Baroreceptor Afferent Input Research Articles

Functional symmetry of the aortic baroreflex in female spontaneously hypertensive rats.

Altered baroreflex function is well documented in hypertension; however, the female sex remains far less studied compared with males. We have previously demonstrated a left-sided dominance in the expression of aortic baroreflex function in male spontaneously hypertensive rats (SHRs) and normotensive rats of either sex. If lateralization in aortic baroreflex function extends to hypertensive female rats remains undetermined. This study, therefore, assessed the contribution of left and right aortic baroreceptor afferents to baroreflex modulation in female SHRs. Anesthetized female SHRs (total n = 9) were prepared for left, right and bilateral aortic depressor nerve (ADN) stimulation (1-40 Hz, 0.2 ms, 0.4 mA for 20 s) and measurement of reflex mean arterial pressure (MAP), heart rate (HR), mesenteric vascular resistance (MVR) and femoral vascular resistance (FVR). All rats were also matched for the diestrus phase of the estrus cycle. Reflex (%) reductions in MAP, HR, MVR and FVR were comparable for both left-sided and right-sided stimulation. Bilateral stimulation evoked slightly larger ( P = 0.03) reductions in MVR compared with right-sided stimulation; however, all other reflex hemodynamic measures were similar to both left-sided and right-sided stimulation. These data show that female SHRs, unlike male SHRs, express similar central integration of left versus right aortic baroreceptor afferent input and thus show no laterization in the aortic baroreflex during hypertension. Marginal increases in mesenteric vasodilation following bilateral activation of the aortic baroreceptor afferents drive no superior depressor responses beyond that of the unilateral stimulation. Clinically, unilateral targeting of the left or right aortic baroreceptor afferents may provide adequate reductions in blood pressure in female hypertensive patients.

Differential frequency-dependent reflex summation of the aortic baroreceptor afferent input.

Reflex summation in the expression of left and right aortic baroreflex control of hemodynamic functions was investigated. In anesthetized Sprague-Dawley rats, mean arterial pressure (MAP), heart rate (HR), and mesenteric vascular resistance (MVR) were recorded following left, right, and bilateral stimulation of the aortic depressor nerve (ADN). Stimulation frequency was varied between low (1Hz), moderate (5Hz), and high (20Hz). At 1Hz, left and right ADN stimulation evoked similar depressor, bradycardic and MVR responses, whereas bilateral stimulation induced larger MAP, HR, and MVR reductions compared with stimulations of either side. The sum of the separate and combined stimulation effects on MAP, HR, and MVR was similar, indicating an additive summation. A similar additive summation was observed with HR responses at 5 and 20Hz. Left-sided and bilateral stimulation produced greater depressor and MVR responses than right-sided stimulation, with responses of the bilateral stimulation mimicking those of the left side. The bilateral MAP or MVR response was smaller than the sum of the separate responses, suggesting an inhibitory summation. In conclusion, reflex summation of the left and right aortic baroreceptor afferent input is differentially expressed in relation to the frequency of the input signal. Summation of baroreflex control of HR is always additive and independent of stimulation frequency. Summation of baroreflex control of MAP is additive when the frequency input is small and inhibitory when the frequency input is moderate to high, with MAP changes mainly driven by parallel baroreflex-triggered changes in vascular resistance.

Differential central integration of left versus right baroreceptor afferent input in spontaneously hypertensive rats.

The blood pressure (BP) regulatory impact of the arterial baroreflex has been well established in health and disease. Under normotensive conditions, we have previously demonstrated functional differences in the central processing of the left versus right aortic baroreceptor afferent input. However, it is unknown if lateralization in aortic baroreflex function remains evident during hypertension. We therefore, investigated the effects of laterality on the expression of baroreflex-driven cardiovascular reflexes in a genetic model of essential hypertension, the spontaneously hypertensive rat (SHR). Anesthetized male SHRs (total n = 9) were instrumented for left, right, and bilateral aortic depressor nerve (ADN) stimulation (1-40 Hz, 0.2 ms, and 0.4 mA for 20 s) and measurement of mean arterial pressure (MAP), heart rate (HR), mesenteric vascular resistance (MVR), and femoral vascular resistance (FVR). Left right, and bilateral ADN stimulation evoked frequency-dependent decreases in MAP, HR, MVR, and FVR. Left and bilateral ADN stimulation evoked greater reflex reductions in MAP, HR, MVR, and FVR compared with right-sided stimulation. Reflex bradycardia to bilateral stimulation was larger relative to both left-sided and right-sided stimulation. Reflex depressor and vascular resistance responses to bilateral stimulation mimicked those of the left-sided stimulation. These data indicate a left-side dominance in the central integration of aortic baroreceptor afferent input. Furthermore, reflex summation due to bilateral stimulation is only evident on the reflex bradycardic response, and does not drive further reductions in BP, suggesting that reflex depressor responses in the SHRs are primarily driven by changes in vascular resistance. Together, these results indicate that lateralization in aortic baroreflex function is not only evident under normotensive conditions but also extends to hypertensive conditions.

