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NEUROHUMORAL CONTROL OF CIRCULATION AND HYPERTENSION
Department of Pharmacology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284-7764
Submitted 9 May 2003 ; accepted in final form 31 July 2003
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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4 wk. The alterations are dependent on the subtype of GABA receptor being activated and whether the neuron receives a mono- or polysynaptic baroreceptor afferent input. electrophysiology; baroreceptor; baroreflex
The sensitivity of NTS neurons to the selective GABAA agonist muscimol was the same whether the neuron received a monosynaptic or a polysynaptic aortic nerve (AN) input (19). In contrast, NTS neurons receiving a monosynaptic AN input were much less sensitive to the inhibitory effects of the GABAB agonist baclofen than were NTS neurons receiving a polysynaptic AN input (19). An in vitro study reported that presynaptic inhibition of monosynaptic tractus inputs to NTS neurons occurred at a dose of baclofen approximately an order of magnitude lower than the dose necessary to induce postsynaptic inhibition (1). In most NTS neurons, stimulation of afferent inputs evokes excitation followed by postsynaptic inhibition (10). The postsynaptic inhibition is largely, but not totally, abolished by blockade of GABAA receptors (18). These results suggest that, under normal conditions, postsynaptic inhibition within the NTS is mediated primarily by activation of GABAA receptors.
Within the past decade, studies have indicated that alterations in GABAergic function within the NTS accompany chronic hypertension (HT). In several models of HT (e.g., spontaneously hypertensive rats, deoxycorticosterone acetate salt, and renal wrap), an enhanced pressor response to the microinjection of baclofen into the NTS has been observed, whereas responses to GABAA agonists remain the same as in normotensive (NT) rats (3, 15, 17). In the renal-wrap model of HT, the enhanced pressor response to NTS microinjections of the GABAB receptor agonist baclofen is associated with increased expression of GABAB receptor mRNA (3). Alterations in the blood pressure responses to GABAergic agonists suggest, but do not demonstrate, alterations in neuronal sensitivity. Changes in the sensitivity of NTS neurons to modulators such as GABA could alter baroreflex function in HT. The present study was designed to examine the sensitivity of NTS neurons receiving arterial baroreceptor afferent inputs to GABAA and GABAB receptor agonists in HT rats.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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1 wk to acclimate before use. All experimental protocols were approved by the Institutional Animal Care and Use Committee and are in accordance with US Public Health Service guidelines. HT model. HT was induced using a one-kidney renal-wrap procedure. Rats were anesthetized with medetomidine (0.5 mg/kg ip; Pfizer) and ketamine (75 mg/kg ip; Fort Dodge Laboratory). A Grollman renal wrap (4) and contralateral nephrectomy were performed on these animals under aseptic conditions. Control animals consisted of sham-operated rats, which were similarly anesthetized and received a unilateral nephrectomy but no wrap of the contralateral kidney, or rats that were subjected to no surgical procedures before the day of the experiment. Because the responses of both control groups of rats were identical, they were grouped together for analysis. Anesthesia was terminated by atipamezole (1 mg/kg ip; Pfizer) at the conclusion of the surgical procedures. Postoperative analgesics [nalidixic acid (Nubaine), administered intramuscularly] were available as needed.
Acute surgical preparation. Rats were initially anesthetized with pentobarbital sodium (60 mg/kg ip) and placed on a thermostatically controlled heating pad. Body temperature was maintained at 36-38°C throughout the experiment. After placement of a venous catheter (tail vein) and cannulation of the trachea, the animal was artificially ventilated with oxygenated room air, and subsequent anesthetic was given as an infusion of 10-20 mg · kg-1 · h-1 iv. Gallamine triethiodide (20 mg · kg-1 · 0.5 h-1 iv) was given for paralysis to reduce respiratory movements of the brain stem. A femoral artery was cannulated for arterial blood pressure monitoring (CDX transducer, Cobe Laboratories, Lakewood, CO). Mean arterial pressure and heart rate were determined from the pulsatile signal using a Coulburn blood pressure processor. Depth of anesthesia was assessed by monitoring the stability of arterial pressure and heart rate in response to pinch of the hindpaw and was adjusted by appropriate changes in the infusion rate. The ANs were isolated bilaterally and marked with small pieces of black suture. The rat was placed in a stereotaxic head frame, and an occipital craniotomy was performed to expose the dorsal surface of the medulla in the region of the calamus scriptorius. The AN ipsilateral to the central recording site was mounted on bipolar stimulating electrodes and covered with a mixture of petroleum jelly and mineral oil.
