Aortic Nerve Research Articles

Chronic AT(1) receptor blockade alters autonomic balance and sympathetic responses in hypertension.

In the coarctation hypertension model, we have shown that chronic treatment with losartan causes both normalization of impaired reflex control of heart rate and partial correction of the depressed aortic nerve activity/pressure relationship, even with the persistence of hypertension. In the present study, we analyzed the effects of angiotensin II blockade on the efferent pathways of coarcted and sham-operated groups treated chronically with vehicle or losartan (10 mg/kg per day PO). Hypertension was induced by subdiaphragmatic aortic coarctation, and the treatments lasted 9 days (4 control and 5 experimental days). On day 5, autoregressive power spectral analysis was performed on heart rate recordings made in conscious rats. Other groups were used for sympathetic splanchnic nerve activity recordings made simultaneously with pressure (anesthetized rats) at basal condition and during loading/unloading of baroreceptors. Losartan treatment induced a significant reduction in basal pressure but did not interfere with the development of hypertension (similar pressure increases of 24% and 28% over control values in losartan and vehicle groups, respectively). In vehicle-treated rats, establishment of hypertension was accompanied by a marked change in power spectral density from high- (1.19+/-0.06 Hz, 33+/-6%) to low-frequency components (0,42+/-0.03 Hz, 54+/-6%), with increased low-frequency-to-high-frequency ratio. When compared with sham-operated vehicle-treated rats, there was also increase in the gain of sympathetic activity/pressure relationship, with displacement of lower plateau toward high levels of sympathetic activity. No changes in the power spectral density and sympathetic activity/pressure relationship were observed when hypertension developed in the presence of chronic angiotensin type 1 (AT(1)) receptor blockade. The data suggest that angiotensin II, activated during the establishment of coarctation hypertension, acts via AT(1) receptors to alter sympathovagal balance, facilitating the sympathetic outflow to heart and peripheral circulation during baroreceptors unloading. Data also indicate that the observed effects are not conditioned by preexisting pressure levels.

Arterial baroreceptors and experimental diabetes.

Alterations of the autonomic reflex control of the cardiovasclar system have been demonstrated in clinical and animal models of insulin-dependent diabetes mellitus. Established neuroaxonal dystrophy is considered the neuropathological hallmark of chronic experimental diabetes. However, the afferent arm of the arterial baroreflex, that is, the carotid sinus nerve and the aortic depressor nerve, has received much less attention in studies dealing with this physiopathological model. The attenuation of the pressure response to bilateral carotid occlusion in conscious rats indicates a derangement of the baroreflex, probably involving an alteration of the carotid sinus nerve. There is histological evidence obtained from adult spontaneous insulin-dependent diabetic rats (strain BB/S) of a carotid sinus nerve with signs of axonal swelling and intramyelinic edema, suggesting diabetic neuropathy. The study of aortic baroreceptor activity in anesthetized rats with short- and long-term streptozotocin diabetes by means of cross-spectral analysis of baroreceptor activity versus arterial pressure revealed a dysfunction in the afferent arm of the baroreflex even during a short period of diabetes. The morphology of the aortic depressor nerve of streptozotocin-diabetic rats indicated axonal atrophy by visual analysis remarkably at the distal segments of the nerves. This finding was confirmed by morphometric study of the myelinated fibers. In conclusion, although studies of the arterial baroreceptors related to experimental diabetes are scanty in the literature, there is electrophysiological and histological evidence demonstrating that the carotid sinus and the aortic depressor nerves are abnormal in this experimental model.

Reliability of monosynaptic sensory transmission in brain stem neurons in vitro.

