Autonomic nervous system and adaptation to cold in man.

The responses to cold hand test (blood pressure increase and tachycardia) and to a cold face test (blood pressure increase and bradycardia) were used to study the role of the autonomic nevrous system in cold adaptation in humans. The Eskimos (men, women, children) were shown to have a very weak sympathetic response to cold but the vagal response (bradycardia) was identical to that of white people. A group of mailmen from Quebec city living outdoors approximately 30 h/wk throughout the year was also studied. A significant decline in the cold pressor response and an enhanced bradycardia (cold face test) were observed at the end of the winter. Similarly the fall in skin temperature of the cheek was not as pronounced when the measurements were made in May compared to those made in October. A group of soldiers was also studied before and after an Arctic expedition. It was found that the bradycardia of the cold face test was also more pronounced after sojourning in the cold. These results indicate that repeated exposures to severe cold in men activate some adaptive mechanisms characterized by a diminution of the sympathetic response and a concomitant enhancement of the vagal activation normally observed when the extremities and the face are exposed to cold.     

Vagal function impairment after exercise training.

The present investigation was undertaken to evaluate the vagal function of trained (T) and sedentary (S) rats by use of different approaches in the same animal. After 13 wk of exercise training (treadmill for 1 h 5 times/wk at 26.8 m/min and 15% grade), T rats had a resting heart rate (HR) slightly but significantly lower than S rats (299 +/- 3 vs. 308 +/- 3 beats/min). T rats had marked reduction of the intrinsic HR (329 +/- 4 vs. 369 +/- 5 beats/min) after blockade by methylatropine and propranolol. They also exhibited depressed vagal and sympathetic tonus. Baroreflex bradycardia (phenylephrine injections) was reduced, bradycardic responses produced by electrical stimulation of the vagus were depressed, and responses to methacholine injection were decreased in T rats. Therefore several evidences of vagal function impairment were observed in T rats. The resting bradycardia after exercise training is more likely to be dependent on alterations of the pacemaker cells, inasmuch as the intrinsic HR was markedly reduced.     

Chlordiazepoxide inhibition of reflex vagal bradycardia in the cat

The effect of chlordiazepoxide (CDZ) on phenylephrine-induced reflex vagal bradycardia was studied in cats anesthetized with chloralose. The sympathetic component of the reflex was eliminated by either pretreating the animals with propranolol (1 mg/kg, i.v.) or sectioning the spinal cord. In animals pretreated with propranolol, CDZ (3, 10 and 20 mg/kg, i.v.) produced a dose-related inhibition of phenylephrine-induced bradycardia. These doses of CDZ had no significant effect on phenylephrine-induced pressor responses. Similar results were obtained with CDZ in animals with spinal cords transected. Chlordiazepoxide did not prevent bradycardia evoked by electrical stimulation of the peripheral cut-end of the right vagus nerve. These results indicate that CDZ can inhibit reflex vagal bradycardia and that the inhibition involves a central action of the drug.     

Leucine-enkephalin interrupts sympathetically mediated tachycardia prejunctionally in the canine sinoatrial node

