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Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska
Submitted 1 February 2006 ; accepted in final form 27 July 2006
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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renal sympathetic nerve activity; phrenic nerve activity; hypothalamus
Recent findings from our (19) and other (7, 10) groups demonstrated the involvement of the paraventricular nucleus (PVN) in processing the pressor and sympathoexcitatory components of the CB chemoreflex. Previous studies (30) have demonstrated that NO within the PVN influences cardiovascular function and sympathetic outflow. Furthermore, we also reported that the endogenous NO-mediated effect within the PVN of HF rats is less potent in suppressing renal sympathetic nerve activity (RSNA) compared with that in control rats. Taken together, these data suggest that the NO system within the PVN, involved in controlling autonomic outflow, is altered during HF and may contribute to the elevated levels of renal sympathoexcitation, commonly observed in HF (29, 30).
Therefore, in the present study, we hypothesized that endogenous NO within the PVN plays a role in the modulation of reflex responses elicited by the CB chemoreflex. Thus an altered NO mechanism within the PVN during HF may influence the sympathetic outflow evoked by the CB chemoreflex and contribute to an overall increase in sympathetic activity observed in HF. To test this hypothesis, the present study examined 1) the sensitivity of CB chemoreflex responses in HF rats compared with those in sham-operated rats, 2) whether endogenous NO within the PVN modulates the sympathoexcitatory and ventilatory components of the CB chemoreflex, and 3) whether there is any change in NO-mediated PVN modulation of CB chemoreflex responses during HF.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Induction of HF Male Sprague-Dawley rats weighing 180–200 g were obtained from Charles River Laboratories (Omaha, NE) and were randomly assigned to a sham-operated and a HF group. HF was produced by coronary artery ligation, as previously described (5, 14). Each rat was anesthetized with pentobarbital sodium (50 mg/kg ip). The trachea was intubated, and the rat was placed on a ventilator. A left thoracotomy was performed, and the left coronary artery was ligated. Sham-operated rats underwent thoracotomy and manipulation of the heart, but the coronary artery was not ligated. Analgesics (Nubain-Stadol, 1 ml/kg sc) were administered on the first 2 days after the surgery. Each rat was caged individually in an environment with ambient temperature maintained at 22°C and humidity at 30–40%. Laboratory chow (Harlan; Madison, WI) and tap water were available ad libitum. All acute experiments were conducted 6–8 wk after ligation of the left coronary artery (HF group) or sham-operated surgery in control rats. At the end of each acute experiment, a 2-Fr micromanometer-tipped catheter (Millar Instruments) was advanced through the right carotid artery into the left ventricle to determine left ventricular (LV) pressures. LV end-diastolic pressure (LVEDP) was determined from the LV pressure recording. LVEDP measurement was determined to provide a measure of diastolic dysfunction.
Acute Experiments All acute experiments on sham-operated and HF rats were performed under anesthesia with urethane (1.2 g/kg ip), supplemented with 15% of the initial dose, as needed. An adequate depth of anesthesia was assessed before surgery by the absence of pedal and corneal reflexes and by failure to withdraw the hindlimb in response to pinching the paw. Animals were instrumented with catheters inserted into the femoral artery and vein (PE-50 tubing) for measuring arterial blood pressure (ABP) and blood gases and for intravenous administration of fluids and drugs, respectively. The arterial catheter was connected to a computer-based data acquisition system (PowerLab) via a pressure transducer (Gould P231D) for recording of ABP and heart rate (HR). Mean arterial blood pressure (MAP) was calculated form ABP.
After tracheal cannulation, rats were ventilated with a respirator (Harvard Apparatus). Arterial blood samples were collected to determine blood gases [arterial PO2 and arterial PCO2] and pH (ABL-500, Radiometer, Copenhagen, Denmark). Arterial blood gases were maintained at normal levels by adjusting the ventilation rate (60–70 breaths/min) and/or tidal volume (2.0 to 3.0 ml), and metabolic acidosis was corrected by intravenous injection of an appropriate amount of warm sodium bicarbonate (NaHCO3) [0.2 x body weight x base excess (in meq)]. The body temperature of the animal was maintained at 37°C with a water circulating pad.