Extracellular recordings and iontophoresis. Extracellular action potential discharge was recorded with a five-barrel electrode. The tip of the electrode was broken to give an outer diameter of 
1 µm. The recording barrel was filled with a solution of 0.5 M sodium acetate containing 2% Chicago sky blue (impedance 10-40 M
). One barrel of each five-barrel electrode was filled with a solution of 3 M NaCl and was used for automatic current balancing, control injections of unbalanced current, and pH control measurements. The remaining barrels were filled with different drug solutions. All recordings were performed within a region 1.2 mm caudal and 1.0 mm rostral to the calamus scriptorius, 0-0.8 mm lateral to the midline, and 0.2-1 mm below the surface. The electrode was lowered into the tissue in 2.0- to 2.5-µm steps by a stepper driver (Burleigh Instrument, Fishers, NY). The AN was stimulated with single pulses (1-ms duration, 0.5 Hz, 500 µA). Recorded action potentials were amplified by a direct-current amplifier (World Precision Instrument, New Haven, CT), passed through an alternating-current filter, and then sent to a digital oscilloscope (Nicolet Instrument, Madison, WI), an audio monitor (Grass Instrument, Quincy, MA), a videotape recorder (Vetter, Reberburg, PA), and a window discriminator (World Precision Instrument, Sarasota, FL). The window discriminator output was led to an analog-to-digital converter (model CED1401, Cambridge Electronics, Cambridge, UK) interfaced with a personal computer. Spike2 data acquisition software (Cambridge Electronic Design) was used for on- and off-line analyses. After an AN-evoked NTS neuron was found, monosynaptic neurons (MSNs) or polysynaptic neurons (PSNs) were characterized using the ability of the AN-evoked responses of MSNs to follow two stimuli separated by 5 ms (13). Peristimulus-time histograms (PSTHs; 1-ms bin width, 40 sweeps of AN stimulation at 0.5 Hz) and ratemeter histograms (180-s duration, 1-s bin width) were collected to analyze evoked and spontaneous discharge, respectively.
After baseline discharge (spontaneous firing rate and/or evoked discharge) was recorded, drugs were administered by application of microiontophoretic ejecting currents to the drug-containing barrels. For current-response curves, drugs were ejected for successive 10-s periods separated by 10- to 20-s intervals. Responses were measured under steady-state conditions. Typically, three to four ejection cycles were required to reach a steady state. The drug solutions for micro-iontophoresis were GABA (2 mM, pH 4.5; Research Biochemicals International, Natick, MA), muscimol (0.04 mM, pH 4.5; RBI), and baclofen (10 mM, pH 4.5; RBI). All drugs were dissolved in 150 mM NaCl, and were ejected as cations. Retaining currents of appropriate polarity were applied to the drug barrels to reduce the passive diffusion of the drug from the electrode tip during nonejection periods. All currents ejected by ejecting barrels were automatically balanced by the iontophoretic unit (Neurophore, Medical Systems) by ejection of opposite currents through the balancing barrel. After a successful recording, dye was iontophoretically ejected from the recording barrel, and standard postmortem histological procedures were performed to localize the recording site.
Data analysis. Iontophoretic "dose-response" curves were constructed from PSTHs of responses to 40 AN stimuli obtained before, during, and 2-5 min after iontophoretic application of agonist at ejection currents of 5, 10, 20, and 40 nA, as previously described (19) (Fig. 1). Data were accepted only if AN-evoked discharge in the recovery PSTH was within ±10% of the discharge in the control PSTH obtained before iontophoresis of agonist. It was not possible to test every drug on each cell. However, for each drug, all ejection currents were tested on each cell presented in the dose-response curves. To account for different levels of basal spontaneous discharge, baseline discharge was measured in the absence of AN stimulation, and this value was subtracted from AN-evoked discharge. Response onset latency was defined as the interval between the stimulus artifact and the bin containing the greatest number of action potentials. Differences in AN-evoked discharge at each iontophoretic ejection current were tested between NT, 1-wk-HT, and 4-wk-HT rats using ANOVA with Student-Newman-Keuls method for post hoc comparisons. For statistical analysis, the absolute number of AN-evoked or spontaneous action potentials was used; for graphical purposes, these values were normalized to the 100% control level of discharge observed in the absence of any drug application. Values are means ± SE, and significance was accepted at P < 0.05. All values of n refer to the number of neurons, except where mean arterial pressure data are reported, in which case n refers to the number of rats.
