespan. Specifically, the effects of sex, age, race, the menstrual cycle, oral contraceptives, estrogen replacement therapy, and normal pregnancy on neural control of blood pressure in healthy women are reviewed. In addition, sympathetic neural activity during neurally mediated (pre)syncope, the Postural Orthostatic Tachycardia Syndrome (POTS), obesity, the Polycystic Ovary Syndrome (PCOS), gestational hypertension, and preeclampsia, chronic essential hypertension, heart failure, and myocardial infarction in women are also reviewed briefly. It is suggested that microneurographic studies provide valuable information regarding autonomic circulatory control in women of different ages and in most cases, excessive sympathetic activation is associated with specific medical conditions regardless of age and sex. In some situations, sympathetic inhibition or withdrawal may be the underlying mechanism. Information gained from previous and recent microneurographic studies has significant clinical implications in women's health, and in some cases could be used to guide therapy if more widely available.

Alpha2-adrenergic receptor distribution and density within the nucleus tractus solitarii of normotensive and hypertensive rats during development

The nucleus tractus solitarii (NTS), located in the brainstem, is one of the main nuclei responsible for integrating different signals in order to originate a specific and orchestrated autonomic response. Antihypertensive drugs are well known to stimulate alpha2-adrenoceptor (alpha2R) in brainstem cardiovascular regions to induce reduction in blood pressure. Because alpha2R impairment is present in several models of hypertension, the aim of the present study was to investigate the distribution and density of alpha2R binding within the NTS of Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats during development (1,15,30 and 90day-old) by an in vitro autoradiographical study. The NTS shows heterogeneous distribution of alpha2R in dorsomedial/dorsolateral, subpostremal and medial/intermediate subnuclei. Alpha2R increased from rostral to caudal dorsomedial/dorsolateral subnuclei in 30 and 90day-old SHR but not in WKY. Alpha2R decreased from rostral to caudal subpostremal subnucleus in 15, 30 and 90day-old SHR but not in WKY. Medial/intermediate subnuclei did not show any changes in alpha2R according to NTS levels. Furthermore, alpha2R are decreased in SHR as compared with WKY in all NTS subnuclei and in different ages. Surprisingly, alpha2R impairment was also found in pre-hypertensive stages, specifically in subpostremal subnucleus of 15day-old rats. Finally, alpha2R decrease from 1 to 90day-old rats in all subnuclei analyzed. This decrease is different between strains in rostral dorsomedial/dorsolateral and caudal subpostremal subnuclei within the NTS. In summary, our results highlight the importance of alpha2R distribution within the NTS regarding the neural control of blood pressure and the development of hypertension.

Autonomic-Immune-Vascular Interaction

Hypertension is the single most important risk factor for cardiovascular disease and, thus, remains a global public health challenge. Significant progress has been made during the last several decades in the treatment of hypertension through the use of inhibitors of the renin-angiotensin (Ang) system, with either Ang-converting enzyme inhibitors or Ang receptor type 1 blockers, diuretics, α-adrenoreceptor antagonists, and calcium channel blockers. Despite these advances, it has been extremely difficult to manage hypertension in ≈40% of hypertensive patients.1 A majority of these unresponsive patients exhibit increased sympathetic drive and display neurogenic components.2,–,4 The role of elevated sympathetic nervous system in drug-resistant hypertension is corroborated by the recent successes in its treatment by renal sympathetic denervation in humans.3,5,6 These observations have led to the realization that elucidation and understanding of cellular, molecular, and physiological mechanisms involved in the development and establishment of neurogenic hypertension are pivotal in advancing new therapeutic strategies that would be effective in a majority of patients. The objectives of this article are to summarize recent advances in this field, underscoring the importance of coordinated neural-peripheral signaling in neural control of blood pressure (BP) and contribution of inflammatory molecules, and to introduce novel and emerging concepts in the pathogenesis of neurogenic hypertension. It is advised to consult other reviewers for details on fundamental studies related to neural pathways, the renin-Ang system, and involvement of other hormonal systems in neurogenic hypertension.7,–,13 ### Neurogenic Hypertension An alteration in neural cardiovascular (vagal/sympathetic) control mechanism is the principal characteristic of neurogenic hypertension. Studies demonstrating a significant enhancement of the vasomotor and cardiac sympathetic drive, as well as a reduction in the parasympathetic drive in borderline hypertensive patients, support this premise.14,–,16 In addition, hypertensive patients …

Central antioxidant therapy inhibits parasympathetic baroreflex control in conscious rats