The timing of events within the nervous system is a critical feature of signal processing and integration. In neurotransmission, the synaptic latency, the time between stimulus delivery and appearance of the synaptic event, is generally thought to be directly related to the complexity of that pathway. In horizontal brain stem slices, we examined synaptic latency and its shock-to-shock variability (synaptic jitter) in medial nucleus tractus solitarius (NTS) neurons in response to solitary tract (ST) electrical activation. Using a visualized patch recording approach, we activated ST 1-3 mm from the recorded neuron with short trains (50-200 Hz) and measured synaptic currents under voltage clamp. Latencies ranged from 1.5 to 8.6 ms, and jitter values (SD of intraneuronal latency) ranged from 26 to 764 micros (n = 49). Surprisingly, frequency of synaptic failure was not correlated with either latency or jitter (P > 0.147; n = 49). Despite conventional expectations, no clear divisions in latency were found from the earliest arriving excitatory postsynaptic currents (EPSCs) to late pharmacologically polysynaptic responses. Shortest latency EPSCs (<3 ms) were mediated by non-N-methyl-D-aspartate (non-NMDA) glutamate receptors. Longer latency responses were a mix of excitatory and inhibitory currents including non-NMDA EPSCs and GABAa receptor-mediated currents (IPSC). All synaptic responses exhibited prominent frequency-dependent depression. In a subset of neurons, we labeled sensory boutons by the anterograde fluorescent tracer, DiA, from aortic nerve baroreceptors and then recorded from anatomically identified second-order neurons. In identified second-order NTS neurons, ST activation evoked EPSCs with short to moderate latency (1.9-4.8 ms) but uniformly minimal jitter (31 to 61 micros) that were mediated by non-NMDA receptors but had failure rates as high as 39%. These monosynaptic EPSCs in identified second-order neurons were significantly different in latency and jitter than GABAergic IPSCs (latency, 2.95 +/- 0.71 vs. 5.56 +/- 0.74 ms, mean +/- SE, P = 0.027; jitter, 42.3 +/- 6.5 vs. 416.3 +/- 94.4 micros, P = 0.013, n = 4, 6, respectively), but failure rates were similar (27.8 +/- 9.0 vs. 9.7 +/- 4.4%, P = 0.08, respectively). Such results suggest that jitter and not absolute latency or failure rate is the most reliable discriminator of mono- versus polysynaptic pathways. The results suggest that brain stem sensory pathways may differ in their principles of integration compared with cortical models and that this importantly impacts synaptic performance. The unique performance properties of the sensory-NTS pathway may reflect stronger axosomatic synaptic processing in brain stem compared with dendritically weighted models typical in cortical structures and thus may reflect very different strategies of spatio-temporal integration in this NTS region and for autonomic regulation.

The discharge of a subset of serotonergic raphe magnus cells is influenced by baroreceptor input

In order to determine whether serotonergic cells in the medullary raphe magnus (RM) receive baroreceptor input, cells were tested for their responses to descending aortic occlusion, aortic nerve stimulation, or systemic phenylephrine administration in the lightly anesthetized rat. Serotonergic cells were identified physiologically by a quantitative analysis of their slow and steady discharge. Greater than 40% of the serotonergic RM cells tested responded to brief occlusion of the descending aorta at the level of the coeliac arteries, a stimulus that elevated blood pressure by about 30 mmHg. Similarly, about 40% of the serotonergic RM cells responded to stimulation of the aortic nerve, a nerve that contains primarily baroreceptor afferents from the aortic arch. Greater than 70% of RM serotonergic cells responded to phenylephrine administration which elevated blood pressure by an average of 50 mmHg. Serotonergic cell responses to all methods of baroreceptor activation were small in magnitude and were largely restricted in time to the stimulus duration. The results indicate that a subset of serotonergic cells in RM are influenced by baroreceptor activity.

Acute response of aortic nerve activity to free drop-induced microgravity in anesthetized rats

To test the hypothesis that arterial baroreflex was stimulated during microgravity (μG), arterial pressure (AP), intrathoracic pressure (ITP), and aortic nerve activity (ANA) were measured in anesthetized rats during 4.5 s of μG produced by free drop. A smooth and immediate reduction in G occurred during free drop, μG being achieved 100 ms after the start of the drop. Acute μG elicited an immediate and striking, but transient, increase in ANA, with no significant change in the AP, but a significant decrease in the end-expiratory ITP. The calculated transmural pressure of the aorta increased by 6.9 mmHg 2 s after the start of the drop. The increase in ANA lasted 2 s, then ANA returned to the control level, despite the calculated end-expiratory transmural pressure still being high. These results suggest that μG conditions stimulate the aortic baroreceptor by increasing transmural pressure by reducing the ITP. However, this effect is only transient, probably due to the high-pass property of the baroreceptors.

Gating of vagal inputs by sciatic afferents in nonspinally projecting neurons in the rat rostral ventrolateral medulla oblongata.