This study examined the role of leucine-enkephalin (LE) in the sympathetic regulation of the cardiac pacemaker. LE was administered by microdialysis into the interstitium of the canine sinoatrial node during either sympathetic nerve stimulation or norepinephrine infusion. In study one, the right cardiac sympathetic nerves were isolated as they exit the stellate ganglion and were stimulated to produce graded (low, 20-30 bpm; high 40-50 bpm) increases in heart rate (HR). LE (1.5 nmoles/min) was added to the dialysis inflow and the sympathetic stimulations were repeated after 5 and 20 min of LE infusion. After 5 min, LE reduced the tachycardia during sympathetic stimulation at both low (18.2 +/- 1.3 bpm to 11.4 +/- 1.4 bpm) and high (45 +/- 1.5 bpm to 22.8 +/- 1.5 bpm) frequency stimulations. The inhibition was maintained during 20 min of continuous LE exposure with no evidence of opioid desensitization. The delta-opioid antagonist, naltrindole (1.1 nmoles/min), restored only 30% of the sympathetic tachycardia. Nodal delta-receptors are vagolytic and vagal stimulations were included in the protocol as positive controls. LE reduced vagal bradycardia by 50% and naltrindole completely restored the vagal bradycardia. In Study 2, additional opioid antagonists were used to determine if alternative opioid receptors might be implicated in the sympatholytic response. Increasing doses of the kappa-antagonist, norbinaltorphimine (norBNI), were combined with LE during sympathetic stimulation. NorBNI completely restored the sympathetic tachycardia with an ED50 of 0.01 nmoles/min. A single dose of the micro -antagonist, CTAP (1.0 nmoles/min), failed to alter the sympatholytic effect of LE. Study 3 was conducted to determine if the sympatholytic effect was prejunctional or postjunctional in character. Norepinephrine was added to the dialysis inflow at a rate (30-45 pmoles/min) sufficient to produce intermediate increases (35.2 +/- 1.8 bpm) in HR. LE was then combined with norepinephrine and responses were recorded at 5-min intervals for 20 min. The tachycardia mediated by added norepinephrine was unaltered by LE or LE plus naltrindole. At the same 5-min intervals, LE reduced vagal bradycardia by more than 50%. This vagolytic effect was again completely reversed by naltrindole. Collectively, these observations support the hypothesis that the local nodal sympatholytic effect of LE was mediated by kappa-opioid receptors that reduced the effective interstitial concentration of norepinephrine and not the result of a postjunctional interaction between LE and norepinephrine.     

Motor reactivity of isolated heart of the grass-snake (Natrix natrix L.)

Stimulation of the vagus nerve with a volley of electric impulses changed the action of grass-snake heart producing a negative chronotropic and inotropic effect. The effect of vagal stimulation was not different from the effect of acetylcholine administration and it was absent in the presence of atropine and hexamethonium. It was not possible to demonstrate sympathetic nervous fibres in the stimulated segment of the vagus nerve and trials of finding a separate nerve increasing the heart rate were unsuccessful. Parasympathicotonic agents caused bradycardia and a fall in the amplitude of cardiac contractions, and in sufficiently high doses they arrested the heart in diastole. The action of muscarine-like agents was stronger than that of nicotine, and the anticholinergic action of tubocurarine was weaker than that of atropine. Catecholamines exerted a positive inotropic and chronotropic effect which was completely blocked by propranolol in some tests only.     

Reflex regulation of the circulation after stimulation of cardiac receptors by prostaglandins

Prostaglandins (PGs) are potent vasoactive substances that may participate in the control of coronary blood flow, platelet aggregation, and inflammation. An important action of PGs may be the stimulation of c fibers in general and vagal cardiac c fibers in particular. The Bezold-Jarisch reflex after intracoronary injection of Veratrum alkaloids is very similar to the vagal bradycardia elicited by stimulation of cardiac PG synthesis or injection of prostacyclin (PGI2). The characteristic features of this reflex are 1) stimulation of c fibers, 2) inferoposterior wall location of receptors, 3) vagal afferents, 4) vagal efferents to the heart, 5) sympathetic efferents to peripheral blood vessels, and 6) interaction with other reflexes. Vagal cardiac c fibers are activated by intracoronary injections of PGI2 or arachidonic acid, resulting in a vagal reflex bradycardia and hypotension due to withdrawal of peripheral alpha-adrenergic tone to resistance vessels. The cardiac receptors are located predominantly in the inferoposterior wall of the left ventricle. When stimulated by PGs, cardiac receptors may also modify the regulation of arterial pressure by the baroreflexes, altering the inverse relationship between systemic arterial pressure and heart rate. Thus, there is a striking parallelism between the veratridine-induced Bezold-Jarisch reflex and PG-induced cardiac reflexes, although the physiological and clinical significance of these reflexes remains to be determined.     

Interaction of the autonomic nervous system with intrinsic cardiac rate regulation in the guinea-pig, Cavia porcellus.