Recording of Efferent RSNA The left kidney was exposed through a left retroperitoneal flank incision. A branch of the renal nerve running along the left renal artery was carefully isolated, the nerve was cut distally, and the central end was placed on a bipolar silver electrode. The nerve and electrode were covered with mineral oil. RSNA was recorded by using a Grass P511 differential amplifier and a storage oscilloscope. The RSNA was filtered at a bandwidth of 100 Hz–3 kHz. The neural signal was also fed to an audio amplifier and loudspeaker. The neural signal was rectified and integrated (1-s time constant), and both the raw and integrated signal were recorded by using the MacLab software. Efferent RSNA that had stabilized over 30–40 min at the beginning of the experiment was defined as the resting nerve discharge. At the end of experiment, the minimum and maximum RSNA activity was recorded during bolus administration of phenylephrine (20 µg/kg) and sodium nitroprusside (SNP; 100 µg/kg), respectively. The background noise, defined as the signal remaining after administration of hexamethonium (20 mg/kg iv), or postmortem was subtracted from renal nerve activity, and, subsequently, renal nerve activity was expressed as the percentage of maximum (in response to SNP).
Recording of Efferent Phrenic Nerve Activity The left phrenic nerve activity (PNA) was dissected via dorsal approach, cut distally, and desheathed, and the central end was placed on bipolar silver recording electrodes and submerged in mineral oil for measurement of nerve activity. Nerve activity was band-pass filtered (100 Hz–3 kHz), amplified (gain, 10–50 x 1,000; Grass P511) and displayed on an oscilloscope (Gould 450). The signal was then rectified, integrated, and stored for later analysis with commercially available software provided with a computer-based data acquisition system (Chart 5.2, AD Instruments).
Microinjections Into the PVN The rat was placed in a stereotaxic apparatus (Davis Kopf Instruments), and small burr holes were placed on either side of the midline of the skull. The coordinates for each side (right and left) of the PVN were determined from the Paxinos and Watson Rat Atlas (13), which were 1.8 mm posterior, 0.4 mm lateral to the bregma, and 7.8 mm ventral to the dura. A cannula (outer diameter, 0.5 mm; and inner diameter, 0.1 mm) connected to a microsyringe (0.5 µl, model 7000.5, Hamilton) was advanced into the PVN with a manipulator (Narishige Z-1). The cannula was flushed with the experimental injectate before each insertion. After microinjection on one side of the PVN, the cannula was withdrawn and then reinserted using the similar coordinates for the opposite side to perform a bilateral microinjection of equal volume (50 nl). The cannula was withdrawn immediately after each microinjection. At the end of the experiments, monastral blue dye (100 nl) was injected through the cannula for histological verification of the site of injection. After the rat was euthanized, the brain was removed and fixed in 10% formaldehyde for at least 24 h. The brain was then frozen, and serial transverse sections (30 µm) were cut using a cryostat (IEC, model CT, International-Harris Cryostat) at –20°C. The sections were thaw-mounted on microscope slides and stained with 1% aqueous neutral red staining procedures. Presence of the blue dye within the PVN was verified microscopically. Data from experiments with sites targeted outside of the PVN region were analyzed separately as anatomical control groups. Figure 1 illustrates the locations of microinjection sites in the PVN region for all groups.
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Experiment 2.
We assessed whether NO within the PVN influences the reflex response of MAP, HR, RSNA, and PNA to CB chemoreceptor stimulation and whether they are altered in rats with HF. Initially, artificial cerebrospinal fluid was microinjected bilaterally into the PVN (50 nl each side) as previously described (19). MAP, HR, RSNA, and PNA were monitored over the subsequent 20–30 min. After the baseline values for all these parameters were recorded, CB chemoreceptors were stimulated by intravenous bolus injection of a submaximal dose of KCN (75 µg/kg), and reflex responses were recorded for 5 to 10 min in both sham-operated and HF rats. Similarly, either an inhibitor of NO synthase, NG-monomethyl-L-arginine (L-NMMA; 50 pmol/50 nl), or NO donor, SNP (50 nmol/50 nl), were injected bilaterally (50 nl each side) into the PVN. Each microinjection was made over a period of 1 min, and MAP, HR, RSNA, and PNA were monitored for 5 to 10 min. Once all the cardiorespiratory parameters stabilized, the same procedure of KCN injections was repeated as in Experiment 1, and reflex responses were recorded for 5 to 10 min.
Experiment 3.