Integration and coordination of somato-visceral sensory information is crucial to achieve adaptive behavioural responses. We have recently shown that sensory vagal and somato-sensory (sciatic nerve) inputs converge in neurons of the rostral ventrolateral medulla oblongata, which was implicated in adjusting visceral activities to changing somatic performances. In the present study, the neuronal mechanism of interaction between sciatic and vagal sensory inputs was examined in the rostral ventrolateral medulla oblongata using in vivo intracellular recording and labelling. Conditioning stimulation of the contralateral sciatic nerve (2 V) led to a time-dependent inhibition of responses to vagal stimulation (100 microA) in each RVLM neuron that received convergent sciatic and vagal sensory inputs (n = 50). None of these neurons had direct spinal projections, and only 8% of them exhibited a visible response to stimulation of the aortic depressor nerve. A significant attenuation of the amplitude of vagal test responses was present for up to 800 ms of conditioning delay, although the duration of this sciatico-vagal inhibition was greatly dependent on the intensity of both stimuli. The electrophysiological data indicated that sciatico-vagal inhibition is mediated presynaptically, via activation of GABAB receptors. Morphological evidence of axo-axonic interactions that may underlie sciatico-vagal inhibition was subsequently found in the electron microscope. It is suggested that during movements of the hindleg, activation of sciatic sensory fibres leads to re-patterning of neuronal activity in RVLM neurons via inhibition of visceral sensory inputs. Sciatico-vagal inhibition is likely to affect the activity of those RVLM neurons that modulate higher neuronal activities via ascending projections.

Chemosensory activity from single or few-fibres of the carotid sinus nerve in the guinea-pig

Humans who are born and raised at high altitude possess a blunted breathing response to hypoxia. The guinea-pig also has a blunted breathing response to hypoxia [1], which may be linked to its high altitude origin in South America. Our laboratory has shown that the carotid bodies of the guinea-pig are not required for the breathing response to hypoxia [1]. Whether the carotid bodies can actually detect hypoxia is uncertain because the central depressive effects associated with hypoxia may attenuate the breathing response to an otherwise potent carotid body stimulant. In a recent study, we looked for evidence of chemoreceptor activity in the whole carotid sinus nerve (CSN), but found that the whole CSN activity was dominated by baroreceptor afferent activity [2]. In this study activity was recorded from single or few-fibre CSN filaments during application of the chemoreceptor stimulants NaCN (200 μgkg-1 i.v.), 8% CO2 (60 s) and 8% O2 (60 s), from guinea-pigs (n = 10; ~420 g; ~50 days old) that were anaesthetised with ketamine/xylazine (20/1 mgkg-1). Of the 10 guinea-pigs, only 8 fibre preparations containing chemoreceptor activity were successfully obtained from 4 guinea-pigs. In general, most of the isolated nerve filaments were multi-fibre preparations. Basal chemoreceptor activity could not be detected. However, NaCN and hypercapnia increased activity in 5 of the fibre preparations that were otherwise silent, or that contained 1 or 2 baroreceptor fibres. The magnitude of response varied considerably between filaments because of the different number of individual fibres in each preparation and, thus, the difference in the actual count of action potentials. Only one of the fibre preparations responded to hypoxia with an increase in activity; no fibres responded with a decrease in activity. The physiological relevance of the latter results could be similar to that of the aortic depressor nerve (ADN) in the rat. Brophy et al. revealed that, in contrast to the general consensus, the rat ADN does contain chemoreceptor afferent fibres, and that such fibres are stimulated by chemoreceptor stimulants [3]. Kobayashi et al. agreed that chemoreceptor fibres were present, but concluded that the rat ADN does not contain a functionally significant number of chemoreceptor afferent fibres that could appreciably contribute to the generation of chemoreflexes [4]. The present study has shown that the carotid bodies of the guinea-pig can detect NaCN and hypercapnia, as expected, and also hypoxia, although the latter was a comparatively weak stimulant. In conclusion, the physiological relevance of the carotid body of the guinea-pig for the ventilatory responses to hypoxia remains uncertain.

Effects of induced hypothermia on renal sympathetic nerve activity and baroreceptor reflex in urethane-anesthetized rabbits.