In the denervated mammalian heart a change in right atrial pressure will still alter heart rate (intrinsic rate response, IRR). We have examined the IRR in isolated right atria of the guinea-pig maintained in oxygenated Krebs-Henseleit solution at 37 degrees C, to compare with and extend studies in other species, and to determine whether the guinea-pig is a suitable model for electrophysiological studies of the IRR. Baseline diastolic transmural pressure was set at 2 mmHg. A 6-mmHg increase in right atrial pressure (RAP) caused an increase in atrial rate that reached a steady value of 15 min(-1) after 1-2 min. This response was enhanced by carbamylcholine and attenuated by isoprenaline. The influence of RAP on the rate response to vagal stimulation was examined. With RAP set at 8 mmHg, the reduction in atrial rate following vagal stimulation was 72+/-5% of that at 2 mmHg (n=6, mean+/-S.E., P<0.005). Continuous vagal stimulation produced a sustained bradycardia, and the effect of this bradycardia on the IRR was examined. When atrial rate was reduced 6% by vagal stimulation, the IRR was augmented to 202+/-21% of the control (n=6, P<0.005). This augmentation was larger (P<0.05) than that seen when atrial rate was reduced 8% by carbamylcholine (130+/-8% of control; n=7, P<0.05). Overall, the IRR in the guinea-pig is similar to that in the rabbit, and shows similar interactions with the autonomic nervous system.     

Thermogenic and hormonal responses to palatable protein and carbohydrate rich food.

Simultaneous variations of oxygen consumption, and plasma insulin and norepinephrine were measured during the postprandial cephalic and gastrointestinal phases of feeding in six human subjects following the ingestion of various nutrients. On alternative days the subjects were given foods (1280 kjoules) either rich in carbohydrates (sugar pie) or in proteins (fish). Both nutrients produced an initial (0-40 min) enhanced thermogenesis and an early (2 min) cephalic insulin release. During that period, elevations of plasma norepinephrine were also observed with pie feeding at 10 and 30 min and at 10 min with fish. Palatability ratings indicated that both food items were equally tasting. During the gastrointestinal phase (40 to 120 min) the variations of these same parameters including glucagon seem to be explained by the content in carbohydrates and proteins in the food rather than by its palatability. Indeed during that period the protein meal was more thermogenic and the carbohydrate meal induced the expected insulin secretion. These results suggest that the palatability of the food is responsible for the early cephalic increase in postprandial thermogenesis, and for the insulin and norepinephrine release. During the subsequent gastrointestinal phase the increased thermogenesis is related to the composition of the food which exerts its action by the biochemical processes involved in the disposal of the absorbed nutrients.     

Sympathetic activation of glucose utilization in brown adipose tissue in rats.

The effects of norepinephrine (NE) infusion and surgical denervation or electrical stimulation of the sympathetic nerves on 2-deoxyglucose (2-DG) uptake in interscapular brown adipose tissue (BAT) were investigated in vivo in rats to obtain direct evidence for sympathetic control of glucose utilization in this tissue. 2-DG uptake was rather low in fasted rats, but after refeeding it increased in the BAT as well as the heart, skeletal muscle, and white adipose tissue, in parallel with an increase in plasma insulin level. Cold exposure also enhanced 2-DG uptake in the BAT without the increase in plasma insulin level, while it had no appreciable effect on 2-DG uptake in other tissues. Sympathetic denervation greatly attenuated the stimulatory effect of cold exposure on 2-DG uptake in BAT, but it did not affect the increased 2-DG uptake after refeeding. Electrical stimulation of the sympathetic nerves entering BAT or NE infusion produced a marked increase in 2-DG uptake in BAT without noticeable effects in other tissues. beta-Adrenergic blockade, but not alpha-blockade, abolished the increased 2-DG uptake in BAT. It was concluded that glucose utilization in BAT is activated directly, independently of the action of insulin, by sympathetic nerves via the beta-adrenergic pathway.     

Atrial natriuretic factor alters autonomic interactions in the control of heart rate in conscious rats

Regulation of heart rate was studied in rats receiving either i.v. saline at 64 microL/min or synthetic 28-residue rat atrial natriuretic peptide (ANF) at a dose sufficient to decrease mean arterial blood pressure by 10%. Autonomic influences were deduced from steady-state heart rate responses of each group to propranolol, atropine, or propranolol and atropine combined. A multiplicative model of heart rate control was used to derive quantitatively from the data the modulation of intrinsic heart rate by sympathetic and parasympathetic mechanisms. Animals receiving ANF showed a lower heart rate than control animals. This relative bradycardia was abolished by atropine. Blocking of sympathetic effects with propranolol had no effect on basal heart rate in either group, and atropinization led to significant increases in heart rate in both groups of rats. Mathematical analysis of the results showed that the bradycardia produced by ANF was due predominantly to a reduced intrinsic heart rate and to enhanced vagal inhibition of postganglionic sympathetic activity. Parasympathetic contribution to heart rate in the absence of sympathetic activity was negligible in control rats and small during ANF. We conclude that the major influences of ANF on heart rate control are a decrease of intrinsic heart rate and enhanced parasympathetic inhibition of postganglionic presynaptic sympathetic activity.     