The CB chemoreflex responses of MAP, HR, RSNA, and PNA were determined in groups of rats in which the bilateral injection sites were not within the PVN area and were considered as anatomical control groups (L-NMMA and SNP microinjections). These experiments were carried out using the same procedures as described in Experiment 2, except the sites of microinjection were placed outside, but adjacent to, the PVN bilaterally.
Cardiac Histology At the end of each experiment, the heart was removed, weighed, and fixed in 4% formaldehyde. The infarct size was determined as previously described (11, 12). Briefly, the hearts were sectioned into four major segments located from the atrium to the apex: segments A–D. Segment A (the atria and the connecting inflow and outflow tracts) and segment D (mainly the apex) were not analyzed for histological damage. Segments B and C (representing the bulk of the left ventricle) were subjected to graded dehydration with ethanol, embedded in paraffin, cut into sequential 10-µm sections, and stained with hematoxylin-eosin. Every 10th section was projected onto a screen, and the outline of the tissue was diagramed after microscopic examination of the infarcted areas of the ventricle to identify the edges of the infarct area. The infarct size was expressed as a fraction of the total cross-sectional circumferences (epicardial or endocardial) of the left ventricle.
Data Analysis All data were analyzed off-line. The baseline values were averaged over 2 min before the experimental stimulus. Changes in MAP and HR during stimulation of chemoreflexes were calculated as the difference between the peak deviation of MAP and HR (5-s average) from the baseline. Baseline levels of RSNA were normalized as a percentage of the maximum level of activity recorded during hypotension (SNP, 100 µg/kg iv), and peak changes in RSNA during chemoreflex stimulation were calculated as the difference between the peak deviation of RSNA (5-s average) discharge from baseline measured before each stimulus. Similarly, PNA (burst amplitude) during chemoreflex activation was expressed as percent change from the immediately preceding baseline. The PNA burst frequency was calculated from the 10-s average of peak response during chemoreflex activation and expressed as change (in bursts/min) above the baseline. The data were analyzed by using GB-Stat 6.0 software. The differences between the control and HF rats were compared using the Student's t-test. The changes in MAP, HR, RSNA, and PNA in response to KCN were subjected to one-way ANOVA to compare the difference among different doses of KCN in sham-operated and HF groups. The changes in MAP, HR, RSNA, and PNA in response to chemoreceptor stimulation with central microinjection of L-NMMA, SNP, or artificial cerebrospinal fluid were subjected to two-way ANOVA followed by Newman-Keuls test for multiple independent comparisons. A value of P < 0.05 was considered statistically significant.
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RESULTS |
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Table 1 summarizes the salient characteristics of sham-operated and HF rats used in the present study. On examination of the histological data, HF rats with myocardial infarcts involving >30% of the LV wall were used in this study. The HF group displayed infarcts extending over 
47 ± 2% of the endocardial surface. Sham-operated rats had no observable damage to the myocardium. The minimum ventricular thickness was significantly less in HF rats than in the sham-operated group (0.33 ± 0.06 vs. 2.1 ± 0.2 mm, P < 0.01), which is indicative of transmural damage. Heart weight was significantly greater in HF rats than in sham-operated rats, which suggests compensatory hypertrophy of noninfarcted regions of the myocardium. LVEDP was significantly elevated in HF rats compared with that in sham-operated rats. Similar findings have been previously observed by us (25, 31, 32) and others (5, 14). Taken together, the observations of increased LVEDP, cardiac hypertrophy, and histological damage to the myocardium of 33–47% in our present study suggest that the rats in the HF group had decreased cardiac contractile function and were experiencing HF.
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The mean baseline values of MAP, HR, and RSNA before chemoreceptor stimulation, but after bilateral microinjection of L-NMMA or SNP or vehicle into the PVN of sham-operated and HF groups, are shown in Table 2. There was no significant difference between baseline hemodynamic parameters of all sham-operated (vehicle) and HF (vehicle) groups (MAP, 86 ± 2 vs. 94 ± 3 mmHg; HR, 306 ± 5 vs. 316 ± 8 beats/min; n = 14 rats/group). However, baseline RSNA of the HF (vehicle) group was significantly higher than in the sham-operated (vehicle) group (33 ± 2% vs. 26 ± 1% of maximum; P < 0.05). Generally, L-NMMA produced an increase in RSNA, MAP, and HR in both groups of rats, but it only reached statistical significance in terms of RSNA in the sham-operated rats, consistent with a previous report (29). In contrast, SNP generally produced a decrease in RSNA, MAP, and HR in both groups and reached statistical significance in terms of RSNA and MAP in both the sham-operated and HF groups. The baseline parameters shown in Table 2 are before chemoreflex activation.