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RESULTS |
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Spontaneous action potential discharge was not observed in all neurons. In those neurons that did discharge spontaneously, there was no difference in discharge rate (action potentials per second) within each MSN and PSN group among neurons from NT [4.4 ± 0.5 (n = 29) for MSN and 6.7 ± 0.7 (n = 45) for PSN], 1-wk-HT [4.9 ± 0.6 (n = 14) for MSN and 6.5 ± 0.9 (n = 24) for PSN], and 4-wk-HT [4.1 ± 0.5 (n = 19) for MSN and 7.1 ± 0.9 (n = 30) for PSN] rats. MSNs had a lower spontaneous discharge frequency than PSNs in NT (P = 0.02) and 4-wk-HT (P = 0.02) rats.
Under control conditions, the number of action potentials evoked by 40 AN stimuli was not different between MSN and PSN groups in NT [34 ± 2 (n = 42) for MSN and 32 ± 1 (n = 63) for PSN], 1-wk-HT [30 ± 1 for MSN (n = 19) and 29 ± 1 for PSN (n = 30)], and 4-wk-HT [37 ± 3 for MSN (n = 25) and 34 ± 2 for PSN (n = 40)] rats. Within each MSN and PSN group, there was no difference between the number of action potentials evoked by 40 AN stimuli in neurons from NT rats and the number evoked in neurons from 1- or 4-wk-HT rats.
Figure 2 illustrates the onset latency distribution of MSNs and PSNs from the NT and HT rats. The latencies for neurons recorded in 1- and 4-wk-HT rats were combined. The mean onset latency for the entire population of MSNs was 16.8 ± 1.5 ms in NT rats (n = 42) and 19.1 ± 1.6 ms in HT rats (n = 44). However, the MSN population in NT and HT rats was clearly bimodal. The onset latency of approximately one-third of the MSNs fell between 2 and 8 ms [4.3 ± 0.6 ms (n = 16) in NT and 4.7 ± 0.5 ms (n = 14) in HT, P > 0.05]. Conduction distance was estimated at 5-6 cm, suggesting that these MSNs received AN afferent inputs conducting at 
10-30 m/s. The onset latency for the remaining MSNs was 16-36 ms [23.7 ± 0.7 ms (n = 26) in NT and 25.9 ± 0.9 ms (n = 30) in HT, P > 0.05], suggesting that these cells received afferent inputs conducting at 1-4 m/s. The latency distribution for PSNs was unimodal, and there was no difference between the latencies of the NT (26.1 ± 1.2 ms, n = 63) and HT (27.4 ± 1.2 ms, n = 70) PSNs (P > 0.05). Reconstruction of the recording sites indicated no differential location of MSNs on the basis of latency or MSNs compared with PSNs (data not shown).
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Sensitivity to GABA. In the MSN population, there was no difference in the inhibition of AN-evoked discharge by GABA between 1-wk-HT (n = 8) and NT (n = 13) rats at any of the ejection currents tested (Fig. 3). In 4-wk-HT rats (n = 8), the inhibition of AN-evoked discharge in MSNs was significantly attenuated at all ejection currents compared with NT and 1-wk-HT rats. In the PSN population the inhibition by GABA was reduced in 1-wk-HT rats at ejection currents of 20 and 40 nA (n = 8), and in 4-wk-HT rats the inhibition of AN-evoked discharge was less at all ejection currents (n = 17) than in NT rats (n = 17; Fig. 3). In NT rats, AN-evoked discharge in MSNs was inhibited less than in PSNs during GABA iontophoresis at 20 and 40 nA (P < 0.05). This difference was not observed in 1- and 4-wk-HT rats.
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Sensitivity to muscimol. In the MSN population, the inhibition of AN-evoked discharge by muscimol was less in 1-wk-HT (n = 8) and 4-wk-HT (n = 9) than in NT (n = 12) rats at all ejection currents (Fig. 4). A similar observation was made in the PSN population; however, the attenuation of muscimol inhibition in 1-wk-HT rats was not significant at the 5-nA ejection current (n = 20, 6, and 9 in NT, 1-wk HT, and 4-wk-HT rats, respectively). In the MSNs and PSNs, muscimol inhibition of AN-evoked discharge in neurons from 1-wk-HT rats was not different from that in neurons from 4-wk-HT rats. In NT and HT rats, there was no difference in the inhibition of AN-evoked discharge between MSNs and PSNs.
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Sensitivity to baclofen. In the MSN population, the inhibition of AN-evoked discharge by baclofen at all ejection currents was greater in 1-wk-HT (n = 6) and 4-wk-HT (n = 6) than in NT (n = 13) rats (Fig. 5). In the PSN population, the sensitivity to baclofen was the same in 1-wk-HT (n = 7) and 4-wk-HT (n = 12) rats compared with NT rats (n = 23). In the MSNs and PSNs, baclofen inhibition of AN-evoked discharge in neurons from 1-wk-HT rats was not different from the inhibition in neurons from 4-wk-HT rats. In NT rats, baclofen iontophoresis inhibited AN-evoked discharge less in MSNs than in PSNs at all ejection currents (P < 0.05). This difference was abolished in 1-wk-HT rats and reversed in 4-wk-HT rats, so that baclofen inhibited MSNs more than PSNs.
