Sustained Increase In Mean Arterial Pressure Research Articles

The Effects of Pregnancy on the Sympathoexcitatory and Pressor Responses to Nanoinjection of Angiotensin II into the Arcuate Nucleus

Pregnancy induces profound increases in sympathetic nerve activity (SNA). Angiotensin II (AngII) may contribute, since systemic or central blockade of AngII production or receptors (AT1aR) decreases SNA in pregnant animals. However, the brain sites involved are unknown. One possibility is the arcuate nucleus (ArcN), since AngII binds to ArcN AT1aR to increase SNA, and the ArcN is a well‐established reproductive integrating center. To begin to test this hypothesis, we measured the changes in SNA and mean arterial pressure (MAP) in response to bilateral nanoinjections of AngII (30 pmol in 30 nL) into the ArcN of α‐chloralose anesthetized pregnant rats and virgin rats throughout the estrus cycle. ArcN AngII slowly increased (P<0.05) lumbar SNA (LSNA) in pregnant rats (by 50±10 % after 90 min; n=6), and the rise was larger than in proestrus rats (‐1±8 %; n=5; P<0.05), similar to diestrus rats (40±9 %; n=4), but less than estrus rats (72±12 %; n=6; P<0.05). ArcN AngII rapidly increased (P<0.05) MAP by ~10 mmHg (after 10 min) in all groups, but after 90 min the increase was sustained (P<0.05) only in pregnant (13±2 mmHg) and estrus (11±4 mmHg) rats. A cohort of ArcN neurons projects to and stimulates vasopressinergic neurons in the hypothalamic paraventricular and supraoptic nuclei. Therefore, to test if the initial or sustained increases in MAP were mediated by vasopressin, another set of estrus and pregnant rats were pretreated with the Manning Compound (V1x; 5 μg iv) 15 min before ArcN AngII. In estrus rats (n=4), V1x had no effects on baseline LSNA or MAP, but completely blocked the initial rise in MAP induced by ArcN AngII (2±3 mmHg). Nevertheless, the increase in MAP at 90 min was unchanged (13±3 mmHg; P<0.05). The LSNA response to ArcN AngII (83±9 %) was also not altered. In pregnant rats pretreated with V1x (n=4), baseline MAP decreased (P<0.05) by 10±1 mmHg, and again ArcN AngII failed to increase MAP initially (2±1 mmHg). However, the increase in MAP 90 min after ArcN AngII (7±2 mmHg) was the same as the increase 90 min after injection of artificial cerebrospinal fluid into the ArcN of V1x‐treated pregnant rats (5±2 mmHg). Again, the increase in LSNA to ArcN AngII was unchanged (30±6 %). Finally, RNAScope was used to assay AT1aR mRNA expression in the ArcN in diestrus, proestrus, and pregnant rats. ArcN AT1aR were undetectable in proestrus rats and were expressed at low but detectable levels in diestrus rats. In contrast, pregnancy markedly increased the expression of AT1aR in the ArcN. In summary, during pregnancy, ArcN AngII produces substantial increases in LSNA in association with elevated AT1aR expression. Moreover, the increase in MAP in response to ArcN AngII was reduced or eliminated in estrus and pregnant rats pretreated with a vasopressin V1 receptor blocker. In conclusion, these data highlight the ArcN as a potential site at which AngII increases SNA during normal pregnancy. The data also suggest that AngII can elicit an increase in vasopressin secretion via an action in the ArcN and that vasopressin contributes to the pressor responses induced by ArcN AngII in both estrus and pregnant rats.Support or Funding InformationHL128181

Abstract P149: VEGF Inhibitor-Induced Hypertension and Renal Injury: Prevention by Aspirin?