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Figure 2 illustrates the dose-response relationships for MAP, HR, RSNA, and PNA of sham-operated and HF rats to the intravenous bolus injection of different doses of KCN per kilogram body weight (25, 50, 75, and 100 µg/kg). There was a graded increase in reflex responses with increasing doses of KCN in both sham-operated and HF rats, with a statistically significant difference between the groups at higher doses (75 and 100 µg/kg). Similar results were observed with an evaluation of phrenic nerve frequency and burst frequency in both groups. These results demonstrated an increase in sensitivity of CB chemoreceptor-mediated responses to KCN in the HF group compared with that in the sham-operated group. Since respiration was mechanically controlled, the baseline blood gases and pH values did not deviate among the different experimental groups, nor were they affected by KCN injection in any group of the study (data not shown).
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Figure 3 illustrates typical tracings of the changes in RSNA, PNA, and ABP in response to peripheral chemoreflex activation before and after bilateral microinjection of L-NMMA (50 pmol in 50 nl) into the PVN in sham-operated and HF rats. In sham-operated rats, bilateral microinjection of L-NMMA into the PVN (n = 7) produced an increase in CB chemoreflex-evoked changes in RSNA (40 ± 3.0%), PNA (burst amplitude, 130 ± 6%; burst frequency, 16 ± 1 bursts/min), and MAP (29 ± 3 mmHg) compared with that in vehicle. However, in HF rats, bilateral microinjection of L-NMMA into the PVN produced no significant changes in chemoreflex responses (Fig. 4). The L-NMMA microinjections targeted outside of the PVN in both groups did not affect reflex responses to peripheral chemoreflex activation (data not shown). Similarly, there was no effect of L-NMMA on chemoreflex-mediated changes in HR in both sham-operated and HF rats (Fig. 4). These data suggest that blockade of endogenous NO synthesis (NOS)-mediated augmentation of the CB chemoreflex responses is blunted in rats with HF.
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Figure 5 is a typical tracing illustrating the changes in RSNA, PNA, and ABP in response to peripheral chemoreflex activation before and after bilateral microinjection of the NO donor SNP (50 nmol in 50 nl; n = 7) into the PVN of sham-operated and HF rats. Bilateral microinjection of SNP into the PVN significantly attenuated the increase in sympathoexcitatory component of chemorefle-evoked changes in both sham-operated and HF rats (Fig. 6). In the sham-operated group, SNP significantly decreased the reflex increase in RSNA, PNA, and MAP (11 ± 1%, 65 ± 7%, and 8 ± 1 mmHg, respectively) compared with those in vehicle (26 ± 2%, 96 ± 6%, and 17 ± 4 mmHg, respectively). Similarly, in HF rats, SNP significantly decreased RSNA and MAP responses (25 ± 2% and 16 ± 1 mmHg, respectively) compared with those with vehicle injections (32 ± 1% and 22 ± 2 mmHg, respectively). The effect of SNP on burst frequency in sham-operated animals was not statistically significant compared with that in the vehicle (8 ± 1 vs. 12 ± 2 bursts/min). Conversely, in the HF group, SNP significantly decreased the PNA (burst frequency) compared with that in the vehicle (10 ± 1 vs. 18 ± 3 bursts/min, P < 0.05). However, the magnitude of the SNP-mediated attenuation of reflex changes in RSNA (8 ± 1%) and MAP (6 ± 2 mmHg) in HF rats was significantly less compared with that in sham-operated rats (14 ± 2% and 11 ± 2 mmHg, respectively; P < 0.05). The SNP microinjections targeted outside of the PVN in the both groups did not affect reflex responses to peripheral chemoreflex activation (data not shown). Similarly, there was no effect of SNP on chemoreflex-mediated changes in HR in both sham-operated and HF rats (Fig. 6). Our data indicate that exogenous NO applied within the PVN has impaired modulation of the sympathoexcitatory component of CB chemoreflex in HF rats.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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In the present study, we used KCN (75 µg/kg) to stimulate arterial chemoreceptors. Typically, intravenous administration of KCN elicited an increase in MAP, RSNA, and PNA and with small decreases in HR. However, it raises the question as to whether chemical activation of CB chemoreceptors reproduces a physiological stimulus such as hypoxia (low inspired O2 tension). To test whether hypoxia activates the sympathetic and cardiorespiratory responses just as KCN does, intact adult rats were exposed to hypoxia (10% O2) for 10–15 s while MAP, RSNA, PNA, and HR were measured. The response of RSNA, PNA, and HR to hypoxia was similar to the KCN-elicited chemoreflex responses in anesthetized rats (data not shown). However, in rats exposed to hypoxia, we noticed hypotension. To avoid the influence of hypotension on reflex responses during chemoreceptor activation, we chose KCN over hypoxia to stimulate peripheral chemoreceptors in anesthetized rats. In addition, hypoxia may act at the level of the central nervous system to influence the chemoreflex.