CENTRAL INTEGRATION OF LEFT VERSUS RIGHT BARORECEPTOR AFFERENT INPUT IN FEMALE SPONTANEOUSLY HYPERTENSIVE RATS

Objective: Neuromodulation of blood pressure using baroreflex activation therapy is an effective means to control hypertension in resistant hypertensive patients. In a genetic rat model of essential hypertension, the spontaneously hypertensive rats (SHRs); we were able to demonstrate in male rats that preferential central integration of left baroreceptor afferent input exists relative to that of the right afferents. It remains unknown whether laterality also influences baroreflex responses in female SHRs. Accordingly, the differences in cardiovascular responses triggered by stimulation of the left and right baroreceptor afferents, as assessed by direct electrical stimulation of the aortic depressor nerve (ADN), were studied in female SHRs. Design and method: Pentobarbital-anesthetized female SHRs (25–29 weeks, n = 6–8) were instrumented for left and right ADN stimulation (1–40 Hz, 0.2 ms, 0.4 mA for 20 s) and recording of mean arterial pressure (MAP), heart rate (HR) and mesenteric (MVR) and femoral (FVR) vascular resistance. Female rats were also matched for the diestrus phase of the estrus cycle. Results: Both left and right ADN stimulation resulted in frequency-dependent reductions (P < 0.001) in MAP, HR, MVR and FVR. Reflex reductions in MAP, HR, MVR and FVR were comparable for both left-sided and right-sided stimulation. Conclusions: Unlike males, female SHRs express no differential central modulation of baroreceptor afferent input as evidenced by the comparable left versus right baroreflex-mediated depressor responses. Similar depressor responses in the left versus right stimulation may have been contributed to by the lack of differences in baroreflex-driven changes in HR and vascular resistance. Clinically, targeting either the left or right aortic nerves may equally provide adequate reductions in blood pressure in female hypertensive subjects. Future studies should elucidate the mechanisms responsible for sex differences in the central processing of baroreflex between male and female SHRs.

Angiotensin II-Vasopressin Interactions in The Regulation of Cardiovascular Functions. Evidence for an Impaired Hormonal Sympathetic Reflex in Hypertension and Congestive Heart Failure.

Angiotensin II (ANG II) and vasopressin (VP) interact in several physiological mechanisms, playing a role in arterial hypertension and congestive heart failure. Aim and Methods of Search: To overview the primary mechanism involved in the regulation of cardiovascular function, PubMed/Medline was searched, and authors selected original articles and reviews written in English. Angiotensin II (ANG II) and vasopressin (VP) are involved in several physiological mechanisms. ANG II stimulates VP release via angiotensin receptor 1. ANG II and VP stimulate aldosterone synthesis and secretion and enhance its action at the renal collecting duct level. VP is also involved in the cardiovascular reflex control of the sympathetic nervous system (SNS). Also, VP potentiates vasoconstriction and cardiac contractility, enhancing the effect of ANG II on sympathetic tone and arterial pressure. On the other hand, ANG II and VP act antagonistically in regulating baroreflex control of the SNS. There is evidence that high VP plasma levels increase baroreflex sympatho-inhibitory responses, and the arterial baroreflex response is shifted to lower pressure. This cardiovascular reflex control is mediated mainly in the brain, specifically in the circumventricular organ area postrema (AP). The modulation of cardiovascular reflex control induced by VP is abolished after lesions of the AP. VP modulation of baroreflex function is also under the control of α2-adrenergic pathway arising from the nucleus of the solitary tract (NTS) and synapsing on VP-ergic neurons of supraoptic and paraventricular nuclei. Presynaptic α2-adrenergic stimulation within the NTS inhibits VP release induced by hypovolemia and the effects of VP and AP on baroreflex control of SNS, thus showing baroreceptor afferent inputs are processed within the NTS and contribute to the increased baroreflex sympatho-inhibitory responses. In patients with congestive heart failure (CHF), plasma VP levels are elevated, inducing an up-regulation of aquaporin 2 water channel expression in renal collecting duct (CD) cells provoking exaggerated water retention and dilutional hyponatremia. Antagonists of VP and ANG II receptors reduce edema, body weight, and dyspnea in CHF patients. Hormonal imbalance between ANG II, VP, and SNS may induce hypertension and impaired water-electrolyte balance in cardiovascular diseases.