Vascular endothelial growth factor inhibitor (VEGFi)-induced hypertension and renal injury in cancer patients mimic the clinical phenotype of preeclampsia. ET-1 has been implicated to be involved. Since aspirin can prevent the onset of preeclampsia, we hypothesized that co-treatment of the VEGFi sunitinib (SU) with aspirin might be beneficial and may improve ET-1 status. Male WKY rats were treated with vehicle, 14 mg/kg/day SU, or SU + low or high dose aspirin (5 or 100 mg/kg/day) for 8 days. Mean arterial pressure (MAP) was measured via radiotelemetry. On day 8, 24h urine was collected to determine albuminuria and prostanoid (PGF2α and TxB2) levels. Plasma endothelin-1 (ET-1) was measured via ELISA. Endothelial dysfunction was assessed in iliac vessels and reactive oxygen species (ROS) was measured via aortic superoxide anion production. Renal cyclooxygenase (COX)-1, COX-2 and ET-1 mRNA expression were determined via PCR. SU induced a rapid and sustained increase in MAP (24±2 versus 1±1 mmHg in vehicle on day 6; P<0.001), which was blunted by both low and high aspirin doses (18±3 and 13±4 mmHg respectively on day 6; P<0.05 versus SU). Plasma ET-1 was increased by SU (2.2±0.3 versus 1.4±0.1 pg/ml in vehicle; P<0.05) and this was not affected by aspirin. SU increased albuminuria (1.2±0.2 versus 0.3±0.1 mg/24h in vehicle; P<0.05) which was prevented by high, but not low dose aspirin (0.5±0.1 and 1.3±0.1 mg/24h, respectively), suggesting that this effect is COX-2 dependent. Although renal mRNA expression levels were unchanged, renal COX-2 and ET-1 mRNA expression correlated positively, suggesting that ET-1 upregulates COX-2. SU increased ROS production 2.5-fold (P<0.05 versus vehicle) and this was prevented by both aspirin doses. SU did not induce endothelial dysfunction, nor did it alter prostanoid levels. However, both aspirin doses reduced TxB2 (P<0.05 versus vehicle). In conclusion, high rather than low dose aspirin was more efficacious for the prevention of VEGFi-induced hypertension and renal injury, suggesting that its beneficial effects largely involve COX-2 inhibition. Aspirin may be a novel intervention to allow cancer patients to gain the full benefit of VEGFi without deleterious cardiovascular and renal side effects.

Abstract P186: Selective ET A Receptor Antagonism versus Dual ET A /ET B Receptor Blockade for Preventing Angiogenesis Inhibitor-induced Hypertension

Angiogenesis inhibitors are a mainstay treatment for cancer. While effective in preventing tumor growth, angiogenesis inhibitors cause off-target effects including cardiovascular toxicity and renal injury, most likely via endothelin-1 (ET-1) upregulation. ET-1 via stimulation of the ET A receptor causes pro-hypertensive effects whereas stimulation of the ET B receptor can elicit both pro- or anti-hypertensive effects. In the present study, we hypothesized that selective ET A receptor blockade versus dual ET A /ET B blockade provides better cardiovascular protection from angiogenesis inhibitor-induced hypertension. Male WKY rats were treated with vehicle, sunitinib (VEGF inhibitor; 14 mg/kg/day) alone or in combination with macitentan (ET A/B receptor antagonist; 30 mg/kg/day) or sitaxentan (ET A receptor antagonist; 30 or 100 mg/kg/day) for 8 days. Mean arterial pressure (MAP) was measured via radiotelemetry at baseline and days 1-6 of treatment. Vasoreactivity to acetylcholine (ACh) and ET-1 was assessed in iliac vessels. Compared to vehicle treatment, sunitinib treatment caused a rapid and sustained increase in MAP (1±1 versus 23±2 mmHg on day 6 of treatment, respectively, P<0.001). Co-treatment with macitentan blunted the pressor response to sunitinib, such that on day 6 of treatment the increase in MAP was 7±4 mmHg (P<0.01 versus sunitinib-treated). Similar results were observed for co-treatment with 30 mg/kg/day of sitaxentan. Conversely, co-treatment with 100 mg/kg/day sitaxentan, which has been shown to induce a depressor response in normotensive Wistar rats, completely abolished sunitinib-induced hypertension, with MAP actually decreasing before returning to near baseline level (-1±1 mmHg on day 6 of treatment, P<0.001 versus sunitinib-treated). Compared to vehicle treatment, ET B receptor stimulation yielded a constrictor response after 8 days of sunitinib treatment, while the response to ACh was unaltered. Both macitentan and sitaxentan reversed the constrictor ET B receptor response. Our results support a key role for the ET-1 system in the development of sunitinib-induced hypertension and suggest that selective ET A receptor blockade is sufficient to block this effect.