To evaluate the role of the autonomic nervous system in hemodynamic changes during induced hypothermia. Prospective, randomized animal study. An animal research laboratory in a medical university. A total of 29 anesthetized rabbits. Animals were anesthetized by intraperitoneal urethane. After tracheostomy and administration of gallamine, respiration was maintained by mechanical ventilatory support. The animals were divided into five groups (one control and the four experimental groups); animals were treated with an intact neuraxis and normothermia (control group), animals with an intact neuraxis (intact group), cervical vagotomized animals (vagotomy group), the carotid sinus and aortic nerves denervated animals (SAD group), and animals with SAD plus vagotomy (SADV group). The left renal sympathetic nerves were exposed by a retroperitoneal approach. We examined the effects of surface cooling on HR, mean arterial pressure, central venous pressure, and renal sympathetic nerve activity (RSNA) in the animals. Changes of baroreflex sensitivity and plasma catecholamines were also measured simultaneously. Surface cooling caused progressive and profound decreases in HR in all experimental groups. In all groups, RSNAs increased at the early phase, which were followed by return to the precooling level. Hemodynamics and RSNA during induced hypothermia are regulated by mechanisms other than the baroreceptor reflex system, possibly the dermal cold receptors. Suppression of the baroreflex occurred on HR but not on RSNA during hypothermia, which may indicate direct effects of hypothermia on the heart. RSNA responses may be activated earlier than systemic catecholamine responses during induced hypothermia.

Effects of aortic nerve on hemodynamic response to obstructive apnea in sedated pigs.

In this study we test the hypothesis that aortic nerve traffic is responsible for the pressor response to periodic apneas. In nine intubated, sedated chronically instrumented pigs, periodic obstructive apneas were caused by occlusion of the endotracheal tube for 30 s, followed by spontaneous breathing for 30 s. This was done under control (C) conditions, after section of the aortic nerve (ANS), and after bilateral cervical vagotomy (Vagot). Blood-gas tensions and airway pressure changed similarly under all conditions: PO(2) decreased to 50-60 Torr, PCO(2) increased to approximately 55 Torr, and airway pressure decreased by 40-50 mmHg during apnea. With C, mean arterial pressure (MAP) increased from 111 +/- 4 mmHg at baseline to 120 +/- 5 mmHg at late apnea (P < 0.01). After ANS and Vagot, there was no change in MAP with apneas compared with baseline. Relative to baseline, cardiac output and stroke volume decreased with C but not with ANS or Vagot during apneas. Increased MAP was due to increased systemic vascular resistance. Heart rate behaved similarly with C and ANS, being greater at early interapnea than late apnea. With Vagot, heart rate increased throughout the apnea-interapnea cycle relative to baseline. We conclude that, in sedated pigs, aortic nerve traffic mediates the increase in MAP and systemic vascular resistance observed during periodic apneas. Increase in MAP is responsible for decreased cardiac output and stroke volume. Additional vagal reflexes, most likely parasympathetic efferents, are responsible for interacting with sympathetic excitatory influences in modulating heart rate.

Subthreshold aortic nerve inputs to neurons in nucleus of the solitary tract.

Subthreshold aortic nerve (AN) inputs to neurons receiving a monosynaptic AN-evoked input (MSNs: respond to each of two AN stimuli separated by 5 ms) and neurons receiving a polysynaptic AN input (PSNs) in the nucleus of the solitary tract (NTS) were identified in anesthetized rats. In extracellular recordings from 24 MSNs and 49 PSNs, 12% of MSNs and 29% of PSNs only responded to AN stimulation during the application of excitatory amino acids. In intracellular recordings from 24 MSNs and 22 PSNs, 12% of MSNs and 14% of PSNs responded to AN stimulation with excitatory postsynaptic potentials that did not evoke action potential discharge. Reductions in arterial pressure produced minimal changes in the spontaneous discharge of suprathreshold AN-evoked neurons, suggesting that these neurons receive excitatory inputs from nonbaroreceptor sources. The results suggest that some baroreflex-related NTS neurons exist in a "reserve state and can be changed to an active state or vice versa. This will change the number of neurons involved in baroreflex circuits and provides a novel mechanism for regulating baroreflex function independently of alterations in peripheral afferent input.

Different cardiovascular neuron groups in the ventral reticular formation of the rostral medulla in rabbits: single neurone studies

To examine whether the cardiovascular neurons of the ventral medulla consist of functionally different kinds of neurons, single neuronal activity of the ventral medulla, activity of the renal sympathetic nerves (RSNA), blood flow of the ear (EarBF) and arterial pressure (AP) were recorded in urethane-anesthetized, vagotomized and immobilized rabbits during electrical stimulation of the aortic nerve (AN, baroreceptor afferent fibers) and electrical stimulation of the dorsomedial hypothalamus (DMH) that reduced EarBF but less affected on AP and RSNA. The dorsolateral funiculus of the second cervical cord was stimulated to evoke antidromic spikes of medullary neurons. Two kinds of reticulo-spinal neurons were identified. Activities of one kind of neurons were facilitated by stimulation of DMH (latency 48.6±27.6 ms, n=11) but they did not respond to stimulation of the AN. Therefore, it was presumed that these neurons controlled vasomotion of the ear through the vasoconstrictor neurons in the spinal cord but did not participate in regulation of systemic AP. Activities of the other neurons were inhibited by stimulation of the AN (latency 47.8±8 4 ms, n=16) but they did not respond to the DMH stimulation. These neurons were identical to those reported previously as the RVLM neurons, and they contributed to regulate systemic AP but might not participate in control of cutaneous vascular movement. The former neurons were located medially to the latter in the reticular formation of the rostral ventral medulla. These results provided evidence at the single neuronal level that the cardiovascular neurons in the ventral medulla were consisted of functionally different sympatho-excitatory neurons and they were located at the different sites in the rostral ventral medulla.

