Aortic Afferents Research Articles

Plasticity of cardiovascular chemoreflexes after prolonged unilateral carotid body denervation: implications for its therapeutic use.

Unilateral carotid body denervation has been proposed as treatment for sympathetic-related human diseases such as systolic heart failure, hypertension, obstructive sleep apnea, and cardiometabolic diseases. The long-term therapeutic effects of carotid body removal will be maintained if the remnant "buffer nerves," that is, the contralateral carotid nerve and the aortic nerves that innervate second-order neurons at the solitary tract nuclei (NTS), do not modify their contributions to the cardiovascular chemoreflexes. Here, we studied the cardiovascular chemoreflexes 1 mo after unilateral carotid body denervation either by excision of the petrosal ganglion (petrosal ganglionectomy, which eliminates central carotid afferents) or exeresis of a segment of one carotid nerve (carotid neurectomy, which preserves central afferents). Cardiovascular chemoreflexes were induced by intravenous (iv) injections of sodium cyanide in pentobarbitone-anesthetized adult cats. After 1 mo of unilateral petrosal ganglionectomy, without significant changes in basal arterial pressure, the contribution of the contralateral carotid nerve to the chemoreflex increases in arterial pressure was enhanced without changes in the contribution provided by the aortic nerves. By contrast, after 1 mo of unilateral carotid neurectomy, the contribution of remnant buffer nerves to cardiovascular chemoreflexes remained unmodified. These results indicate that a carotid nerve interruption involving denervation of second-order chemosensory neurons at the NTS will trigger cardiovascular chemoreflex plasticity on the contralateral carotid pathway. Then, unilateral carotid body denervation as therapeutic tool should consider the maintenance of the integrity of carotid central chemoafferents to prevent plasticity on remnant buffer nerves.NEW & NOTEWORTHY Unilateral carotid body denervation has been proposed as treatment for sympathetic hyperactivity-related human disorders. Its therapeutic effectiveness for maintaining a persistent decrease in the sympathetic outflow activity will depend on the absence of compensatory chemoreflex plasticity in the remnant carotid and aortic afferents. Here, we suggest that the integrity of central afferents after carotid body denervation is essential to prevent the emergence of plastic functional changes on the contralateral "intact" carotid nerve.

Structural remodeling of vagal afferent innervation of aortic arch and nucleus ambiguus (NA) projections to cardiac ganglia in a transgenic mouse model of type 1 diabetes (OVE26)

Diabetes-induced structural changes of vagal aortic afferent and cardiac efferent axons are not well understood. FVB control and OVE26 diabetic mice at different ages received injections of the tracer tetramethylrhodamine dextran (TMR-D) into the nodose ganglion to label vagal aortic afferents (at 3 and 6 months), or DiI injections into the nucleus ambiguus to label vagal cardiac efferents (at 3, 6, and 9 months). The aortic arch and atria were examined by using confocal microscopy. In the aortic arch, TMR-D labeled large and small vagal afferent axons (axons(L) and axons(S)) that formed different types of terminals: axons(L) produced large flower-sprays (flower-sprays(L)) and end-nets (end-nets(L)), whereas axons(S) produced small flower-sprays (flower-sprays(S)) and end-nets (end-nets(S)). In the atria, DiI-labeled vagal efferent axons formed basket endings around ganglion principle neurons (PNs). The vagal afferents, PNs and vagal cardiac efferents in diabetic mice were compared with age-matched control mice. We found (P < 0.05) that: 1) the size of axons(L), flower-sprays(L), flower-sprays(S) and end-nets(S) were reduced at 6 and 9 months; 2) the size of cardiac ganglia and the somatic area of the PNs were decreased, and the PN density in cardiac ganglia was increased at all ages and the PN nuclei/soma area ratio was increased at 9 months; and 3) the percentage of DiI-labeled axons-innervated PNs was decreased at all ages. Furthermore, the number of synaptic-like terminal varicosities around PNs was decreased. Compared with 3 months, more advanced diabetes at 9 months further reduced the number of varicosities/PN. In addition to these changes, swollen axons and terminals, as well as leaky-like DiI-labeled terminals, were observed in long-term diabetic mice (6 and 9 months of age). Taken together, our data show that chronic diabetes induces a significant structural atrophy of vagal aortic afferent and cardiac efferent axons and terminals. Although different morphologies of vagal afferent terminals in the aortic arch may serve as substrates for the future investigation of aortic depressor afferent physiology, structural remodeling of vagal afferents and efferents provides a foundation for further analysis of diabetes-induced impairment of cardiac autonomic regulation.