Possible Respiratory Modulation of Sympathetic Activity in Rats After Sino‐aortic Denervation

It is well known that several days after sino‐aortic denervation (SAD) rats present normal levels of sympathetic activity and mean arterial pressure (MAP). However, the mechanisms involved in the modulation of the sympathetic activity after SAD remain unclear. Here we hypothesized that the respiratory network may contribute to the modulation of the pre‐sympathetic neurons preventing sustained increase in MAP in SAD rats. To study this mechanism we recorded the activities of phrenic, thoracic sympathetic (tSNA) and cervical vagus nerves (cVN) in male juvenile Wistar rats in the working heart‐brainstem preparation, at high or low respiratory drive induced by hypercapnia or hypocapnia, respectively (SAD, n = 26 and Sham, n = 33). The duration of inspiration significantly increased in SAD rats (1.46 ± 0.05 vs 1.14 ± 0.07 s, P < 0.001). It was also observed that SAD increases cVN inspiratory activity (25 ± 1 vs 32 ± 2%, P < 0.05) and decreases in its post‐inspiratory component (76 ± 1 vs 68 ± 2%, P < 0.05), suggesting an increased upper airway resistance during inspiration in SAD rats. Regarding the baseline tSNA, no changes were observed in the baseline tSNA in all phases of the respiratory cycle in SAD rats, which presented significant reduction in the Traube‐Hering waves magnitude (2.57 ± 0.04 vs 1.19 ± 0.20 mmHg, P = 0.0048). In order to reveal the influence of the respiratory network on the modulation of sympathetic activity rats were exposed to hypercapnia (from 5 to 10 % of CO2) or hypocapnia (from 5 to 3 and 1 % of CO2). High respiratory drive induced by hypercapnia increases tSNA in all phases of respiration in Sham rats (n=13), but in SAD rats (n=14) a significant increase in tSNA was observed only during inspiration (43 ± 3% vs 55 ± 3%, P < 0.01). On the other hand, hypocapnia reduced the respiratory drive and induced sympatho‐inhibition in the SAD (n=8) and in Sham rats (n=10). The data show that in spite of longer inspiratory activity, the baseline sympathetic activity is normal in SAD rats. Whether or not the longer inspiratory activity is driving the sympathetic activity in SAD rats is still matter for further investigation.Support or Funding InformationFAPESP, CAPES and CNPq

Angiotensin II type 1a receptors in subfornical organ contribute towards chronic intermittent hypoxia-associated sustained increase in mean arterial pressure

Sleep apnea is associated with hypertension. The mechanisms contributing to a sustained increase in mean arterial pressure (MAP) even during normoxic awake-state remain unknown. Rats exposed to chronic intermittent hypoxia for 7 days, a model of the hypoxemia associated with sleep apnea, exhibit sustained increases in MAP even during the normoxic dark phase. Activation of the renin-angiotensin system (RAS) has been implicated in chronic intermittent hypoxia (CIH) hypertension. Since the subfornical organ (SFO) serves as a primary target for the central actions of circulating ANG II, we tested the effects of ANG II type 1a receptor (AT1aR) knockdown in the SFO on the sustained increase in MAP in this CIH model. Adeno-associated virus carrying green fluorescent protein (GFP) and small-hairpin RNA against either AT1aR or a scrambled control sequence (SCM) was stereotaxically injected in the SFO of rats. After recovery, MAP, heart rate, respiratory rate, and activity were continuously recorded using radiotelemetry. In the normoxic groups, the recorded variables did not deviate from the baseline values. Both CIH groups exhibited significant increases in MAP during CIH exposures (P < 0.05). During the normoxic dark phase in the CIH groups, only the SCM-injected group exhibited a sustained increase in MAP (P < 0.05). The AT1aR-CIH group showed significant decreases in FosB/ΔFosB staining in the median preoptic nucleus and the paraventricular nuclei of the hypothalamus compared with the SCM-CIH group. Our data indicate that AT1aRs in the SFO are critical for the sustained elevation in MAP and increased FosB/ΔFosB expression in forebrain autonomic nuclei associated with CIH.

Abstract MP04: In Vivo Bioluminescence Imaging Reveals a Pre-Hypertensive Surge of Nuclear-Factor-κ-B (NF-κB) Activity in the Subfornical Organ (SFO) During Obesity-Induced Hypertension