Integration of aortic nerve inputs in hypertensive rats.

The integration of arterial baroreceptor afferent inputs was studied in renal wrap hypertensive (HT) and normotensive (NT) rats. In anesthetized and paralyzed rats, aortic nerve (AN)-evoked depressor responses were reduced in HT compared with NT rats (P<0.05). We tested the hypothesis that the attenuated baroreflex was associated with altered integration of baroreceptor inputs within the nucleus of the solitary tract. Based on onset latency and the ability of monosynaptic neurons (MSNs) to respond to each of 2 AN stimuli separated by 5 ms, cells in HT and NT rats were divided into 3 groups: short-latency MSNs (SLMSNs), long-latency MSNs (LLMSNs), and polysynaptic neurons (PSNs). A higher percentage of PSNs (73% versus 61%) and a lower percentage of SLMSNs (20% versus 27%) or LLMSNs (7% versus 12%) were found in HT rats (P<0.05). In addition, in HT compared with NT rats, the AN onset latency was greater in PSNs (29. 9+/-1.1 versus 26.7+/-0.8 ms) but not in SLMSNs (5.0+/-0.5 versus 5. 0+/-0.3 ms) or LLMSNs (22.9+/-1.2 versus 24.1+/-0.7 ms) (P<0.05). Finally, in HT compared with NT rats, the number of PSNs responding to a single AN stimulus with multiple action potentials was increased (40% versus 19%) (P<0.05). This was not observed in SLMSNs (26% versus 13%) or LLMSNs (12% versus 18%). The results indicate that renal wrap hypertension is associated with reduced AN-evoked depressor responses. There also were alterations in the integration of AN afferent inputs within the nucleus of the solitary tract, and these alterations were most marked in the PSN population.

Reflex cardiovascular responses to somatic stimulation in spontaneously hypertensive rats.

This study aimed to test whether the cardiovascular responses to somatic stimulation in spontaneously hypertensive rats (SHR) were enhanced compared with those in normotensive Wistar-Kyoto (WKY) rats, and to examine any role of the impaired baroreflex function in the hypertensive rats. Experiments were done in anaesthetized SHR (n = 34) and WKY (n = 31). Baroreceptor reflexes were assessed by continuous infusion of incremental doses (5-30 microg/kg per min) of phenylephrine over a 3 min infusion period. Cardiovascular responses to sciatic nerve stimulation (5 s trains, 1 ms pulse duration, 400 microA intensity) were studied before and after baroreceptor deactivation. The latter was achieved either by carotid occlusion and cutting the vagi and aortic nerves (SHR, n = 28 and WKY rats, n = 27), or by complete baroreceptor denervation (SHR, n = 6 and WKY rats, n = 4). We confirmed that baroreceptor sensitivity was significantly lower in SHR (0.40 +/- 0.05 ms/mmHg) than in WKY rats (0.90 +/- 0.04 ms/mmHg). Sciatic nerve stimulation elicited significantly greater increases in mean arterial pressure (MAP) and in heart rate in SHR than in WKY rats (+32.5 +/- 1.9 mmHg versus +20.2 +/- 1.1 mmHg and +13.5 +/- 1.5 bpm versus +8.0 +/- 1.1 bpm, respectively). Following baroreceptor deactivation, the responses to the same sciatic nerve stimulation of MAP and heart rate in SHR (+38.5 +/- 2.4 mmHg and +15.5 +/- 1.5 bpm) were still significantly greater than those in WKY rats (+29.5 +/- 1.3 mmHg and +11.6 +/- 1.2 bpm). These results show that cardiovascular responses to sciatic nerve stimulation are increased in SHR compared to WKY rats, and that this increased reactivity to somatic stimuli in hypertensive rats does not depend upon the impairment in baroreflex function demonstrated in this strain.