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MSNs receiving slowly vs. rapidly conducted AN inputs. As illustrated in Fig. 2, the distribution of onset latencies for MSNs was bimodal. Sensitivity to muscimol and baclofen was examined in MSNs receiving slowly vs. rapidly conducting AN afferent inputs. Data from 1- and 4-wk-HT rats were combined. The reduced inhibition by muscimol and the enhanced inhibition by baclofen was observed in MSNs, regardless of the apparent conduction velocity of the afferent input: in NT rats receiving rapidly conducting inputs, n = 5 for muscimol and baclofen; for NT rats receiving slowly conducting inputs, n = 7 for muscimol and n = 8 baclofen; in HT rats receiving rapidly conducting inputs, n = 8 for muscimol and n = 6 for baclofen; in HT rats receiving slowly conducting inputs, n = 9 for muscimol and n = 6 for baclofen (Fig. 6).
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Responses of nonevoked neurons. During the course of the examination of NTS neurons receiving AN inputs, a number of recordings were obtained from spontaneously discharging neurons that did not respond to the AN stimulus. The inhibition of the spontaneous discharge of these non-AN-evoked neurons was examined in NT, 1-wk-HT, and 4-wk-HT rats. There was no difference in GABA inhibition in non-AN-evoked neurons recorded between HT (n = 8 and 40 for 1- and 4-wk-HT rats, respectively) and NT (n = 26) rats (Fig. 7). There was a trend toward reduced muscimol inhibition in non-AN-evoked neurons recorded in HT rats (n = 14 and 25 for 1- and 4-wk-HT rats, respectively); however, it did not reach statistical significance compared with non-AN-evoked neurons recorded in NT rats (n = 43). Baclofen inhibition was enhanced in non-AN-evoked neurons recorded in 1-wk-HT rats (n = 8) at 40-nA ejection current and in neurons recorded in 4-wk-HT rats (n = 41) at 20 and 40 nA compared with NT rats (n = 56).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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4 wk after induction of HT. Previous studies have demonstrated enhanced responses to NTS microinjection of the GABAB receptor agonist baclofen in this (3, 17) and other (15) models of HT. This finding is consistent with the enhanced inhibition of monosynaptic AN-evoked discharge in NTS neurons by iontophoretic application of baclofen. In NT rats, baclofen inhibited AN-evoked discharge less in MSNs than in PSNs, as we previously reported (19). Within 1 wk of HT, MSN sensitivity to baclofen is comparable to that in the PSNs, and by 4 wk, MSNs are more sensitive than PSNs. These changes occur regardless of the conduction velocity of the afferent input.
MSNs exhibit reduced muscimol inhibition and enhanced baclofen inhibition after 1 wk of HT; therfore it is not clear why GABA inhibition of MSNs was not altered after 1 wk of HT. This could reflect the relative proportion of GABAA to GABAB receptors on a neuron after 1 wk of HT, relative binding affinities, differences in desensitization produced by GABA compared with muscimol, or any number of other factors that cannot be differentiated in the present study.
In contrast to GABAB receptor-mediated inhibition, previous studies have not found alterations in the responses to microinjection of muscimol in HT rats (3, 15). Therefore, one might predict that the sensitivity of AN-evoked neurons to muscimol would not be altered in HT rats. However, we found that MSNs and PSNs are less sensitive to muscimol-evoked inhibition within 1 wk of HT. The attenuated inhibition is present and quantitatively similar after 4 wk of HT. Microinjections will influence the total population of neurons that ultimately subserve a sympathoinhibitory function in a given area: some that receive AN inputs and some that do not. The data presented in Fig. 7 suggest that muscimol-evoked inhibition of non-AN-evoked neurons, some of which may subserve sympathoinhibitory functions, is not altered in HT rats. Normal responses to microinjections of muscimol within the non-AN-evoked neuron population could mask reduced inhibition within the population of AN-evoked neurons.
The method for presumptive identification of NTS neurons receiving monosynaptic inputs used in this study (13) has previously identified MSNs receiving rapidly or slowly conducting AN afferent inputs (19, 21). The present report reinforces and extends the previous observation that sensitivity to muscimol or baclofen is similar, regardless of the conduction velocity of the afferent input (19), by demonstrating that the alterations in sensitivity to GABA agonists are similar, regardless of the conduction velocity of the afferent input.