Baroreceptor reflex is an important system for neural control of blood pressure. Recently, reactive oxygen species (ROS) have been shown to play an important role in neuronal activity of central areas related to blood pressure control. The aim of this study was to investigate the effects elicited by ascorbic acid (AAC) and N-acetylcysteine (NAC) injections into the 4thV on the parasympathetic component of the baroreflex. Male Wistar rats were implanted with a stainless steel guide cannula into the 4thV. One day prior to the experiments, the femoral artery and vein were cannulated for pulsatile arterial pressure, mean arterial pressure and heart rate measurements and drug administration, respectively. After baseline recordings, the baroreflex was tested with a pressor dose of phenylephrine (PHE, 3μg/kg, i.v.) and a depressor dose of sodium nitroprusside (SNP, 30μg/kg, i.v.) before (control) and 5, 15, 30 and 60min after AAC or NAC into the 4thV. Control PHE injection induced baroreflex-mediated bradycardia (−93±13bpm, n=7). Interestingly, after AAC injection into the 4thV, PHE injection produced a transient tachycardia at 5 (40±23bpm), 15 (26±22bpm) and 30min (59±21bpm). No changes were observed in baroreflex-mediated tachycardia evoked by SNP after AAC injection on 4thV (control: 151±23bpm vs. 135±18bpm at 5min after AAC, n=7). In the NAC treated group, PHE induced a reduction in reflex bradycardia at 5min when compared to control (−11±17bpm vs. −83±15bpm, n=7). No changes were observed in baroreflex-mediated tachycardia evoked by SNP after NAC injection on 4thV. The antioxidants AAC and NAC may act in the central nervous system affecting the parasympathetic component of the cardiac baroreflex.

Altered cardiovascular reflexes responses in conscious Angiotensin-(1-7) receptor Mas-knockout mice

This study evaluated the physiological importance of Angiotensin-(1-7) receptor Mas on reflex control of circulation. Experiments were performed in male Mas-knockout (Mas-KO) and Wild Type (WT) conscious mice (12–20 wk of age). Baroreceptor reflex was evaluated by the bradycardic response induced by phenylephrine (0.25 μg/5 μl, i.v.). Bezold–Jarisch reflex was evaluated by phenylbiguanide (0.5 μg/5 μl, i.v.) and chemoreflex by potassium cyanide (2.5 μg/5 μl, i.v.). Baseline mean arterial pressure was higher in Mas-KO ( n = 14) as compared with WT mice ( n = 18) (118 ± 1 mm Hg vs. 109 ± 2 mm Hg); however, heart rate was similar in both strains (615 ± 30 bpm vs. 648 ± 13 bpm). Baroreflex bradycardia was lower (0.78 ± 0.44 ms/mm Hg vs. 1.30 ± 0.14 ms/mm Hg) in Mas-KO compared with WT mice. The depressor (−17 ± 5 mm Hg vs. −45 ± 6 mm Hg) and bradycardic (−212 ± 36 bpm vs. −391 ± 29 bpm) components of the Bezold–Jarisch reflex were also lower in Mas-KO mice. In addition, chemoreflex pressor response (+20 ± 3 mm Hg vs. +12 ± 0.8 mm Hg) and bradycardic response (−250 ± 74 bpm vs. −52 ± 26 bpm) were significantly higher in Mas-KO. These results further advances previous studies by showing that the lack of Mas receptor induced important imbalance in the neural control of blood pressure, altering not only the baroreflex but also the chemo- and Bezold–Jarisch reflexes.

Neuregulin‐1/erbB signaling in rostral ventrolateral medulla of brainstem is involved in blood pressure regulation alteration of major neurotransmitters

BackgroundNeuregulin‐1 (NRG‐1) is a multifunctional modulator that acts through epidermal growth factor family of tyrosine kinase receptors, including erbB2‐4. In the central nervous system, NRG‐1/erbB pathway has been shown to affect both glutamatergic and GABAergic function. However, it is totally unknown if this signaling pathway is involved in central blood pressure regulation. Therefore, we determined if NRG‐1/erbB signaling in the rostral ventrolateral medulla (RVLM) contributes to blood pressure regulation by altering the major neurotranmsiiters' function.Methods and ResultsIn anesthetized male Wistar rats, we microinjected NRG‐1β(0.025 pmol), erbB2‐receptor antagonist (AG825: 1.0 pmol) into the RVLM. NRG‐1 decreased mean arterial pressure (MAP) and heart rate (HR) ΔMAP −23.2 ± 1.8 mmHg, Δ HR −40.7 ± 5.5 bpm, n=5), while AG825 increased MAP and HR (Δ MAP 19.2 ± 2.9 mmHg, ΔHR 16.8 ± 1.2 bpm, n=4). Pre‐microinjection of NMDA receptor antagonist (AP‐5) into the RVLM attenuated the AG825 induced‐pressor response (6.5 ± 1.2 mmHg). Pre‐microinjection of GABAA receptor antagonist (bicuculine) into the RVLM attenuated the NRG‐1β induced‐depressor response (−4.3 ± 2.5 mmHg).ConclusionNRG‐1/erbB signaling in the RVLM contributes to AP and HR regulation via the modulation of both glutamatergic and GABAergic function. This pathway in the RVLM is involved in neural control of blood pressure.