Laterality Influences Central Integration of Baroreceptor Afferent Input in Male and Female Sprague Dawley Rats.

We explored the effects of baroreceptor afferents laterality and sexual dimorphism on the expression of cardiovascular reflex responses to baroreflex activation in Sprague Dawley (SD) rats. Under urethane anesthesia, rats of either sex (total n = 18) were instrumented for left, right and bilateral aortic depressor nerve (ADN) stimulation (1–40 Hz, 0.2 ms, 0.4 mA for 20 s) and measurement of mean arterial pressure (MAP), heart rate (HR) and mesenteric (MVR) and femoral (FVR) vascular resistance. Female rats were matched for the diestrus phase of the estrus cycle. Left, right and bilateral ADN stimulation evoked frequency-dependent drops in MAP, HR, and MVR, and increases in FVR. Irrespective of sex, left and bilateral ADN stimulation as compared to right-sided stimulation mediated greater reflex reductions in MAP, HR, and MVR but not in FVR. In males, reflex bradycardic responses were greater in response to bilateral stimulation relative to both left- and right-sided stimulation. In females, left ADN stimulation evoked the largest increase in FVR. Left and bilateral ADN stimulations evoked greater reductions in MAP and MVR while left-sided stimulation produced larger increases in FVR in females compared with males. All other reflex responses to ADN stimulation were relatively comparable between males and females. These results show a differential baroreflex processing of afferent neurotransmission promoted by left versus right baroreceptor afferent inputs and sexual dimorphism in the expression of baroreflex responses in rats of either sex. Collectively, these data add to our understanding of physiological mechanisms pertaining to baroreflex control in both males and females.

Hypertensive Young Adult Female Obese Zucker Rats (OZR) do not have the Blunted Baroreflexes and Poor Glycemic control observed in age‐matched Hypertensive Male OZR

Obese Zucker rats (OZR) have hyperphagia owing to dysfunctional leptin receptors and gain excess weight compared to lean Zucker rats (LZR) with functional leptin receptors. Young adult male OZR (12–14 wks) develop hypertension and impaired baroreflexes coincident with blunted activation of the nucleus tractus solitarius (NTS), the brain stem site that receives baroreceptor afferent inputs. Male OZR at this age have hyperinsulinemia and chronically elevated fed glucose levels (despite normal fasting glucose) with significant glucose intolerance as measured by telemetry (DSI). Treatment with metformin (300mg/day, 4 wks) restores glycemic control in OZR without eliminating hypertension or hyperinsulinemia, with no effect on these measures in LZR. After treatment with metformin male OZR have improved baroreflexes and activation of the NTS, suggesting hyperglycemia contributes to these deficits in adult male OZR. In contrast to males, at this age female OZR are hypertensive but do not develop impaired baroreflex‐mediated changes in heart rate (HR; Tenorio et al., 2013). The present study examined whether preserved baroreflex‐mediated changes in HR in female OZR extend to sympathetic baroreflexes and diminished activation of the NTS, and whether female OZR maintain glycemic control at this age (13–14 wks). Female OZR had excess weight gain (215±8 g vs. 483±14 g in 9 LZR and 10 OZR, P<0.05), similar to male OZR. Female rats were instrumented with indwelling femoral catheters run through a tether to record MAP and HR and infuse drugs while rats were conscious and undisturbed. As expected, female OZR had higher MAP (135±2 vs. 121±2 mmHg in 10 OZR and 7 LZR, P<0.05). However, infusion of phenylephrine (PE) to raise MAP by 40 mmHg evoked a comparable bradycardia in female OZR and LZR (−111±13 vs. −129±20 bpm in 9 OZR and 7 LZR) and c‐Fos expression in NTS (311±38 and 390±32 counts). A different set of rats was anesthetized with isoflurane for surgical preparation to measure MAP (femoral artery) and splanchnic sympathetic nerve activity (SNA) and to infuse drugs (femoral vein). Then, the rat was anesthetized with urethane (1.5g/kg iv LZR body weight), ventilated, and paralyzed. As seen with PE‐induced bradycardia, iv infusions of PE and nitroprusside to evoke wide range of MAP elicited comparable changes in SNA of female 5 OZR and 5 LZR (range, 90±16% in OZR vs. 94±3% in LZR and slope, −1.96±0.4 in OZR vs. −2.86±0.4 in LZR). As seen in males, adult female OZR were hyperinsulinemic compared to LZR (7.5±2.0 vs. 1.0±0.1 ng/dl, p<0.05). In contrast to hyperglycemia seen in male OZR, 24hr fed glucose measured by telemetry was equivalent in female OZR and LZR (95±3 vs. 89 ±1 mg/dl in 7 LZR and 6 OZR), and when challenged with glucose (1g/kg, ip) the AUC in female OZR and LZR were comparable (275±38 vs. 195±12 in 6 OZR and 6 LZR). These data suggest better maintenance of glycemic control in hypertensive, hyperinsulinemic young adult female OZR may preserve activation of the NTS and baroreflexes. In addition, these data highlight differing mechanisms for the development of hypertension and impaired control of SNA and HR by baroreflexes in the setting of metabolic syndrome.Support or Funding InformationNIHR01HL138109 to AMS AHA GRNT18880005 to AMS PRE27260088 to PCThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Evidence that activation of both vagal and glossopharyngeal afferents cause the release of 5‐HT in the NTS