The central nervous system has been implicated in obesity-induced sympathetic activation and hypertension, although the underlying mechanisms remain unclear. We tested the hypothesis that the transcription factor NF-κB is activated in the SFO, a key cardioregulatory brain center, during the development of obesity-induced hypertension. Male C57Bl/6 mice were instrumented with radiotelemeters for mean arterial pressure (MAP) recording, and underwent SFO-targeted microinjection of an adenovirus encoding firefly luciferase downstream of the NF-κB response elements. After recovery, mice were fed high fat diet (60% fat) or normal chow (5% fat), and SFO NF-κB activity was longitudinally monitored in vivo by bioluminescence imaging coupled with luciferin injections. In response to HFD, a slowly developing hypertension was observed, with an initial rise in MAP at 4 weeks (109 ± 1 vs 117 ± 1 mmHg; day 0 vs day 28; n=8; p&lt;0.05) that was sustained for 8 weeks. NF-κB activity in the SFO increased gradually during HFD feeding, with a surge at 3 weeks, prior to a rise in MAP (day 21: 0.91 ± 0.08 vs 1.70 ± 0.25 photons/s fold baseline; normal chow vs HFD; n=4-7; p&lt;0.05). SFO NF-κB activity transiently subsided and a second elevation was noted during the maintenance of obesity-induced hypertension at 6.5 weeks (day 42: 0.72 ± 0.14 vs 1.52 ± 0.07 photons/s fold baseline; normal chow vs HFD; n=4-7; p&lt;0.05). These findings suggest that NF-κB is activated in the SFO during HFD feeding. The biphasic increase in NF-κB activity prior to and during a sustained increase in MAP suggests a casual role for SFO NF-κB in the development of obesity-induced hypertension. HL63887, HL84207, AHA13POST14410020, K99HL166776

Angiotensin II receptor type‐1a knockdown in subfornical organ prevents sustained increase in mean arterial pressure associated with chronic intermittent hypoxia (686.20)

Sleep apnea (SA) is associated with a sustained increase in mean arterial pressure (MAP) even during waking hours. Chronic intermittent hypoxia (CIH) models the hypoxemia associated with SA and produces elevated MAP during CIH and normoxia. Angiotensin II (Ang II) is implicated in the CIH associated increase in MAP. Subfornical organ (SFO), a forebrain circumventricular organ, lacks blood brain barrier and is a major site for the central effects of circulating Ang II. We investigated the effects of Ang II type 1a receptor knockdown (AT1aRKD) in the SFO on CIH hypertension in adult male rats. Adeno‐associated viral vectors carrying GFP and either AT1aR shRNA or scrambled shRNA (SCM) were injected in SFO. Using laser‐capture microdissection and qRT‐PCR of amino‐allyl RNA, AT1aRKD rats showed decreased SFO AT1aRmRNA in comparison with SCM rats (p&lt;0.05). During light phase, the AT1aRKD rats exposed to CIH(3 min 10% O2 and 3 min room air cycles for 8 h during light phase for 7 d) exhibited significant increases in MAP vs. AT1aRKD‐Normoxia group (p&lt;0.05). During the normoxic dark phase, there was no difference in MAP between CIH and normoxic AT1aRKD rats (p=0.69). SCM‐CIH group showed significant increase in MAP from SCM‐Normoxia group during light phase CIH (p&lt;0.001) and the normoxic dark phase (p&lt;0.001). Our data indicate that AT1aRs in SFO may play a role in the sustained increases in MAP during normoxia associated with CIH.Grant Funding Source: Supported by: P01HL088052‐05

AT1a Receptor Knockdown in the Median Preoptic Nucleus Attenuates the Sustained Component of Hypertension Resulting from Chronic Intermittent Hypoxia

Obstructive sleep apnea produces hypertension and increases sympathetic nerve activity during the hypoxic sleeping events as well as during the waking hours. To model the hypoxemia experienced during sleep apnea, rodents are exposed to chronic intermittent hypoxia (CIH). The median preoptic nucleus (MnPO) is a forebrain region that contributes to this sustained increase in mean arterial pressure (MAP) from CIH. This region integrates information from forebrain circumventricular organs and projects to the paraventricular nucleus to influence sympathetic nerve activity. Our lab has previously shown that in response to CIH there is increased ΔFosB expression in the MnPO and that after a 7 day hypoxia protocol MnPO AT1a receptor mRNA is increased 7 fold whereas AT1b shows no change. In this study, we tested the hypothesis that MnPO AT1a receptors contribute to CIH hypertension using adult male Sprague Dawley rats injected with a neuron specific adenoviral vector with either shRNA to knock down expression of AT1a receptors in the MnPO or a scrambled RNA sequence. All rats showed an increase in MAP during the hypoxic light period, but rats receiving the AT1a knock down did not exhibit the sustained increase in MAP during the normoxic dark phase (P&lt;.05). This data indicates that the AT1a receptor in the MnPO is necessary for the sustained component of hypertension resulting from CIH. P01 HL‐88052

Role of cardiac output versus peripheral vasoconstriction in mediating muscle metaboreflex pressor responses: dynamic exercise versus postexercise muscle ischemia