Induction of hypertension and peripheral inflammation by deletion of extracellular superoxide dismutase in the central nervous system

Superoxide has been implicated in central neural control of blood pressure. The circumventricular organs (CVO) lack a well‐formed blood‐brain barrier and produce superoxide (O2·‐) in response to angiotensin II and other hypertensive stimuli. The extracellular superoxide dismutase (SOD3) is expressed in cells associated with the CVO. To understand the role of SOD3 in the CVO in blood pressure regulation, we injected an adenovirus encoding Cre‐recombinase (AdCre, 5x108 particles/ml) intracerebroventricularly (ICV) in mice with loxP sites flanking the SOD3 coding region. Deletion of CVO SOD3 increased baseline blood pressure modestly and markedly augmented the hypertensive response to low‐dose angiotensin II (140 ng/kg/day). Deletion of CVO SOD3 also increased sympathetic modulation of heart rate and blood pressure variability, increased vascular superoxide production and T cell activation as characterized by increased circulating CD69+/CD3+ cells. Deletion of CVO SOD3 also markedly increased vascular T cell and leukocyte infiltration caused by angiotensin II. We conclude that SOD3 in the CVO plays a critical role in regulation of blood pressure and its loss promotes T cell activation and vascular inflammation. These findings provide insight into how central signals produce vascular inflammation in response to hypertensive stimuli such as angiotensin II. Funded by NIH R01 HL39006 and PPG HL58000.

A Molecular Sensor for the Baroreceptor Reflex?

The reflex that provides rapid neural control of blood pressure is triggered by an unknown molecular pressure sensor. ASIC2, an ion channel in a family that includes a mechanosensor from C. elegans, is shown by Lu et al. in this issue of Neuron to be critical for this reflex in mice, perhaps because ASIC2 is the elusive pressure sensor.

Age-dependent changes in adenosine A1 receptor distribution and density within the nucleus tractus solitarii of normotensive and hypertensive rats

This study shows the distribution and density of adenosine A1 receptor (A1R) within the nucleus tractus solitarii (NTS) of Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) from birth to adulthood (1, 15, 30 and 90 days old). The NTS shows heterogeneous distribution of A1R in dorsomedial/dorsolateral, subpostremal and medial/intermediate subnuclei. A1R decrease from rostral to caudal within dorsomedial/dorsolateral subnucleus in 15-, 30- and 90-day-old WKY and SHR. A1R increase from rostral to caudal subpostremal subnucleus in 30- and 90-day-old WKY, and in 15-, 30- and 90-day-old SHR. Furthermore, A1Rs are increased in SHR as compared with WKY within dorsomedial/dorsolateral in 30- and 90-day-old and within subpostremal of 15-, 30- and 90-day-old rats. Finally, A1Rs increase from 1- to 30-day-old rats. Medial/intermediate did not show any changes in A1R from rostral to caudal levels, age or strain. In summary, our result highlights the importance of A1 adenosine system regarding the neural control of blood pressure and the development of hypertension.

Neural control of blood pressure and cardiovascular reactivity to stress in a spontaneously hypertensive mouse