Pharmacological studies indicate that 5‐HT is released in the nucleus tractus solitarii (NTS) in response to cardiovascular afferent activation. Experiments using a modified form of fast differential voltammetry were carried out to determine if this release of 5‐HT could be detected in the NTS. Rats were anaesthetized with [alpha]‐chloralose (120 mg kg−1; i.v), neuromuscular blocked and artificially ventilated. Activation of cardiopulmonary afferents by phenylbiguanide (PBG; i.a.) caused a transient rise in 5‐HT of 17.8 ± 2.5nM. Citalopram (1 mg kg−1; i.v.) had no effect, while the OCT3/PMAT inhibitor decynium‐22 (600 [micro]g kg−1, i.v.) potentiated this increase in 5‐HT from 18 ± 4 to 70 ± 11 nM. Increasing baroreceptor afferent input with i.v. noradrenaline increased 5‐HT release, while decreasing this input with i.v. sodium nitroprusside had no effect. Citalopram (1 mg kg−1) had no effect on these responses. Activation of the chemoreflex with i.a. sodium cyanide caused a maintained rise in 5‐HT of 27 ± 6 nM. The data supports the view that cardiovascular afferents cause the release of 5‐HT in the NTS.

Inhibition of Cardiac Sympathetic Afferent Reflex and Sympathetic Activity by Baroreceptor and Vagal Afferent Inputs in Chronic Heart Failure

BackgroundCardiac sympathetic afferent reflex (CSAR) contributes to sympathetic activation and angiotensin II (Ang II) in paraventricular nucleus (PVN) augments the CSAR in vagotomized (VT) and baroreceptor denervated (BD) rats with chronic heart failure (CHF). This study was designed to determine whether it is true in intact (INT) rats with CHF and to determine the effects of cardiac and baroreceptor afferents on the CSAR and sympathetic activity in CHF.Methodology/Principal FindingsSham-operated (Sham) or coronary ligation-induced CHF rats were respectively subjected to BD+VT, VT, cardiac sympathetic denervation (CSD) or INT. Under anesthesia, renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) were recorded, and the CSAR was evaluated by the RSNA and MAP responses to epicardial application of capsaicin. Either CSAR or the responses of RSNA, MAP and CSAR to Ang II in PVN were enhanced in CHF rats treated with BD+VT, VT or INT. Treatment with VT or BD+VT potentiated the CSAR and the CSAR responses to Ang II in both Sham and CHF rats. Treatment with CSD reversed the capsaicin-induced RSNA and MAP changes and the CSAR responses to Ang II in both Sham and CHF rats, and reduced the RSNA and MAP responses to Ang II only in CHF rats.ConclusionsThe CSAR and the CSAR responses to Ang II in PVN are enhanced in intact CHF rats. Baroreceptor and vagal afferent activities inhibit CSAR and the CSAR responses to Ang II in intact Sham and CHF rats.