Localization and action of adenosine A 2a receptors in regions of the brainstem important in cardiovascular control

In vitro autoradiography and central microinjections of a P 1 adenosine A 2a receptor antagonist have been employed to investigate a possible role for centrally located adenosine A 2a receptors in modulation of the baroreceptor reflex. In vitro autoradiography using [ 125I]4-(2-[7-amino-2-[2-furyl][1,2,4]triazolol[2,3-a][1,3,5]triazin-5-yl-amino]ethyl)phenol ([ 125I]ZM241385), the high-affinity adenosine A 2a receptor antagonist, revealed a heterogeneous distribution of adenosine A 2a binding sites within the lower brainstem of the rat. Image analysis showed high levels of binding in rostral regions of both the nucleus tractus solitarius and the ventrolateral medulla. Intermediate levels of binding were observed in the commissural nucleus tractus solitarius and the dorsal vagal motor nucleus, with low levels of binding in caudal regions of the nucleus tractus solitarius and the ventrolateral medulla, and the hypoglossal nucleus. Unilateral microinjections of unlabelled ZM241385 into the nucleus tractus solitarius had no effect on baseline levels of arterial pressure, heart rate and phrenic nerve activity recorded in anaesthetized, artificially ventilated rats. However, microinjections of ZM241385 reduced the bradycardia evoked by stimulation of the ipsilateral aortic nerve. In contrast, ZM241385 had no effect on the depressor response or the reduction in phrenic nerve activity evoked by aortic nerve stimulation. Our results indicate that adenosine A 2a binding sites are located in a number of brainstem regions involved in autonomic function, consistent with the idea that adenosine acts as a neuromodulator of a variety of cardiorespiratory reflexes. Specifically, the data support the hypothesis that adenosine A 2a receptors located within the nucleus tractus solitarius are activated during baroreceptor stimulation and have an important modulatory role in the pattern of cardiovascular changes associated with this reflex.

Inhibition of Baroreflex Vagal Bradycardia by Selective Stimulation of Arterial Chemoreceptors in Rats

We reported recently that hypoxia inhibits baroreflex vagal bradycardia (BVB) in rats and that this inhibition persists following chemoreceptor denervation. However, since it is possible that hypoxia also affects the central processing of chemoreceptive input, the existence of chemoreceptor-mediated inhibition of BVB cannot be ruled out. Therefore, we have studied whether selective chemoreceptor activation affects BVB in normoxic conditions. In pentobarbital-urethane-anaesthetized, succinylcholine-immobilized, artificially ventilated rats, BVB was provoked by electrical stimulation of the aortic depressor nerve. Arterial chemoreceptors were selectively activated by intracarotid injection of a minute amount of sodium cyanide. Cyanide injection consistently increased blood pressure while changing heart rate variably. BVB was inhibited in a dose-dependent manner. This inhibition, as well as changes in blood pressure and heart rate, was abolished following transection of the carotid sinus nerve (CSN) ipsilateral to the injection. Spinal cord transection at the C2 level did not affect the inhibition. On the other hand, intracarotid cyanide had no effect on bradycardia elicited by electrical stimulation of a peripheral cut end of the cervical vagus nerve. We conclude that chemoreceptor activation definitely inhibits BVB and that this inhibition is mediated by the CSN, and predominantly occurs in the central nervous system. The possibility is suggested that severe hypoxia suppresses not only BVB but also the chemoreceptor-mediated inhibition of BVB, both via the direct, central action.

Afferent and efferent nerve activity of arterial baroreceptor reflex under nonpulsatile systemic circulation.

We studied the changes in arterial baroreceptor reflex (ABR) afferent activity and efferent activity induced by nonpulsatile systemic circulation (NC) during total left heart bypass (TLHB) in rabbits. To evaluate the influence of the circuit priming fluid and exposure to NC, we directly measured aortic depressor nerve activity (ADNA) (n = 5) and renal sympathetic nerve activity (RSNA) (n = 5) before the start of partial left heart bypass (PLHB) (Before), after PHLB (After), and 5 min after the start of TLHB (During THLB) while maintaining the mean aortic pressure. The circuit priming fluid did not affect the ABR. ADNA exhibited periodic discharge at Before and After, but at During THLB, this periodic discharge transformed into a continuous discharge, and ADNA increased significantly. However, there were no significant differences in RSNA. Our results suggested that in the acute phase under NC, the ABR differed from that under natural circulation.