The sensitivity of non-AN-evoked NTS neurons to GABAA receptor activation was not altered; however, at higher ejection currents, sensitivity of these neurons to GABAB receptor activation was enhanced, as in the AN-evoked neurons, albeit to a lesser degree. It is quite likely that some percentage of the non-AN-evoked neurons consists of neurons that receive baroreceptor inputs from the carotid sinus and/or cardiopulmonary vagal afferent inputs, and these neurons might also exhibit altered sensitivity to GABAergic agonists in HT, as do neurons receiving AN baroreceptor afferent inputs. Depending on the percentage of the total population that these non-AN-evoked neurons receiving other baroreceptor afferent inputs comprise, they could influence the population response. Alternatively, the alterations in sensitivity to GABAB agonist described in this report might represent a more general change within the NTS whether or not the neuron receives a baroreceptor input.
Mechanism of alterations. It is appropriate to speculate on the possible triggers that initiate the alterations in sensitivity to GABAergic agonists observed in this study. Enhanced excitatory (7) or inhibitory synaptic input and/or circulating hormones (e.g., angiotensin and catecholamines) (5, 6, 16) could serve to initiate the alterations. Modulation of GABAA receptor function can be the result of any number of potential mechanisms, including, but not restricted to, regulation of receptor number and/or affinity, regulation of the phosphorylation status of the receptor, and alterations in receptor subunit composition (12). For example, prolonged exposure to GABA downregulates the GABAA receptor (12). In addition, GABAA receptor currents are suppressed during concomitant application of N-methyl-D-aspartate (2) or brief (1-s) depolarizations of the postsynaptic membrane (11). These results suggest that increased synaptic input, either excitatory or inhibitory, could play a role in the reduced sensitivity to muscimol.
In comparison to GABAA receptors, little is known about potential mechanisms that may alter GABAB receptor function. Prolonged exposure to GABA induces expression of GABAB receptors in cerebellar granule cells (14). Increased nociceptive afferent inputs from the hindlimb increased the expression of the GABAB mRNA in dorsal root ganglia and dorsal regions of the lumbar spinal cord (9), suggesting that synaptic activity can regulate the expression of GABAB receptors. We have reported that HT is associated with an increased expression of GABAB receptor mRNA (3) and provided indirect evidence that this change occurs primarily in postsynaptic, as opposed to presynaptic, elements of the NTS (17). This suggests an enhanced expression of GABAB receptors, and our data further suggest that this expression occurs in MSNs.
Physiological significance of alterations. The results demonstrate that within 1 wk of HT there is a shift in the balance of sensitivity to receptor-selective GABAergic agonists and that these alterations persist for 4 wk after the induction of HT. In the NT rat, AN-evoked excitatory inputs are often followed by inhibitory inputs, and this inhibition is mediated predominantly by GABAA receptors (10), with GABAB receptors playing a relatively minor role (18). In previous work (19) and the present study, this is mirrored in the sensitivity of MSNs, inasmuch as they are very sensitive to muscimol inhibition but not very sensitive to baclofen. In MSNs in the HT rat, this GABAergic sensitivity profile is reversed.
GABAA-mediated inhibition through ionotropic chloride channels is relatively rapid in onset and short in duration, whereas GABAB inhibition through G protein-coupled mechanisms is slower in onset and longer lasting. As a consequence, tonic inhibition via GABAA receptors may require greater energy expenditure or may be less effective than inhibition mediated by GABAB receptors. It has been suggested that in renal HT there is an increase in baroreceptor excitatory inputs, particularly from unmyelinated afferent fibers (7). A shift from predominantly GABAA- to GABAB-mediated inhibition may provide a more metabolically favorable mechanism to offset increased baroreceptor excitatory inputs to NTS neurons in HT rats (7). Our previous work (20) and the present study found no difference in the spontaneous discharge of AN-evoked NTS neurons between NT and HT rats; therefore, enhanced GABAB inhibition may normalize the discharge of NTS neurons receiving increased baroreceptor inputs in HT. It has been suggested that such adaptations enable the neurons to respond normally to changes in arterial pressure (10) and limit reductions in baroreflex performance in HT.
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DISCLOSURES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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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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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONDISCLOSURESREFERENCES |
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-aminobutyric acid-mediated responses in nucleus tractus solitarius of hypertensive rats. Hypertension 22: 819-825, 1993.
-Aminobutyric acidB receptor-mediated responses in the nucleus tractus solitarius are altered in acute and chronic hypertension. Hypertension 37: 619-622, 2001.
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