The direct effect of the thyroid hormone on cardiac chronotropism

To establish whether thyroid hormone modifies the heart rate directly or through an action on other neuroendocrine modulators, the authors have examined several animals models differing in the plasma levels of such compounds. Induction of the hypothyroid state in rats produced a slow onset of bradycardia, which may be removed by a prolonged triiodothyronine treatment. The involvement of TSH was excluded as, by comparing thyroidectomized, hypophysectomized and cold exposed rats, the heart rate was found to vary according to the thyroid levels and not to the TSH levels. Moreover growth hormone, corticotropin and gonadotropins do not influence the heart rate, as the bradycardia induced by hypophysectomy was fully removed by triiodothyronine treatment. The lack of influence by ACTH and GnH was confirmed by treatment of thyroidectomized rats with corticosteroids or testosterone, respectively. Finally, thyroid hormone did not act on the heart rate by changing the norepinephrine output at the sympathetic nerve endings in the heart. In fact, thyroidectomy produced a more intense bradycardia than sympathectomy, and such bradycardia was equally removed by triiodothyronine treatment in thyroidectomized rats and in thyroidectomized and then sympathectomized ones. The authors suggest that the direct effect of the thyroid hormone on cardiac chronotropism is due to an early enhancement of beta-adrenoceptors, followed by a late modification of the electrophysiological properties of the myocardium.     

Peptide YY reduces effects of sympathetic nerves and neuropeptide Y on cardiac vagal action.

In anesthetized dogs intravenous injection of neuropeptide Y (NPY) or stimulation of the cardiac sympathetic nerve is followed by a period of attenuation of vagal action at the heart lasting from many minutes to over an hour. Peptide YY (PYY), a related peptide (but one not reported to occur in the heart or its autonomic innervation), also inhibits cardiac vagal action but is more powerful and has a longer duration action. In 5 of 9 dogs, cardiac sympathetic nerve stimulation inhibited vagal action on the heart in control conditions, but relieved preexisting inhibition when repeated in the presence of PYY. In 3 dogs, exogenous NPY inhibited cardiac vagal action in control conditions, but failed to augment preexisting inhibition in the presence of PYY. An explanation offered for these results is that when PYY is occupying receptors on vagal nerve terminals, nerve-released NPY or exogenous NPY is either unable to produce an effect, because it cannot gain access to the receptors, or displaces PYY from at least some receptors and, being less powerful than PYY in its inhibitory action, lessens the preexisting vagal attenuation. The results reported are consistent with the proposal that the factor released from the sympathetic nerves following their stimulation and which is responsible for cardiac vagal inhibition is NPY.     

The possibility of peripheral cholinolytic action of psychostimulants

The cholinolytic effect of sydnophen discovered in earlier anesthetized cats was confirmed on unanesthetized fish and frogs: the vagal bradycardia induced by electric stimulation of peripheral vagal end was decreased or even abolished by intravenous injection of sydnophen (0.2-20 mg/kg). The amphetamine (0.2-30 mg/kg) also blocked the vagal bradycardia in anesthetized cats and unanesthetized frogs. The maximum vagolytic action of amphetamine appeared later (in 4-8 min after injection) in compared with sydnophen (1-3 min). The small dose of amphetamine (0.2-0.3 mg/kg) in contrast to sydnophen didn't decrease the vagal bradycardia but even increased it. It was suggested that the cholinolytic effect of sydnophen and amphetamine is due to different mechanisms.     