Vagal modulation of responses elicited by stimulation of the aortic depressor nerve in neurons of the rostral ventrolateral medulla oblongata in the rat

Stimulation of cervical vagal afferents inhibits central sympathetic outflows in part by inhibiting the ongoing activity of putative baroreceptive neurons in the rostral ventrolateral medulla oblongata. The aim of the present study was to examine the electrophysiological characteristics of vagal responses and their interactions with responses elicited by stimulation of the aortic nerve in neurons there. The study focused on the role of the long-lasting, late-onset vagal inhibition, which is likely to play an important role in the tonic inhibitory effects of vagal afferent stimulation. In vivo intracellular recordings were obtained from 33 neurons that received convergent inputs from aortic and vagal afferents. Sixty-four percent of these neurons exhibited a late inhibition following electrical stimulation of myelinated vagal afferents (mean onset latency of 100±5 ms). The average duration of late inhibition (294±19 ms) exceeded the duration of the cardiac cycle. As a consequence of this, sustained vagal stimulation diminished the effect of rhythmic baroreceptor inputs in neurons that exhibited late vagal inhibition. Simultaneous activation of aortic and vagal afferents significantly increased the magnitude of late inhibition, even in those neurons where stimulation of the aortic nerve alone did not elicit a response ( n=15). This suggested that the convergence between vagal and aortic afferent inputs occurred in inhibitory interneurons antecedent to the recorded rostral ventrolateral medulla oblongata neurons. Focal stimulation of the caudal part of the nucleus of the solitary tract also elicited a late-onset inhibition in 73% of the neurons that responded to stimulation of the aortic nerve. This inhibition appeared to be similar to the late vagal inhibition, except for its shorter average onset latency (64±7 ms). Based on this observation, it is proposed that inhibitory interneurons that mediate late inhibition to rostral ventrolateral medulla oblongata neurons may lie within the caudal part of the nucleus of the solitary tract. The present study established that activation of myelinated vagal afferents exerts a complex modulation over the ongoing and evoked activity of neurons that respond to stimulation of the aortic nerve. The complex interaction that occurs between aortic and vagal inputs in neurons of the rostral ventrolateral medulla may be implicated in long-term modulation of sympathetic outflows in response to changes in the activation of visceral receptors supplied by vagus afferents. The modulation elicited by late vagal inhibition may help to adjust cardiovascular outflows according to requirements set by the thoraco-abdominal visceral environment.

L-DOPAergic components in the caudal ventrolateral medulla in baroreflex neurotransmission

l-3,4-Dihydroxyphenylalanine ( l-DOPA) is probably a transmitter of the primary baroreceptor afferents terminating in the nucleus tractus solitarii; l-DOPA functions tonically to activate depressor sites of the caudal ventrolateral medulla, which receives input from the nucleus tractus solitarii [Misu Y. et al. (1996) Prog. Neurobiol. 49, 415–454]. We have attempted to clarify whether or not l-DOPAergic components within the caudal ventrolateral medulla are involved in baroreflex neurotransmission in anesthetized rats. Electrolytic lesions of the right nucleus tractus solitarii (1 mA d.c. for 10 s, 10 days before measurement) selectively decreased by 45% the tissue content of l-DOPA in the dissected ipsilateral caudal ventrolateral medulla. Electrolytic lesions did not decrease dopamine, norepinephrine and epinephrine levels. During microdialysis of the right caudal ventrolateral medulla, extracellular levels of l-DOPA, norepinephrine, epinephrine and 3,4-dihydroxyphenylacetic acid were consistently detectable using high-performance liquid chromatography with electrochemical detection. However, extracellular dopamine levels were lower than the assay limit. Baroreceptor activation by i.v. phenylephrine selectively evoked l-DOPA without increasing the levels of norepinephrine, epinephrine and 3,4-dihydroxyphenylacetic acid. This l-DOPA release was suppressed by acute lesion in the ipsilateral nucleus tractus solitarii. Intermittent stimulation of the right aortic depressor nerve (20 Hz, 3 V, 0.3 ms duration, for 30 min) repetitively and constantly caused l-DOPA release, hypotension and bradycardia, without increases in levels of norepinephrine, epinephrine and 3,4-dihydroxyphenylacetic acid. Local inhibition of l-DOPA synthesis with α-methyl- p-tyrosine (30 μM) infused into the ipsilateral caudal ventrolateral medulla gradually decreased basal levels of l-DOPA and 3,4-dihydroxyphenylacetic acid without decreasing norepinephrine and epinephrine. The inhibition of l-DOPA synthesis interrupted l-DOPA release and decreased by 65% depressor responses elicited by aortic nerve stimulation; however, it produced no effect on bradycardic responses. CoCl 2 (119 ng), a mainly presynaptic inhibitory transmission marker, and l-DOPA methyl ester (1 μg), a competitive l-DOPA antagonist, when microinjected into depressor sites of the right caudal ventrolateral medulla, reduced by 60% depressor responses to transient ipsilateral stimulation of the aortic nerve (20 Hz, 3 V, 0.1 ms duration, for 10 s). No changes in bradycardic responses were observed. There may exist an l-DOPAergic relay from the nucleus tractus solitarii to the caudal ventrolateral medulla. l-DOPAergic components in the caudal ventrolateral medulla are involved in baroreflex neurotransmission via a baroreceptor–aortic depressor nerve–nucleus tractus solitarii–caudal ventrolateral medulla relay in the rat.