Muscle metaboreflex activation (MMA) during submaximal dynamic exercise in normal individuals increases mean arterial pressure (MAP) via increases in cardiac output (CO) with little peripheral vasoconstriction. The rise in CO occurs primarily via increases in heart rate (HR) with maintained or slightly increased stroke volume. When the reflex is sustained during recovery (postexercise muscle ischemia, PEMI), HR declines yet MAP remains elevated. The role of CO in mediating the pressor response during PEMI is controversial. In seven chronically instrumented canines, steady-state values with MMA during mild exercise (3.2 km/h) were observed by reducing hindlimb blood flow by ~60% for 3-5 min. MMA during exercise was followed by 60 s of PEMI. Control experiments consisted of normal exercise and recovery. MMA during exercise increased MAP, HR, and CO by 55.3 ± 4.9 mmHg, 42.5 ± 6.9 beats/min, and 2.5 ± 0.4 l/min, respectively. During sustained MMA via PEMI, MAP remained elevated and CO remained well above the normal recovery levels. Neither MMA during dynamic exercise nor during PEMI significantly affected peripheral vascular conductance. We conclude that the sustained increase in MAP during PEMI is driven by a sustained increase in CO not peripheral vasoconstriction.

Rapid, dynamic changes in glomerular permeability to macromolecules during systemic angiotensin II (ANG II) infusion in rats

The actions of systemic angiotensin II (ANG II) infusions on glomerular permeability were investigated in vivo. In anesthetized Wistar rats (250-280 g), the left ureter was cannulated for urine collection, while simultaneously blood access was achieved. Rats were continuously infused intravenously with either of four doses of ANG II ranging from 16 ng·kg(-1)·min(-1) (Lo-ANG II) to 1.82 μg·kg(-1)·min(-1) (Hi-ANG II), and in separate experiments with aldosterone (Aldo; 0.22 mg·kg(-1)·min(-1)), or with the calcium channel blocker nimodipine, or with the Aldo antagonist spironolactone together with a high ANG II dose (910 ng·kg(-1)·min(-1); Hi-Int-ANG II), respectively, and with polydisperse FITC-Ficoll-70/400 (molecular radius 10-80 Å) and (51)Cr-EDTA. Plasma and urine samples were taken at 5, 15, 30, 60, and 120 min and analyzed by high performance size-exclusion chromatography for determination of glomerular sieving coefficients (θ) to Ficoll. Mean arterial pressure (MAP) and glomerular filtration rate (GFR) were also assessed. For ANG II, there was a rapid, marked, partly reversible increase in glomerular permeability (θ) for Ficoll molecules >34 Å in radius, peaking at 5-15 min, which was completely abrogated by the ANG II blocker candesartan but not affected by spironolactone at 15 and 30 min. For Aldo, the response was similar to that found for the lowest dose of ANG II infused. For the two highest ANG II doses given (Hi-Int-ANG II and Hi-ANG II), GFR decreased transiently, concomitant with marked, sustained increases in MAP. Nimodipine completely blocked all hemodynamic ANG II actions, whereas the glomerular permeability response remained unchanged. Thus ANG II directly increased glomerular permeability independently of its hemodynamic actions and largely independently of the concomitant Aldo response. The ANG II-induced increases in glomerular permeability were, according to a two-pore and a log-normal distributed pore model, compatible with an increased number of "large pores" in the glomerular filter, and, to some extent, an increase in the dispersity of the small-pore radius.

Role of cardiac output vs. peripheral vasoconstriction in mediating the muscle metaboreflex pressor response during dynamic exercise and post‐exercise muscle ischemia

Muscle metaboreflex activation (MMA) during sub‐maximal dynamic exercise in normal individuals increases mean arterial pressure (MAP) via increases in cardiac output (CO) with little peripheral vasoconstriction. The rise in CO occurs primarily via increases in heart rate (HR) with maintained or slightly increased stroke volume. When the reflex is sustained during recovery (postexercise muscle ischemia ‐ PEMI), HR declines yet MAP remains elevated. The role of CO in mediating the pressor response during PEMI is controversial. In five chronically instrumented canines, steady state values with MMA during mild exercise (3.2 kph) were observed by reducing hindlimb blood flow by ~60% for 3–5 minutes. MMA was followed by 60 seconds of PEMI. Control experiments consisted of normal exercise and recovery. MMA during exercise increased MAP, HR and CO by 61.4 ± 4.0 mmHg, 47.1 ± 7.8 bpm, and 2.71 ± 0.43 l/min, respectively. During sustained MMA via PEMI, MAP remained elevated and CO remained well above the normal recovery levels. Neither MMA during dynamic exercise nor during PEMI significantly affected peripheral vascular conductance. We conclude that the sustained increase in MAP during PEMI is driven by a sustained increase in CO not peripheral vasoconstriction. HL‐55743 and HL‐095819

Involvement of activation of Janus kinase (JAK)2 in the mechanisms utilized by Norepinephrine (NE) to cause hypertension.