We investigated the contribution of the sympathetic nervous system (SNS) to spontaneous hypertension in the BPH/2J Schlager mouse. Male hypertensive (n = 6) and normotensive (BPN/3J; n = 8) mice were implanted with telemetry probes and recordings of cardiovascular and activity parameters made before and during aversive stress (shaker, restraint, cage‐swap) and non‐aversive stress (feeding). MAP was higher in BPH/2J than BPN/3J mice (128±1 vs 111±1 mmHg; P&lt;0.001) as was the day‐night difference in MAP in BPH/2J animals (17±2 vs 6±1 mm Hg; P&lt;0.001). Heart rate and activity were also greater in BPH/2J compared to BPN/3J (+19% and +88%, P&lt;0.001). BPH/2J showed greater pressor responses to aversive stress (+70–100%) but a slightly greater pressor responses to feeding (+21%) compared with BPN/3J. Sympathetic blockade by pentolinium reduced blood pressure to comparable levels in both strains. The greater pressor response to aversive stimuli in BPH/2J mice but not feeding also suggests that the greater stress response observed in these animals is not due to a vascular amplifying effect which would likely affect all behavioural responses. Our findings of an exaggerated day‐night rhythms, responses to pentolinium as well as the hyper‐responsiveness to aversive stimuli suggests a major contribution from the SNS in the hypertension observed in this animal model.

Neural Control of Blood Pressure: Focusing on Capsaicin-Sensitive Sensory Nerves

Hypertension is a major risk factor leading to devastating cardiovascular events such as myocardial infarction, stroke, heart failure, and renal failure. Despite intensive research in this area, mechanisms underlying essential hypertension remain to be defined. Accumulating evidence indicates that neural components including both sympathetic and sensory nerves innervating the cardiovascular and renal tissues play a key role in regulating water and sodium homeostasis and blood pressure, and that abnormalities in these nervous systems contribute to increased salt sensitivity and development of hypertension. In contrast to relatively well-defined sympathetic nervous system, the role of sensory nerves in the control of cardiovascular homeostasis is largely unknown. Data from our laboratory show that degeneration of capsaicin-sensitive sensory nerves renders a rat salt sensitive in terms of blood pressure regulation. Evidence is also available indicating that sensory nerves, in interacting with other neurohormonal systems including the sympathetic nervous system, the renin-angiotensin aldosterone system, the endothelin system, and superoxide, regulate cardiovascular and renal function in such that they play a counter-balancing role in preventing salt-induced increases in blood pressure under pathophysiological conditions. Altered activity of the sensory nervous system, a condition existed in both genetic and experimental models of hypertension, contributes to the development of hypertension. This article focuses on reviewing the current knowledge regarding the possible role of sensory nerves in regulating blood pressure homeostasis as well as the function and regulation of novel molecules expressed in sensory nerves.

Expression of Hypertension over Six Generations in Spontaneous Hypertension/Brown Norway (SHR/BN) Congenic Rats

Altered neural control of blood pressure is a major contributor to hypertension in the Aoki-Okamoto strain of SHR. This study measured the arterial blood pressures of offspring over six generations (F1–F6) of breeding in a congenic colony derived from mating a female hypertensive, SHR with a mean arterial pressure (MAP) averaging 151 mmHg with a normotensive BN male (MAP averaging 94 mmHg). Hypertension was defined in all offspring as a MAP ≥ 125mmHg, normotension as MAP ≤ 105mmHg and borderline hypertension as 105mmHg < MAP < 125mmHg. F1 – F5 female offspring with a MAP ≥ 125mmHg were back bred to the original, normotensive, BN male. Offspring at each generation were raised to adulthood and blood pressure measurements were obtained by tail cuff plethysmography at 8, 12, and 16 weeks of age, as well as into later adulthood ages. F6 generation (n=25), hypertension has been maintained in 24% (n=6) of the offspring of the original BN/SHR cross, with pressures ranging from 125mmHg-135mmHg. Borderline hypertension has been maintained in 60% (n=15) of F6 rats whereas normotension accounts for 16% (n=4). These results document that the dominant alleles responsible for the development of neurogenic hypertension can be isolated on a genetic background of BN rats that are resistant to hypertension.

Time course analysis of tyrosine hydroxylase and angiotensinogen mRNA expression in central nervous system of rats submitted to experimental hypertension