A “love triangle” elicited by electrochemistry: complex interactions among cardiac sympathetic afferent, chemo-, and baroreflexes

there are three major cardiovascular reflexes: the baroreflex, chemoreflex, and cardiac sympathetic afferent reflex (CSAR). This commentary provides a brief overview of these three reflexes and also discusses the interplay among them. In addition, it outlines the potential centrally integrative

Transient Voltage-Dependent Potassium Currents Are Reduced in NTS Neurons Isolated From Renal Wrap Hypertensive Rats

Whole cell patch-clamp measurements were made in neurons enzymatically dispersed from the nucleus of the solitary tract (NTS) to determine if alterations occur in voltage-dependent potassium channels from rats made hypertensive (HT) by unilateral nephrectomy/renal wrap for 4 wk. Some rats had the fluorescent tracer DiA applied to the aortic nerve before the experiment to identify NTS neurons receiving monosynaptic baroreceptor afferent inputs. Mean arterial pressure (MAP) was greater in 4-wk HT (165 +/- 5 mmHg, n = 26, P < 0.001) rats compared with normotensive (NT) rats (109 +/- 3 mmHg measured in 10 of 69 rats). Transient outward currents (TOCs) were observed in 67-82% of NTS neurons from NT and HT rats. At activation voltages from -10 to +10 mV, TOCs were significantly less in HT neurons compared with those observed in NT neurons (P < 0.001). There were no differences in the voltage-dependent activation kinetics, the voltage dependence of steady-state inactivation, and the rise and decay time constants of the TOCs comparing neurons isolated from NT and HT rats. The 4-aminopyridine-sensitive component of the TOC was significantly less in neurons from HT compared with NT rats (P < 0.001), whereas steady-state outward currents, whether or not sensitive to 4-aminopyridine or tetraethylammonium, were not different. Delayed excitation, studied under current clamp, was observed in 60-80% of NTS neurons from NT and HT rats and was not different comparing neurons from NT and HT rats. However, examination of the subset of NTS neurons exhibiting somatic DiA fluorescence revealed that DiA-labeled neurons from HT rats had a significantly shorter duration delayed excitation (n = 8 cells, P = 0.022) than DiA-labeled neurons from NT rats (n = 7 cells). Neurons with delayed excitation from HT rats had a significantly broader first action potential (AP) and a slower maximal downstroke velocity of repolarization compared with NT neurons with delayed excitation (P = 0.016 and P = 0.014, respectively). The number of APs in the first 200 ms of a sustained depolarization was greater in HT than NT neurons (P = 0.012). These results suggest that HT of 4-wk duration reduces TOCs in NTS neurons, and this contributes to reduced delayed excitation and increased AP responses to depolarizing inputs. Such changes could alter baroreflex function in hypertension.

NITRIC OXIDE and SYMPATHETIC NERVE ACTIVITY IN THE CONTROL OF BLOOD PRESSURE

1. Endothelial dysfunction marked by impairment in the release of nitric oxide (NO) is seen very early in the development of hypertension and is considered important in mediating the impaired vascular tone evident in essential hypertensive patients. 2. Recently, a hypothesis has emerged that NO acting as a neurotransmitter in the brain can modulate levels of sympathetic nerve activity and thereby blood pressure. The NO inhibition model of hypertension has been used to explore the possibility that a decrease in levels of NO can cause an increase in levels of sympathetic nerve activity that can mediate the hypertension. 3. In the present review, we examine the literature regarding the role of NO in setting the mean level of sympathetic nerve activity and blood pressure. Although the acute effects of NO inhibition are well understood, the chronic interaction between the sympathetic nervous system and NO has only been investigated using indirect measures of sympathetic nerve activity, such as ganglionic blockade. This has led to inconsistent results regarding the role of NO in modulating sympathetic nerve activity chronically. 4. Some of the conflicting results may be explained by differences in the 'background' levels of angiotensin (Ang) II. Evidence suggests that NO may interact with AngII and baroreceptor afferent inputs in the central nervous system to set the mean level of sympathetic nerve activity. 5. We suggest chronic NO inhibition can increase sympathetic nerve activity if baroreceptor input is intact and AngII levels are elevated. Although studies exploring the actions of NO or AngII in isolation are useful for gathering initial information, future studies should focus on their interactions and their role in setting the long-term levels of sympathetic activity and blood pressure.