Estrogen enhancement of baroreflex sensitivity is centrally mediated.

We have recently shown that estrogen enhances baroreceptor control of reflex bradycardia in conscious rats. The present study replicated this finding in pentobarbital sodium-anesthetized rats, and the study was extended to investigate whether this effect of estrogen is centrally or peripherally mediated. Hemodynamic responses to electrical stimulation of the central end of the aortic depressor or the vagal efferent nerve were evaluated in pentobarbital sodium-anesthetized sham-operated (SO), ovariectomized (OVX), and OVX estradiol-treated Sprague-Dawley rats. Phenylephrine (1-16 microgram/kg iv) elicited dose-dependent pressor and bradycardic responses. Regression analysis of the baroreflex curves, relating changes in mean arterial pressure and heart rate, revealed a significantly smaller baroreflex sensitivity in OVX compared with SO anesthetized rats (-0.54 +/- 0.05 and -0.91 +/- 0.12 beats. min-1. mmHg-1, respectively; P < 0.05). Treatment of OVX rats with 17beta-estradiol (E2, 50 microgram. kg-1. day-1 for 2 days subcutaneously) significantly enhanced baroreflex sensitivity to a level similar to that of SO rats (P < 0.05). The enhancing effect of E2 on the baroreflex-mediated bradycardia, observed in conscious and anesthetized rats, seems to be selective because the baroreflex-mediated tachycardic responses measured in a separate group of conscious rats were not altered by ovariectomy or E2 administration. Electrical stimulation of the aortic nerve elicited frequency-dependent depressor and bradycardic responses that were significantly smaller in OVX compared with SO values (P < 0.05). Treatment of OVX rats with E2 restored the hemodynamic responses to aortic stimulation to near SO levels. On the other hand, hemodynamic responses to vagal stimulation were not affected by OVX or treatment with E2. These findings suggest that enhancement of reflex bradycardia by estrogen is centrally mediated and involves interaction with central projections of the aortic nerve.

The cause of the difference between the arterial baroreceptor reflex under natural pulsatile circulation and under nonpulsatile systemic circulation

In a previous study we investigated the relation between afferent and efferent activity of the arterial baroreceptor reflex under nonpulsatile systemic circulation using total left heart bypass. The results indicated that the regulation of the arterial baroreceptor reflex was converted under nonpulsatile systemic circulation, and we inferred that a possible reason for this conversion was the transformation in discharge of the afferent activity of the arterial baroreceptor reflex that took place under nonpulsatile systemic circulation. In the present study we tested this hypothesis by sectioning carotid sinus and aortic depressor nerves and electrically stimulating bilateral aortic depressor nerves under anesthesia in five rabbits (400 spikes for 20s, with 0.02ms pulse width and 8 V amplitude), while recording changes in aortic pressure, mean aortic pressure, and heart rate. Continuous stimulation was taken as discharge of the afferent activity of the arterial baroreceptor reflex under nonpulsatile systemic circulation, and periodic stimulation was taken as discharge under natural pulsatile circulation. Aortic pressure, mean aortic pressure, and heart rate decreased under both continous and periodic stimulation. The decreases in mean aortic pressure and heart rate during continuous stimulation were significantly lower than those during periodic stimulation. Our results suggest that the transformation in discharge of the afferent activity of the arterial baroreceptor reflex under nonpulsatile systemic circulation may have played an important causative role in the conversion of the regulation of the arterial baroreceptor reflex under nonpulsatile systemic circulation.