Catecholaminergic and angiotensinergic systems are involved in the neural control of blood pressure. The present study analysed the expression of tyrosine hydroxylase (TH), a key enzyme for catecholamine synthesis and of angiotensinogen (AGT), the precursor of angiotensin II (Ang II), in areas of the central nervous system (CNS) involved with cardiovascular regulation such as nucleus tractus solitarius (NTS), ventrolateral medulla (VLM), locus coeruleus (LC) and hypothalamic paraventricular nucleus (PVN) 2 h, 3 and 7 days after aortic coarctated hypertensive rats. In situ hybridization, was employed for the analysis of messenger RNA (mRNA) expression with anatomical resolution. No changes were seen in TH and AGT mRNA expression in the analysed areas 2 h and 3 days after aortic coarctation when compared to the respective sham group. TH mRNA expression was increased in the NTS and LC of rats 7 days after coarctation hypertension when compared to sham rats. Time course analysis, showed an increase in TH mRNA expression in the NTS 7 days after aortic coarctation when compared to 2 h and 3 days groups, as well as an increase in LC 3 days and 7 days following coarctation hypertension in comparison with the 2 h group. Analysis of AGT mRNA in the NTS expression revealed a decrease at 3 days, followed by an increase in mRNA expression 7 days following coarctation hypertension when compared to the sham group. Time course analysis, showed an increase in AGT mRNA expression in the NTS 7 days after coarctation when compared to 2 h and 3 days groups. The results show that TH and AGT mRNA expression changes during the different phases of experimental hypertension, suggesting that the noradrenaline (NOR) and angiotensin II (Ang II) might participate in the modulation/maintenance of coarctation hypertension.

Superoxide Mediates Angiotensin II–Induced Influx of Extracellular Calcium in Neural Cells

We recently demonstrated that superoxide (O2*-) is a key signaling intermediate in central angiotensin II (Ang II)-elicited blood pressure and drinking responses, and that hypertension caused by systemic Ang II infusion involves oxidative stress in cardiovascular nuclei of the brain. Intracellular Ca2+ is known to play an important role in Ang II signaling in neurons, and it is also linked to reactive oxygen species mechanisms in neurons and other cell types. However, the potential cross-talk between Ang II, O2*-, and Ca2+ in neural cells remains unknown. Using mouse neuroblastoma Neuro-2A cells, we tested the hypothesis that O2*- radicals are involved in the Ang II-induced increase in intracellular Ca2+ concentration ([Ca2+]i) in neurons. Ang II caused a rapid time-dependent increase in [Ca2+]i that was abolished in cells bathed in Ca2+-free medium or by pretreatment with the nonspecific voltage-gated Ca2+ channel blocker CdCl2, suggesting that voltage-sensitive Ca2+ channels are the primary source of Ang II-induced increases in [Ca2+]i in this cell type. Overexpression of cytoplasm-targeted O2*- dismutase via an adenoviral vector (AdCuZnSOD) efficiently scavenged Ang II-induced increases in intracellular O2*- and markedly attenuated the increase in [Ca2+]i caused by this peptide. Furthermore, adenoviral-mediated expression of a dominant-negative isoform of Rac1 (AdN17Rac1), a critical component for NADPH oxidase activation and O2*- production, significantly inhibited the increase in [Ca2+]i after Ang II stimulation. These data provide the first evidence that O2*- is involved in the Ang II-stimulated influx of extracellular Ca2+ in neural cells and suggest a potential intracellular signaling mechanism involved in Ang II-mediated oxidant regulation of central neural control of blood pressure.

Blockade of dorsal hippocampal kappa-opioid receptors increases blood pressure in normotensive and isolation-induced hypertensive rats

Previous research in our laboratory has established a restraining role of the hippocampal kappa-opioid receptor system in the neural control of blood pressure. Chronic or acute hippocampal administration of kappa-agonists has been shown to reduce blood pressure. Isolation of male Sprague–Dawley rats provokes an increase in blood pressure, which has been proposed as a valid model of mild emotionally induced hypertension. It was the purpose of this study to investigate the blood pressure effects of dorsal hippocampal administration of nor-binaltorphimine (nor-BNI), a selective kappa-opioid receptor antagonist; in conscious male Sprague–Dawley rats subjected to isolation-induced hypertension. Chronic bi-hippocampal microinjection of nor-BNI (10 nmol per side, twice a day for 13 days) caused increases in systolic blood pressure in grouped rats from a mean of 125 to 148 mmHg, and in isolated rats from a mean of 125 to 151 mmHg. This hypertension was similar in magnitude to the increase observed after rats were isolated for 7 days and treated with vehicle in a similar fashion (mean systolic blood pressure 144 mmHg). The increases in blood pressure were accompanied by bradycardia. No significant responses were seen in the blood pressure of grouped rats treated with vehicle. The hypotensive response to a single hippocampal microinjection of the kappa-agonist U62, 066E (10 or 20 nmol) was prevented in anesthetized rats treated previously with nor-BNI, indicating that in the nor-BNI treated rats there was effective blockade of dorsal hippocampal receptors. These data suggest that the rat hippocampal kappa-opioid receptor system and the endogenous neuropeptide dynorphin may be involved in the central neural regulation of blood pressure.