There is accumulating evidence implicating the peripheral chemoreceptors in various diseases, including HF (16) and certain forms of hypertension (20). Previous studies by Schultz and colleagues (22) demonstrated that peripheral chemoreflex control of RSNA and ventilation was enhanced in conscious rabbits with pacing-induced HF and that enhanced peripheral chemoreflex function contributes to the sympathetic activation in the HF state. In subsequent studies, they also demonstrated that there was an enhanced input from the CB in a rabbit model of pacing-induced HF and that impaired NO production contributed to this alteration. These findings provide direct evidence for the involvement of peripheral NO in modulating CB chemoreceptor activity. The data imply that a reduction of NO release in the HF state may lead to a disinhibition of the CB chemoreceptors, which would provide a primary contribution to the augmentation of chemoreceptor afferent input.
Systemic hypoxia typically causes an increase in sympathetic activity and cardiorespiratory function. Various central inhibitory mechanisms may act at different levels of the brain and counterbalance the excess activation of presympathetic vasomotor neurons during hypoxia, subsequently maintaining the cardiorespiratory homeostasis upon normoxia. However, in the context of recent studies (8) that have demonstrated altered central inhibitory mechanisms during HF, it is quite reasonable to speculate that these altered neurohumoral responses may influence the excitatory output evoked by stimulation of chemoreceptor input in HF. However, very little is known about the central neural pathways and their neurotransmitter influence on modulation of CB chemoreceptor inputs in HF.
The PVN is a major site of integration of autonomic and endocrine cardiorespiratory responses (23, 24). There is electrophysiological and neuroanatomical evidence of connections between the nucleus tractus solitarii (NTS) and the PVN (2), as well as projections from the PVN to the rostral ventrolateral medulla (RVLM) (18, 26), and to the spinal cord (4). In addition, Yeh and coworkers (27) reported direct connections between the PVN and phrenic motoneurons. Later, Mack and colleagues (9) demonstrated that oxytocin neurons in the PVN were involved in neuronal modulation of breathing by projecting to the RVLM pre-Bötzinger complex neurons and the phrenic motorneurons. Probably these connections to respiratory centers, and autonomic regions involved in regulation of sympathetic and cardiovascular functions, would provide the PVN with mechanism, which could potentially influence the sympathetic and cardiorespiratory responses during the activation of CB chemoreceptors.
Consistent with this notion, previous studies from our group specifically documented the involvement of PVN in the peripheral chemoreflex-mediated regulation of sympathetic activity and ventilation. Previous work (30) from our group has shown that administration of the NO donor SNP into the PVN produces a decrease in RSNA and pressor responses in rats. Conversely, it has been observed that administration of the NOS blockers L-NMMA or NG-nitro-L-arginine methyl ester into the PVN increases RSNA in rats (30). Based on these observations, it would not seem unlikely that the NO within the PVN might be part of a neural mechanism in modulating the peripheral chemoreceptor-mediated responses. It is conceivable that impaired NO mechanism within the PVN during HF may contribute to altered chemoreceptor input processing.