Angiotensin II (ANG II) utilizes activation of JAK2 signaling pathways to cause hypertension. It is unknown if NE is dependent on JAK2 pathway activation to increase in blood pressure. We hypothesized that NE requires JAK2 activation to increase blood pressure. Male Sprague‐Dawley rats were catheterized via abdominal aorta and femoral vein to chronically measure blood pressure and infuse drugs. NE and ANG II were infused for 18 days and tissues harvested for western blot analysis. Mean arterial pressure (MAP) increased significantly in the ANG II and NE infused rats. There was a significant increase in phosphorylation levels of JAK2 as measured by Western blot analysis in the ANG II (10 ng/kg/min) and NE (2.8 mg/kg/day) treated rats than the saline controls. Infusion of JAK2 inhibitor AG490 (10 ng/kg/min) did not inhibit initial NE‐induced increases in blood pressure but did reduce NE's ability to maintain sustained increases in MAP. To determine if NE also requires a vascular component that involves JAK2 activation we utilized ex vivo myograph recordings. Using the thoracic aorta from naïve male rats we tested whether NE requires JAK2 activation for vascular contraction. We found that NE‐induced contraction was not significantly reduced by treatment with the JAK2 inhibitor AG490. These data suggest that NE and ANG II both increase and utilize JAK2 activation but via different mechanisms. (ABB NHLBI R00; MWB NHLBI R01).

Baroreceptors and the long-term control of blood pressure.

The current consensus is that arterial baroreceptors are vitally important in the short term (seconds to minutes) control of mean arterial pressure (MAP) but are unimportant in determining the long-term level of MAP. The latter statement is based primarily on two observations: first, that baroreceptors rapidly reset to the prevailing level of MAP and second, that total baroreceptor denervation has no lasting effect on the average daily MAP, although the variability of MAP is increased dramatically. However, recent studies in intact experimental animals have produced results that suggest baroreceptor resetting may not be as rapid or complete as previously thought. Furthermore, reconsideration of the responses to baroreceptor denervation suggest that the condition may accurately represent responses to short-term baroreceptor unloading but not long-term unloading. Results obtained using a new model of chronic baroreceptor unloading indicate that the condition results in a sustained increase in MAP. These results strongly suggest that the role of baroreceptors in the long term control of MAP needs to be revisited.

Circadian differences in stress-induced pressor reactivity in mice.

The objective of this study was to determine the effect of chronic stress exposure on the circadian pattern of cardiovascular responses in mice. Using male C57BL6 mice with carotid arterial catheters, we tested the effect of 7 days of intermittent shaker stress on body weight, food intake, drinking activity, plasma corticosterone, mean arterial pressure (MAP), and heart rate. The stress was delivered automatically for 2-minute periods (150 cycles/min), 45 times/d for 7 days. Plasma corticosterone was significantly increased in acutely and chronically stressed mice, with a partial attenuation in the chronic condition. Stress increased water intake, produced no change in food intake, and significantly decreased body weight (5% change). MAP and heart rate were measured continuously on stress days 1, 3, and 7 and during the basal and recovery periods. Chronic stress did not produce a sustained increase in MAP; however, there was an increase in MAP during the first stress day and a decrease during the recovery period. There was a circadian pattern in the pressor responses, with greater increases seen during the light period (nonactive phase) than in the dark period (+24% versus +11% on stress day 3, light versus dark). The results suggest that a stress delivered during the nonactive phase represents a higher cardiovascular risk.

Shifting hemodynamics of blood pressure control during prolonged mental stress

The present study examined the hemodynamics underlying blood pressure elevations for evidence of a shift in the control of blood pressure during prolonged mental stress. Mean arterial pressure (MAP), cardiac output (CO), and total peripheral resistance (TPR) were measured at rest, during a 28-min mental arithmetic stress task, and during recovery, in 30 young healthy men and women. The stress task elicited a sustained increase in MAP: CO rose during the first half of the task but returned to baseline levels during the last quarter of the task, whereas TPR increased as the task progressed. When participants' hemodynamic reactions were classified as cardiac, vascular, or neither, there were more cardiac reactors early relative to late in the task, whereas there were more vascular reactors late relative to early. Thus, the sustained pressor response was initially supported mainly by cardiac mechanisms but subsequently by predominantly vascular mechanisms.