Opposite effects of iv amiodarone on cardiovascular vagal and sympathetic efferent activities in rats

It is unknown whether amiodarone exerts a direct central action on the cardiovascular autonomic nervous system. This study was designed to evaluate the effects of acute amiodarone administration on vagal and sympathetic efferent nerve discharges. Experiments were carried out in 25 decerebrate unanesthetized rats. In one group, vagal activity was recorded from preganglionic fibers isolated from the cervical vagus nerve. In another group, sympathetic recordings were obtained from fibers isolated from the cervical sympathetic trunk in intact conditions or after barodenervation. Recordings were performed before and for 60 min after amiodarone (50 mg/kg iv) administration. In all groups, amiodarone induced bradycardia and hypotension. Vagal activity increased immediately, reaching a significant difference after 20 min (260 +/- 131% from 16.4 +/- 3.3 spikes/s) and was unmodified by the barodenervation. At difference, sympathetic activity after an initial and short-lasting increase (150 +/- 83% from 24.8 +/- 5.7 spikes/s) began to decrease significantly after 20 min (36 +/- 17%) throughout the experiment. The initial increase in sympathetic activity was not observed in barodenervated animals. These changes in vagal and sympathetic activity could play an important role in contributing to the antiarrhythmic action of amiodarone.     

Interactions within the intrinsic cardiac nervous system contribute to chronotropic regulation

The objective of this study was to determine how neurons within the right atrial ganglionated plexus (RAGP) and posterior atrial ganglionated plexus (PAGP) interact to modulate right atrial chronotropic, dromotropic, and inotropic function, particularly with respect to their extracardiac vagal and sympathetic efferent neuronal inputs. Surgical ablation of the PAGP (PAGPx) attenuated vagally mediated bradycardia by 26%; it reduced heart rate slowing evoked by vagal stimulation superimposed on sympathetically mediated tachycardia by 36%. RAGP ablation (RAGPx) eliminated vagally mediated bradycardia, while retaining the vagally induced suppression of sympathetic-mediated tachycardia (-83%). After combined RAGPx and PAGPx, vagal stimulation still reduced sympathetic-mediated tachycardia (-47%). After RAGPx alone and after PAGPx alone, stimulation of the vagi still produced negative dromotropic effects, although these changes were attenuated compared with the intact state. Negative dromotropic responses to vagal stimulation were further attenuated after combined ablation, but parasympathetic inhibition of atrioventricular nodal conduction was still demonstrable in most animals. Finally, neither RAGPx nor PAGPx altered autonomic regulation of right atrial inotropic function. These data indicate that multiple aggregates of neurons within the intrinsic cardiac nervous system are involved in sinoatrial nodal regulation. Whereas parasympathetic efferent neurons regulating the right atrium, including the sinoatrial node, are primarily located within the RAGP, prejunctional parasympathetic-sympathetic interactions regulating right atrial function also involve neurons within the PAGP.     

Somatostatin as a modulator of vagal effects on heart rhythm]

In 11 experiments on anesthetised cats burst stimulation of peripheral cut end of right vagus nerve leads to synchronization of cardiac and vagus rhythms. Alterations of burst sequence frequency within definite limits has been synchronously reproduced by heart thus creating managed bradycardia possibility. Somatostatin (10(-8)-10(-9) M intravenously) decreases heart rate and inhibits total vagus chronotropic effect. Vagolytic effect of somatostatin caused a decrease of tonic component of the vagus chronotropic effect. On the other hand, somatostatin augmented the extent of the vagal synchronizing influences and caused enlargement of the ranges of managed bradycardia. The observed results testify to participation of the peptidergic mechanisms in genesis of vagal managed bradycardia.     

Participation of alpha and beta adrenoreceptors in facilitating and inhibiting the action of the sympathetic nervous system in parasympathetic bradycardia

Electrical stimulation of the distal vagal cervical end in urethane chloralose anesthetized cats caused bradycardia that could be both enhanced and inhibited during sympathetic activation. Sympathetic activation was induced by electrical stimulation of the sympathetic outflow of the spinal cord at the level of Th 1-Th 3 in pitched cats or by an intravenous injection of tyramine. It has been proved pharmacologically that alpha-adrenoceptors are involved in potentiation. The inhibitory influences are realized via both alpha- and beta-adrenoceptors.     