The cardiac-related rhythm in preganglionic sympathetic activities of developing piglets

This investigation was performed to determine whether partial spectral analysis of preganglionic sympathetic nerve discharges would reveal age-related differences in the distribution of baroreceptor afferent information to brainstem sympathetic-related neurons. Any influence of baroreceptor afferent activity on ordinary spectra of cervical sympathetic and splanchnic nerves was removed by partialization using the arterial blood pressure signal which represented baroreceptor activity. An absence of statistically significant coherence in partialized nerve spectra would indicate that sympathetic-related neurons receive peripheral baroreceptor afferent input, but are not interconnected, whereas the presence of significant coherence would mean that these neurons are interconnected. Ordinary spectral analysis did not demonstrate age-related differences in the relationship between nerve activity and baroreceptor afferent input. In many animals, large peaks, located at cardiac frequencies (range 2.75–5.6 Hz), were noted in ordinary nerve autopower spectra, and were significantly correlated in ordinary coherence spectra. Partialization of nerve spectra eliminated or reduced cardiac-related peaks in autopower spectra regardless of age, and, in 8 of 10 animals, reduced coherence estimates to non-significant values. In two animals, 19 and 36 days old, significant coherence values remained after partialization. These results demonstrated that cardiac-related peaks in coherence in spectra of preganglionic splanchnic and cervical sympathetic nerves were dependent upon peripheral afferent baroreceptor input in most animals. Further, the finding that significant residual coherence was absent in most cases suggested a paucity of intrabulbar pathways connecting brainstem sympathetic-related neurons.

Functional interaction between nucleus tractus solitarius NK and 5-HT receptors in the inhibition of baroreflex in rats

Previous data showed that in the nucleus tractus solitarius (NTS), 5-HT(3) receptors are critically involved in the inhibition of cardiac baroreceptor reflex response occurring during the defense reaction. Since stimulation of NTS NK(1) receptors has been found to inhibit the baroreflex bradycardia, we examined in this study whether this reflex response is inhibited during the defense reaction via an interaction between NK(1) and 5-HT(3) receptors. For this purpose, we analyzed in urethane-anaesthetized rats the effects of intra-NTS GR205171, a selective NK(1) receptor antagonist, on the baroreflex bradycardia inhibition observed either during the defense reaction triggered by electrical stimulation of the dorsal periaqueductal grey matter (dPAG) or after NTS 5-HT(3) receptor activation. Intra-NTS GR205171, reversed, in dose-dependent manner, the inhibitory effect of dPAG stimulation on baroreflex bradycardia. This reversion was of 49% when both sinus carotid and aortic baroreceptors were stimulated by phenylephrine, and of 84% when aortic depressor nerve was stimulated. Similarly, intra-NTS GR205171 reversed partially or almost totally the inhibitory effect of local microinjections of phenylbiguanide, a 5-HT(3) receptor agonist, on baroreflex bradycardia induced either by phenylephrine administration or aortic nerve stimulation, respectively. These results strongly suggest that NK(1) receptors contribute downstream to the 5-HT(3) receptor-mediated inhibition of the aortic but not carotid cardiac baroreflex response occurring during the defense reaction, therefore implying that baroreceptor afferent inputs may be differentially modulated depending on their origin. This differentiation may be useful for a better understanding of baroreflex dysfunction in disease-induced conditions.

Hypertension alters GABA receptor-mediated inhibition of neurons in the nucleus of the solitary tract.