Chronic AT1 receptor blockade alters aortic nerve activity in hypertension.

In the chronic phase of coarctation hypertension (CH) we have shown both reduction in baroreceptor sensitivity (Hypertension. 1992;19[suppl II]:II-198-II-201.) and normalization of the depressed baroreceptor reflex control of heart rate, even with the persistence of hypertension in losartan-treated animals (Am J Physiol. 1995;269:H812-H818). In the present study we analyzed the effects of angiotensin II blockade on afferent aortic nerve activity of CH and sham-operated groups treated chronically with vehicle or losartan (10 mg/kg per day p.o.). CH was induced by subdiaphragmatic aortic coarctation, and the treatments lasted 8 days (4 control and 4 experimental days). Aortic pressure (conscious rats) and aortic nerve activity simultaneous to pressure (anesthetized rats) were recorded on the fourth day of the experimental period. Losartan-treated rats showed reduced tail pressure (104+/-3 versus 117+/-3 mm Hg in the vehicle group). In both groups, aortic coarctation caused a significant increase in pressure (25% and 28%, respectively) and a depression of the aortic nerve activity/pressure relationship when compared with sham-operated coarcted animals. In the physiological range of pressure changes, the depression was significantly smaller after losartan treatment (3.30+/-0.33 versus 2.18+/-0.37%/mm Hg in the losartan- and vehicle-treated CH groups, respectively, versus 5.05+/-0.33%/mm Hg in the sham-operated vehicle-treated group). Angiotensin type 1 (AT1) receptor blockade was also accompanied by reduced variability of the afferent discharge. The data suggested that apart from its pressure effect, angiotensin II acts at AT1 receptors to decrease the sensitivity of aortic afferents during physiological (+/-10 mm Hg) increases and decreases in pressure. Thus, angiotensin II may contribute to reductions of baroreceptor gain in chronic hypertension.

Central antidysrhythmic action of substance P in rabbits

The effect of substance P (SP) and a neurokinin 1 (NK1) receptor antagonist, SR 140 333, infused in the vertebral artery or directly into the fourth ventricle was examined in rabbits subject to spontaneously occurring cardiac dysrhythmias. These experiments were conducted in order to see if SP, already known to increase the baroreflex, could interfere in this cardiac pathology. The results showed that the intravertebral infusion of SP did not change the heart beat pattern, within the limits of the doses used (0.7×10 -4 to 3.7×10 -9 M). Conversely the same dose of SP, injected into the fourth ventricle, induced a total block of the pathological heart beat pattern. This antidysrhythmic effect is blocked dose dependently by a specific NK1 receptor antagonist, SR 140 333. The extrasystoles could also be abolished by an electric stimulation of aortic nerves or naturally occurring increase of blood pressure. These results suggest that SP may be implied as a neurotransmitter in the baroceptive aortic afferents and demonstrates that it is able to normalize the pathologic heart beat pattern by acting on the baroreflex at the medullar level.

Temporal processing of aortic nerve evoked activity in the nucleus of the solitary tract.