In the present study, the bilateral microinjection of L-NMMA into the PVN augmented the increase in RSNA and ventilatory response typically elicited by stimulation of CB chemoreceptors. Conversely, microinjection of SNP into the PVN attenuated the reflex responses evoked by the chemoreceptor stimulation. However, microinjections of these compounds targeted to adjacent sites but, outside the PVN, had no effect on these reflex responses, clearly implicating the contribution of NO mechanisms within the PVN in modulating the sympathetic and ventilatory responses to the peripheral chemoreflex.
In this study, we also examined the reflex responses to the administration of L-NMMA or SNP into the PVN of HF rats. In HF rats, the L-NMMA-mediated increase in chemoreflex responses was blunted, indicating the possible impairment of endogenous NO synthesis. The results of the present study are consistent with previous observations where they demonstrated a decrease in message for neuronal NOS (nNOS) and protein levels of nNOS in the PVN of HF rats (31). Conversely, after microinjection of SNP into the PVN, there was a significant decrease in reflex-mediated changes in the RSNA and MAP of HF rats. However, the magnitude of the SNP-mediated attenuation in the RSNA and MAP is significantly smaller in HF rats compared with that in sham-operated rats. These results suggest that although the exogenous NO is able to reduce the enhanced response in HF rats, it was unable to attenuate the reflex responses to the same extent that it does in sham-operated rats.
Based on our results, it appears that NO within the PVN may be involved in coordinating and maintaining the cardiorespiratory homeostasis by regulating the sympathetic activity during the CB chemoreflex. However, the important question that arises from the present study is the exact neural pathways through which the NO synthesized within the PVN and subsequently influences the reflex responses of CB chemoreceptors. In the previous study (19), our group speculated that NTS projections to the PVN may possibly excite PVN neurons during peripheral chemoreceptor stimulation. It appears that the excitatory input of CB chemoreceptors possibly activates N-methyl-D-aspartate receptors within the PVN via direct projections from NTS. As described by Zanzinger and colleagues (28), it may cause NOS activation by increasing the intracellular calcium as shown in other areas of the brain (1, 6).
We do not know the precise cellular mechanisms and pathways through which NO within the PVN modulates the excitatory component of CB chemoreflex. Previous studies from our group proposed that the effect of NO within the PVN on the modulation of sympathetic activity may be mediated by the release of GABA. In support of this notion, studies from our laboratory have demonstrated that prior blockade of GABAergic mechanism within the PVN eliminated the endogenous NO-mediated inhibitory effects on blood pressure and RSNA, suggesting the interdependence of these two mechanisms in restraining the excitatory inputs within the PVN. At this point, we do not know whether the impaired NO-mediated modulation of sympathoexcitatory component of peripheral chemoreflex in HF is a direct or indirect effect. However, based on our previous data, the current results indicate that the reduced response of PVN neurons to NO and subsequent impairment of inhibitory effects downstream from NO, such as GABAergic mechanism, may partly contribute to the potentiation of sympathoexcitatory and ventilatory response during activation of CB chemoreflex in HF rats.
In conclusion, the present study brings to light the involvement of NO within the PVN in modulating the sympathetic and ventilatory responses to the selective stimulation of peripheral chemoreceptors in anesthetized rats. Our study also demonstrates the impairment of NO-mediated PVN modulation of the sympapthoexcitatory component of CB chemoreflex in HF rats. The possible impairment in the signaling pathway downstream from NO, like the GABAergic mechanism, may also partly contribute to the potentiation of the sympathoexcitatory component of CB chemoreflex during HF. However, this possibility has yet to be tested thoroughly. Our data suggest that beside augmentation of sensitivity of peripheral afferent input, the impaired central inhibitory modulation in structures involved in cardiorespiratory regulation contributes to the overall increase in peripheral chemoreflex control of sympathetic function in HF. However, whether similar changes in nNOS activity within the brain stem areas, such as the NTS and RVLM, etc., are involved in HF remains to be elucidated.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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This article has been cited by other articles:
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  Y. Ding, Y.-L. Li, and H. D. Schultz Downregulation of carbon monoxide as well as nitric oxide contributes to peripheral chemoreflex hypersensitivity in heart failure rabbits J Appl Physiol, July 1, 2008; 105(1): 14 - 23. [Abstract] [Full Text] [PDF]
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) and heart failure (HF, 
) rats and sites of termination of injections outside of the PVN region (
) are shown. 3V, 3rd ventricle; AH, anterior hypothalamus; f, fornix.
MAP, A), heart rate (