Previous studies have demonstrated that microinjection of baclofen, a GABA(B) receptor agonist, into the nucleus of the solitary tract (NTS) results in an enhanced pressor response in hypertensive (HT) rats compared with normotensive (NT) rats, suggesting a possible alteration in the responses of neurons in this area to activation of GABA(B) receptors. The following studies were designed to determine whether HT alters the sensitivity of neurons in the NTS to GABA receptor agonists. Sham-operated NT and unilateral nephrectomized, renal-wrap HT Sprague-Dawley rats were anesthetized, and the responses of NTS neurons receiving aortic nerve (AN) afferent inputs to iontophoretic application of GABA, the GABA(A) receptor agonist muscimol, and the GABA(B) agonist baclofen were examined. The AN input was classified as monosynaptic (MSN) if the cell responded to each of two stimuli separated by 5 ms with an action potential. If the cell did not respond, the input was considered polysynaptic (PSN). In MSNs, inhibition of AN-evoked discharge by GABA was not altered in 1 wk of HT but was reduced in 4 wk of HT, whereas in PSNs, sensitivity to GABA was reduced at 1 and 4 wk of HT. In HT rats, inhibition of AN-evoked discharge by baclofen was enhanced in MSNs, but not in PSNs, after 1 and 4 wk of HT, whereas inhibition by muscimol was reduced in MSNs and PSNs at 1 and 4 wk of HT. Changes in sensitivity to muscimol and baclofen within MSNs were the same whether the MSN received a slowly or a rapidly conducted AN afferent input. The results demonstrate that early in HT the sensitivity of NTS neurons to inhibitory amino acids is altered and that these changes are maintained for > or =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.

Cardiovascular responses to hypocretin-1 in nucleus ambiguus of the ovariectomized female rat

Experiments were done to investigate the effect of chronic estrogen (E; 30 pg/ml plasma) treatment (15–25 days) in the ovariectomized (OVX) female Wistar rat on the cardiovascular responses to hypocretin-1 (hcrt-1) in the nucleus ambiguus (Amb). Microinjections of hcrt-1 (0.5–2.5 pmol) into the external formation of Amb (Ambe) in the urethane anaesthetized, E treated OVX animal or OVX only animal, elicited a dose-related decrease in heart rate (HR). On the other hand, hcrt-1 injections into Ambe did not elicit consistent changes in mean arterial pressure (MAP). The HR response was mediated by vagal excitation as ipsilateral vagotomy abolished the bardycardia response. The bradycardia responses were consistently of greater magnitude and longer duration in the OVX+E animals compared to the OVX only female animals. Finally, it was found that the reflex bradycardia to activation of arterial baroreceptors, as a result of increasing systemic arterial pressure with phenylephrine, was only significantly potentiated in the OVX+E animals. These data suggest that hcrt-1 in the Ambe of the female elicits an increase in vagal cardiomotor neuronal activity to the heart, and that the circulating level of E alters not only the sensitivity of Ambe neurons to hcrt-1 but also the sensitivity of these neurons during activation of baroreceptor afferent inputs.

NTS neuronal response to conversion from pulsatile to nonpulsatile pressure in isolated carotid sinus baroreceptors.

The purpose of this study was to demonstrate the effect of pulsatile pressure (PP) and nonpulsatile pressure (NP) on the carotid sinus baroreceptors and baroreceptor-related neurons in the nucleus tractus solitarius (NTS), using an isolated carotid sinus preparation in anesthetized rats. The baroreceptor activities were recorded from the carotid sinus nerves (CSN). Fifteen baroreceptor-related NTS neurons were recorded extracellularly. Conversion of PP to NP corresponded to a shift from phasic to irregular activity in the CSN and caused an increase in CSN activity at a mean pressure of 100 mm Hg. Under this condition, however, the discharge rate of baroreceptor-related NTS neurons was decreased and the systemic blood pressure was elevated. These results indicate that the increasing baroreceptor afferent input resulting from depulsation was not faithfully transmitted in the NTS, and suggest that the NTS is an important site for modifying the arterial baroreflex under NP.

Glutamate release in midbrain periaqueductal gray by activation of skeletal muscle receptors and arterial baroreceptors.