Shifting hemodynamics of blood pressure control during prolonged mental stress

The present study examined the hemodynamics underlying blood pressure elevations for evidence of a shift in the control of blood pressure during prolonged mental stress. Mean arterial pressure (MAP), cardiac output (CO), and total peripheral resistance (TPR) were measured at rest, during a 28‐min mental arithmetic stress task, and during recovery, in 30 young healthy men and women. The stress task elicited a sustained increase in MAP: CO rose during the first half of the task but returned to baseline levels during the last quarter of the task, whereas TPR increased as the task progressed. When participants' hemodynamic reactions were classified as cardiac, vascular, or neither, there were more cardiac reactors early relative to late in the task, whereas there were more vascular reactors late relative to early. Thus, the sustained pressor response was initially supported mainly by cardiac mechanisms but subsequently by predominantly vascular mechanisms.

Endothelin-1-induced elevation in blood pressure is independent of increases in sympathetic nerve activity in normotensive rats.

This study was performed to determine if endothelin-1 (ET-1)-induced pressor responses in urethane-anesthetized, normotensive rats are due to increased sympathetic nerve activity. Renal sympathetic nerve activity (RSNA) was used as an index of sympathetic nerve activity. ET-1 (30- 1000 pmol/kg) or sarafotoxin (S6c, ET B receptor agonist, 10-3,000 nmol/kg) given by bolus injection produced transient decreases in mean arterial pressure (MAP) and increases in RSNA and heart rate (HR). ET-1 caused a delayed but sustained increase in MAP that was not inhibited by acute sinoaortic denervation or alpha 1 -adrenergic receptor blockade. ET-1 never caused a sustained change in HR or RSNA. A-192621 (ET B receptor antagonist, 12 mg/kg) increased MAP (10-20 mm Hg) and decreased HR and RSNA. A-192621 blocked the transient decrease in MAP and increase in RSNA and HR caused by ET-1 and S6c. In A-192621-treated rats, ET-1, but not S6c, caused a sustained increase in MAP and decrease in HR and RSNA. After A-192621 treatment, ET-1 infusion caused a sustained elevation in MAP; HR and RSNA decreased only after the highest ET-1 dose. These results indicate that the initial increase in RSNA after ET-1 or S6c is secondary to ET B receptor-mediated vasodilation. Increased RSNA does not contribute to ET-1-induced pressor responses; these responses are likely due to vasoconstriction in normotensive, anesthetized rats. Finally, baroreceptor reflexes function after ET-1 or S6c treatment.

Baroreflexes prevent neurally induced sodium retention in angiotensin hypertension.

Recent studies indicate that renal sympathetic nerve activity is chronically suppressed during ANG II hypertension. To determine whether cardiopulmonary reflexes and/or arterial baroreflexes mediate this chronic renal sympathoinhibition, experiments were conducted in conscious dogs subjected to unilateral renal denervation and surgical division of the urinary bladder into hemibladders to allow separate 24-h urine collection from denervated (Den) and innervated (Inn) kidneys. Dogs were studied 1) intact, 2) after thoracic vagal stripping to eliminate afferents from cardiopulmonary and aortic receptors [cardiopulmonary denervation (CPD)], and 3) after subsequent denervation of the carotid sinuses to achieve CPD plus complete sinoaortic denervation (CPD + SAD). After control measurements, ANG II was infused for 5 days at a rate of 5 ng. kg(-1). min(-1). In the intact state, 24-h control values for mean arterial pressure (MAP) and the ratio for urinary sodium excretion from Den and Inn kidneys (Den/Inn) were 98 +/- 4 mmHg and 1.04 +/- 0.04, respectively. ANG II caused sodium retention and a sustained increase in MAP of 30-35 mmHg. Throughout ANG II infusion, there was a greater rate of sodium excretion from Inn vs. Den kidneys (day 5 Den/Inn sodium = 0.51 +/- 0.05), indicating chronic suppression of renal sympathetic nerve activity. CPD and CPD + SAD had little or no influence on baseline values for either MAP or the Den/Inn sodium, nor did they alter the severity of ANG II hypertension. However, CPD totally abolished the fall in the Den/Inn sodium in response to ANG II. Furthermore, after CPD + SAD, there was a lower, rather than a higher, rate of sodium excretion from Inn vs. Den kidneys during ANG II infusion (day 5 Den/Inn sodium = 2.02 +/- 0.14). These data suggest that cardiac and/or arterial baroreflexes chronically inhibit renal sympathetic nerve activity during ANG II hypertension and that in the absence of these reflexes, ANG II has sustained renal sympathoexcitatory effects.