1. Temporal processing of heterogenous afferent signals by nucleus of the solitary tract (NTS) neurons has been previously characterized. Experiments were performed in 26 pentobarbital-sodium-anesthetized male Sprague-Dawley rats to characterize the temporal processing of evoked activity in NTS neurons with the use of the aortic nerve, which contains exclusively arterial baroreceptor afferent fibers. 2. Extracellular single-cell activity was examined in the NTS during electrical stimulation of the aortic nerve with the use of a conditioning-test paradigm. 3. Results were obtained from 49 neurons, 22 of which were characterized as receiving monosynaptic input from aortic nerve afferents. The average number of evoked potentials per aortic nerve stimulation was 1.1 +/- 0.1 (SE) for the monosynaptic neurons and 1.2 +/- 0.2 for the polysynaptic neurons. Spontaneous activity averaged 3.7 +/- 0.7 Hz. No neuron exhibited an obvious pulse-rhythmic discharge. The average peak onset latency for monosynaptic cells of 17 +/- 2 ms (range 3-31 ms) was significantly (P < 0.05) shorter than the average of 26 +/- 1 ms (range 13-38 ms) for the polysynaptic cells. The average onset latency variability was also less in monosynaptic compared with polysynaptic cells (4 +/- 1 ms vs. 8 +/- 1 ms; P < 0.05). 4. Neurons characterized as receiving a monosynaptic input from the aortic afferents generally did not exhibit time-dependent inhibition. Significant inhibition was observed only at a conditioning-test interval of 50 ms, when the average test response was 79 +/- 8% of control. In contrast, the average response following a 50-ms conditioning-test interval for neurons receiving polysynaptic input from the aortic nerve was only 32 +/- 8% of control. Significant inhibition was observed at conditioning-test intervals of up to 200 ms. 5. At a conditioning-test interval of 50 ms, only 5 of 22 monosynaptic neurons were inhibited by > 50%. Mean arterial pressure during the conditioning-test procedure was significantly lower for these neurons than for the 17 cells that were inhibited by < 50%. This suggests that the level of activity in convergent afferent input might influence the magnitude of time-dependent inhibition. 6. There was an essentially linear recovery from time-dependent inhibition evident in polysynaptic neurons that were tested at all conditioning-test intervals, suggesting a single mechanism of variable duration. Results reported here are consistent with current theory that time-dependent inhibition is mediated by disfacilitation. 7. The results demonstrate that NTS neurons receiving monosynaptic input from the aortic depressor nerve infrequently exhibit time-dependent inhibition. This could allow for the original, unmodified afferent information to be dispersed to subsequent neurons. In contrast, neurons receiving polysynaptic input undergo time-dependent inhibition similar to that which has been reported for other afferent inputs. This could allow for differential degrees of fidelity in the transfer of the afferent information to specific efferent pathways. Therefore the temporal pattern of firing in individual baroreceptor afferents could play a critical role in the function of the arterial baroreflex and therefore in the regulation of blood pressure.

Functional recovery of the ventilatory chemoreflexes after partial chronic denervation of the nucleus tractus solitarius

In pentobarbitone-anesthetized cats breathing spontaneously, we studied whether excision of one petrosal ganglion would modify the reflex efficacy of the remaining carotid and aortic chemoafferences in ventilatory control. Resting ventilation was not affected shortly after the ganglionectomy, but decreased sensitivities and reactivities for changes in tidal volume and respiratory frequency were revealed by dose-response curves for ventilatory chemoreflexes evoked by NaCN i.v. After 2 weeks ganglionectomy, basal tidal volume was increased, being slightly reduced by contralateral carotid neurotomy, but persisting abov control after section of all buffer nerves. The ventilatory chemosensory drive — tested by breathing 100% O 2 — was unmodified with respect to the acute condition, but the tonic ventilatory influence exerted by the right carotid nerve was diminished. Dose-response curves for reflex changes in tidal volume exhibited increased sensitivity, while those for changes in respiratory frequency showed increased reactivity. Thus, partial chemosensory denervation of the nucleus tractus solitarius triggers a slowly developing increase in the reflex efficacy of the remaining chemosensory inputs. The recovery of sensitivity for reflex changes in tidal volume required the presence of contralateral carotd afferents, while the increased reactivity in respiratory frequency needed the integrity of aortic afferents. The results also suggest an enhanced contribution of central structures other than chemosensory inputs in respiratory control after partial deafferentation.

Role of chemical afferents in the maintenance of rhythmic respiratory movements.

In seven anesthetized cats central chemosensitivity was eliminated (cold block) and peripheral chemoreceptors were either stimulated or eliminated (sectioned) to test whether nonchemical vagal afferents can maintain rhythmic ventilation and to determine the relative contribution of the carotid and aortic chemoreceptors to ventilatory drive without central chemosensitivity. Elimination of all chemical afferents invariably induced apnea, whereas ventilation was reduced from 533 to 159 ml X min-1 during cold block of central chemosensitivity and to 478 ml X min-1 after sectioning both sinus nerves. Cold block with only the aortic chemoreceptors and vagal afferents intact produced apnea in four of six cases tested. Stimulation of peripheral chemoreceptors during cold block remained effective and interrupted apnea in three of the four cats with only aortic chemoreceptors intact. We conclude that the nonchemical vagal respiratory afferents alone are unable to maintain rhythmic ventilation. Respiratory rhythm generation is, under the conditions of our experiments, critically dependent on sufficient afferent input from chemical afferents. Of these, central chemosensitivity plays the major role, followed by carotid body and, least importantly, by aortic afferents.