We have previously reported that both skeletal muscle receptor and arterial baroreceptor afferent inputs activate neurons in the dorsolateral (DL) and lateral regions of the midbrain periaqueductal gray (PAG). In this study, we determined whether the excitatory amino acid glutamate (Glu) is released to mediate the increased activity in these regions. Static contraction of the triceps surae muscle for 4 min was evoked by electrical stimulation of the L7 and S1 ventral roots in cats. Activation of arterial baroreceptor was induced by intravenous injection of phenylephrine. The endogenous release of Glu from the PAG was recovered with the use of a microdialysis probe. Glu concentration was measured by the HPLC method. Muscle contraction increased mean arterial pressure (MAP) from 98 +/- 10 to 149 +/- 12 mmHg (P < 0.05) and increased Glu release in the DL and lateral regions of the middle PAG from 0.39 +/- 0.10 to 0.73 +/- 0.12 microM (87%, P < 0.05) in intact cats. After sinoaortic denervation and vagotomy were performed, contraction increased MAP from 95 +/- 12 to 158 +/- 15 mmHg, and Glu from 0.34 +/- 0.08 to 0.54 +/- 0.10 microM (59%, P < 0.05). The increases in arterial pressure and Glu were abolished by muscle paralysis. Phenylephrine increased MAP from 100 +/- 13 to 162 +/- 22 mmHg and increased Glu from 0.36 +/- 0.10 to 0.59 +/- 0.18 microM (64%, P < 0.05) in intact animals. Denervation abolished this Glu increase. Summation of the changes in Glu evoked by muscle receptor and arterial baroreceptor afferent inputs was greater than the increase in Glu produced when both reflexes were activated simultaneously in intact state (123% vs. 87%). These data demonstrate that activation of skeletal muscle receptors evokes release of Glu in the DL and lateral regions of the middle PAG, and convergence of afferent inputs from muscle receptors and arterial baroreceptors in these regions inhibits the release of Glu. These results suggest that the PAG is a neural integrating site for the interaction between the exercise pressor reflex and the arterial baroreceptor reflex.

Direct injection of substance P-antisense oligonucleotide into the feline NTS modifies the cardiovascular responses to ergoreceptor but not baroreceptor afferent input

Substance P (SP) is released from the feline nucleus tractus solitarius (NTS) in response to activation of skeletal muscle afferent input. However, there are differing results about SP release from the rostral NTS in response to baroreceptor afferent input. An anti-sense oligonucleotide to feline SP (SP-asODN) was injected directly into the rostral NTS of chloralose-anesthetized cats to determine whether blood pressure or heart rate responses to ergoreceptor activation (muscle contraction) or baroreceptor unloading (carotid artery occlusion) were sensitive to SP knockdown. Control injections included either buffer alone or a scrambled-sequenced oligonucleotide (SP-sODN). Both muscle contractions and carotid occlusions were performed 3, 6 and 12 h after the completion of the oligonucleotide injections. The cardiovascular responses to contractions were significantly attenuated 3 and 6 h after SP-asODN, but not by the injection of the SP-sODN. The cardiovascular responses to contractions returned to control levels 12 h post anti-sense injection. No detectable release of SP (using antibody-coated microprobes) was measured 3 and 6 h after SP-asODN injections and the expression of SP-immunoreactivity (SP-IR) in the NTS was significantly attenuated, as determined by immunohistochemistry procedures. In contrast, neither the injection of SP-asODN nor the s-ODN attenuated the cardiovascular responses to carotid occlusions, or altered the pattern of release of SP from the brainstem. Injection of the SP-sODN did not affect the expression of SP-IR. These results suggest that the SP involved with mediating the peripheral somatomotor signal input to the rostral NTS comes from SP-containing neurons within the NTS. Our results also suggest that SP in the rostral NTS does not play a direct role in mediating the cardiovascular responses to unloading the carotid baroreceptors. We suggest that the SP released during isometric contractions excites an inhibitory pathway modulating baroreceptor input, thus contributing to the increase in mean blood pressure.

Rhythmicities in sympathetic discharge: a signal of cardiorespiratory integration in developing animals.

We have been pursuing various avenues of investigation to elucidate the postnatal maturation of neural regulation of cardiovascular and respiratory integration. In this paper we present our results from a systematic analysis of age-related modulations of sympathetic (SYMP) activity with respect to experimental alterations in baroreceptor afferent inputs. The three age groups of piglets were chosen based on different responses to a complex stimulus, i.e., the Valsalva maneuver. Postnatal maturation of SYMP activity was examined by spectral analysis of SYMP discharge using cross-power, full and partial coherence. Three general oscillations were observed in spontaneous SYMP discharges in the 0-30 Hz range. We divided that range into five frequency bands (0-2, 2-6, 6-12, 12-20, 20-30 Hz), which included periodicities in phase with both central respiratory activity and the cardiac cycle. Spectral analyses of SYMP activity after either baroreceptor activation (phenylephrine) or deactivation (nitroprusside) revealed that respiratory modulation was age-related across all frequencies while baroreceptor modulation was usually age-related within three of the five frequency bands. These results lead to questions concerning the possible role of the autonomic nervous system and/or central interactions between the respiratory and SYMP rhythm generators in the etiology of sudden infant death syndrome (SIDS).