Subtypes of metabotropic glutamate receptors in the nucleus of the solitary tract of rats

We have determined the role of subgroups of metabotropic glutamate receptors (mGluRs) in the nucleus of the solitary tract (NTS) of normotensive Wistar rats. Unilateral microinjection of ( S)-3,5-dihydroxyphenylglycine (3,5-DHPG), an agonist of group I mGluRs, into the NTS significantly decreased mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) (−19.4±2.6 mmHg, −16.4±5.1 beats/min, and −30.6±5.7% by 1 nmol). Microinjection of ( R, S)-1-aminoindan-1,5-dicarboxylic acid (AIDA; 1 nmol), a putative antagonist of group I mGluRs, into the NTS caused transient decreases in MAP and RSNA, followed by sustained increases in MAP (+8.3±2.4 mmHg) and RSNA (+27.7±10.8%). Pretreatment with AIDA failed to prevent the cardiovascular and RSNA responses to microinjection of 3,5-DHPG. Unilateral microinjection of ( S)-4-carboxy-3-hydroxyphenylglycine (4C3HPG), an agonist of group II mGluRs, into the NTS also significantly decreased MAP, HR, and RSNA, whose responses were not inhibited by pre-microinjection of (2 S)-α-ethylglutamic acid (EGLU; 2 nmol), a putative antagonist of group II mGluRs. On the other hand, unilateral microinjection of l(+)-2-amino-4-phosphonobutyric acid ( l-AP4), an agonist of group III mGluRs, into the NTS caused dose-related decreases in MAP (−8.3±1.5 mmHg by 0.1 nmol and −45.1±3.4 mmHg by 0.3 nmol), HR, and RSNA (−21.3±3.9% by 0.1 nmol and −77.2±6.5% by 0.3 nmol), whose responses were suppressed by pre-microinjection of ( R, S)-α-cyclopropyl-4-phosphonophenylglycine (CPPG; 0.3 nmol), an antagonist of group III mGluRs. These results suggest that all subgroups of mGluRs participate in cardiovascular and sympathetic regulations in the NTS of rats, and that endogenous group I mGluRs in the NTS may contribute to tonic cardiovascular and sympathetic regulations.

Cerebrospinal fluid sodium concentration and osmosensitive sites related to arterial pressure in anaesthetized rats.

Intracerebroventricular injection of hypertonic saline induces experimental hypertension. To measure [Na] in the vicinity of osmosensitive sites, we continuously measured [Na] in cerebrospinal fluid ([Na]csf) in the lateral ventricle (LV, n = 6), in the third ventricle (V3, n = 6) and in the medial preoptic nucleus (MPO, n = 6) ([Na]MPO) with a Na-sensitive electrode together with mean arterial pressure (MAP) during infusion of hypertonic artificial cerebrospinal fluid (ACSF, [Na] = 1,000 meq/kg H2O) at 5 "mu"l/min for 3 min into the LV in urethane- anaesthetized rats. [Na]csf in the LV began to increase at the beginning of infusion, reaching a peak of 48 +/- 9 meq/kg H2O (mean +/- SE) around the end of infusion, then recovering to the pre-infusion level by 17 min. [Na]csf in V3 changed similarly to that in the LV without any delay, although the peak value was reduced (61% , P < 0.05). In the MPO, in contrast the increase in [Na]MPO was delayed (3 min, P < 0.002) and the peak reduced even further (to 37%, P < 0.01) compared with that in V3. Thereafter, it remained higher than the pre-infusion level until the end of recovery (P < 0.05). MAP began to increase at the onset of infusion (P < 0.05); the maximum increase of 16 +/- 2 mm Hg (n = 18) was reached at the end of infusion, whereafter this level was almost sustained until the end of the 22-min recovery period. To analyse quantitatively the relationship between MAP and [Na]csf, hypertonic ACSF was infused at 2.5 "mu"l/min into the LV. [Na]csf in the LV and MAP increased at half the rates seen with 5 "mu"l/min. These results suggest that the first increase in MAP after hypertonic infusion into the LV is due to the increase in [Na] in the LV and V3, and that the subsequent sustained increase in MAP is related to the delayed increase in [Na] in the periventricular tissues of the V3.