Brain stem projections of the aortic nerve in the cat: A study using tetramethyl benzidine as the substrate for horseradish peroxidase

The intra-axonal transport of horseradish peroxidase (HRP) has been used to trace the nodose ganglion and brain stem projections of a physiologically distinct nerve — the aortic depressor nerve — following electrophysiological identification. Tetramethyl benzidine (TMB) has been used as the substrate for demonstrating the centrally transported HRP 15,16. This sensitive method for horseradish peroxidase histochemistry has permitted the visualization of the central projections of aortic nerve afferents and has also provided information regarding the anatomical localization of cell bodies of these sensory nerve fibers within the nodose ganglion. This study demonstrates the usefulness of using TMB as a substrate for HRP histochemistry in anatomical studies where the detection of anterogradely transported HRP is an essential prerequisite. The uptake of HRP from the cut central ends of sensory nerve fibers and the transport of this enzyme to the sensory ganglion and subsequently into the central processes of these sensory neurons have made possible this study of the central projections of a functionally distinct peripheral nerve. Information has been provided by this study that cell bodies of aortic nerve afferent fibers are localized in the rostrolateral pole of the nodose ganglion. Dense central projections of sensory terminals of aortic afferents have been found in the dorsolateral and medial subdivisions of the nucleus of the tractus solitarius. These central projections of aortic afferents extend for 6 mm rostrocaudally in the medulla with the densest projection being found at the level of the obex. These projections are bilateral at all rostrocaudal levels. This anatomical demonstration of the dorsolateral and medial subdivision of the nucleus of the tractus solitarius confirms earlier reports based on electrophysiological studies 5–8,14. Of particular interest in this study is the new observation that there exists a dense projection of aortic nerve afferents to the area postrema. The possible physiological implications of a direct input of peripheral chemoreceptor afferents to a region of central chemosensitivity are discussed. The complete absence of any retrogradely labeled cell body in the brain stem from exposure of the aortic nerve to horseradish peroxidase is noteworthy. This indicates that the aortic nerve is purely afferent in function and that reflex control of afferent activity in the aortic nerve is not mediated by brain stem neurons projecting down the same nerve.

Maintained depressor responses evoked by continuous and intermittent stimulation of aortic nerve in the rabbit.

Stability of depressor responses evoked by long-lasting continuous and intermittent stimulation of the aortic nerve was studied in rabbits anaesthetized with urethane. Continuous stimulation produces blood pressure falls whose stability at low frequencies (1-10 cycles/sec) ranges from 91 to 86%. With rise of the stimulation frequency stability is decreased : at 500 cycles/sec, it amounts to 19%. Intermittent stimulation consisting in switching excitation on and off every 10 sec increases stability of depressor responses and at 500 cycles/sec, it is significantly higher than stability of effects produced by continuous stimulation. Following transection of aortic nerves, stability is increased at all frequencies of continuous stimulation and at all but the lowest frequency of intermittent stimulation. Vagotomy performed after section of the aortic nerves does not significantly affect the changes in stability observed after severing the aortic afferents. It is suggested that at high frequencies of stimulation, stability of depressor responses is reduced by homosynaptic depression. During intermittent stimulation, its effect is counteracted by post-tetanic changes occurring at intervals when the stimulation is switched off. The increase in stability after section of aortic nerves is probably related to its effect on excitability of the vasomotor centres.

The discrete anatomical localization of vagal aortic afferents within a catecholamine-containing cell group in the nucleus solitarius

The centripetal transport of horseradish peroxidase (HRP) was used to visualize the central projections of afferent fibers of the aortic arch nerve to the nucleus solitarius in pigeons. Our results indicate that aortic nerve afferents have a restricted distribution within one subdivision of the nucleus solitarius, designated the subnucleus sulcalis dorsalis. Histofluorescence studies revealed that the aortic nerve projection area is extremely rich in catecholamine-containing neurons.