Cardiovascular Vagosympathetic Activity in Rats with Ventromedial Hypothalamic Obesity

Objective: Rats with ventromedial hypothalamic lesion (VMH) are massively obese with endogenous hyperinsulinemia, insulin resistance, low sympathetic activity, and high parasympathetic activity, which are likely to induce hypertension. The goal was to follow in this model the long‐term hemodynamic changes and to investigate the role of autonomic nervous system and insulin resistance in these changes. Research Metho ds and Procedures: Heart rate and blood pressure were monitored for 12 weeks after operation using a telemetric system in VMH and sham rats. Plasma catecholamines and heart β‐adrenoceptors were measured. Glucose tolerance was studied after an intravenous glucose injection and insulin sensitivity during a euglycemic hyperinsulinemic clamp test. Results: A marked bradycardia and only a mild increase in blood pressure occurred in VMH rats compared with sham animals. Response to autonomic‐acting drugs showed an increase in heart vagal tone and responsiveness to a β‐agonist drug. Plasma catecholamine levels were markedly increased, and the density and affinity of heart β‐adrenoceptors were similar in VMH, sham, and control rats. Muscle glucose use was reduced by 1 week after operation in VMH animals. Discussion: These results show the following in this model of massively obese rats with sympathetic impairment: 1) adrenal medulla secretion is increased, probably as a result of hyperinsulinemia and increased vagal activity; 2) cardiac responsiveness to β‐agonist stimulation is increased; and 3) despite these changes and suspected resistance to the vasodilative effect of insulin, blood pressure does not increase. We conclude that high vagal activity may be protective against hypertension associated with obesity.     

Cardiac sympathetic nerve stimulation does not attenuate dynamic vagal control of heart rate via alpha-adrenergic mechanism

Complex sympathovagal interactions govern heart rate (HR). Activation of the postjunctional beta-adrenergic receptors on the sinus nodal cells augments the HR response to vagal stimulation, whereas exogenous activation of the presynaptic alpha-adrenergic receptors on the vagal nerve terminals attenuates vagal control of HR. Whether the alpha-adrenergic mechanism associated with cardiac postganglionic sympathetic nerve activation plays a significant role in modulation of the dynamic vagal control of HR remains unknown. The right vagal nerve was stimulated in seven anesthetized rabbits that had undergone sinoaortic denervation and vagotomy according to a binary white-noise signal (0-10 Hz) for 10 min; subsequently, the transfer function from vagal stimulation to HR was estimated. The effects of beta-adrenergic blockade with propranolol (1 mg/kg i.v.) and the combined effects of beta-adrenergic blockade and tonic cardiac sympathetic nerve stimulation at 5 Hz were examined. The transfer function from vagal stimulation to HR approximated a first-order, low-pass filter with pure delay. beta-Adrenergic blockade decreased the dynamic gain from 6.0 +/- 0.4 to 3.7 +/- 0.6 beats x min(-1) x Hz(-1) (P < 0.01) with no alteration of the corner frequency or pure delay. Under beta-adrenergic blockade conditions, tonic sympathetic stimulation did not further change the dynamic gain (3.8 +/- 0.5 beats x min(-1) x Hz(-1)). In conclusion, cardiac postganglionic sympathetic nerve stimulation did not affect the dynamic HR response to vagal stimulation via the alpha-adrenergic mechanism.     

Comparison of enkephalin and atropine in the inhibition of vagally stimulated gastric and pancreatic secretion and gastrin and pancreatic polypeptide release in dogs

Enkephalins have been detected in vagal nerves and myenteric plexus neurons but no study has been performed to determine their action on vagally stimulated gastric and pancreatic secretion. In this study we infused IV methionine-enkephalin (Met-enk) alone, naloxone (a pure opiate antagonist) alone, or their combination before, during and after vagal stimulation in 4 dogs with esophageal, gastric and pancreatic fistulas. For the comparison, atropine was given before, during and after vagal stimulation in the same animals. Vagal stimulation was obtained by 15 min sham-feeding, which produced an increase in gastric H⁺ output to a peak of about 75% of the maximal response to pentagastrin and pancreatic protein secretion amounting to about 71% of the maximal response to caerulein. It was accompanied by a significant rise in serum gastrin and pancreatic polypeptide (PP) levels. Met-enk inhibited significantly both gastric H⁺ and pancreatic protein secretion and reduced plasma PP but not gastrin levels. Similar effects were obtained after the administration of atropine. The effects of Met-enk were partly reversed by the addition of naloxone. We conclude that (1) enkephalin suppresses vagally stimulated gastric and pancreatic secretion and plasma PP release; (2) these secretory effects of enkephalin seem to be mediated by opiate receptors and could be explained by its inhibitory action on acetylcholine release (“anticholinergic” action) in the stomach and the pancreas.