RELATIVE CONTRIBUTIONS OF VAGAL AND CARDIAC SYMPATHETIC NERVES TO THE REFLEX BRADYCARDIA INDUCED BY A PRESSOR STIMULUS IN THE CONSCIOUS RABBIT: COMPARISON OF 'STEADY STATE' AND 'RAMP' METHODS

1. The bradycardic response to a pressor stimulus, phenylephrine, was studied simultaneously in conscious rabbits by two different methods. 2. The ‘steady state’ method, in which bradycardia was measured at the peak of each pressor stimulus, demonstrated the existence of two groups of animals, in which the maximal heart periods were 867 (s.e.m. =49) and 563 (s.e.m. =34) ms and the slopes of the MAP-HP relationship were 24.6 (s.e.m. =1.6) and 8.1 (s.e.m. =0.7) ms/mmHg, respectively. 3. The difference in baroreflex sensitivity in the two groups was abolished by sympathetic nerve blockade with guanethidine (10 mg/kg) but not by vagal blockade. 4. The ‘ramp method’ which measures bradycardia during the rapid phase of MAP rise after phenylephrine did not detect any difference in response of the two groups of rabbits. 5. Guanethidine did not alter the slope of the MAP-HP relationship in either group of rabbits when this was assessed by the ‘ramp’ method. 6. These findings demonstrate that the ‘steady state’ method can detect changes in both vagal and sympathetic activity, while the ‘ramp’ method measures only vagally induced bradycardia. 7. It is concluded that some rabbits may have a genetic ability to activate baroreflex pathways mediating cardiac sympathetic inhibition in addition to vagal stimulation in response to a pressor stimulus.     

Effects of vasopressin on heart rate in conscious rabbits

The effects of vasopressin on heart rate and on the baroreceptor-heart period reflex were assessed during graded intravenous infusions of arginine vasopressin. Infusions which elevated plasma arginine vasopressin to 200 pg/ml had no effect on blood pressure, but induced a fall in heart rate and cardiac output and an increase in peripheral resistance. These effects were unaltered by vagal blockade with methylscopolamine and cardiac sympathetic blockade with propranolol but were prevented by pretreatment with a specific vascular antagonist to vasopressin, d(CH2)5Tyr(Me)AVP. Baroreflex control of heart rate was studied during vasopressin infusion by monitoring the heart period responses to graded changes in mean arterial blood pressure produced by inflation of balloon occluders around the abdominal aorta and thoracic vena cava. Elevation of plasma arginine vasopressin to 50 pg/ml and 200 pg/ml had no significant effect on the slope or sensitivity of the baroreceptor-heart period reflex but increased the maximum bradycardia elicited in response to large increases in blood pressure. We conclude that at physiological levels, arginine vasopressin has a direct cardiodepressant action that is not dependent on cardiac vagal or sympathetic activity. Our results indicate that arginine vasopressin increases the maximum bradycardia that can be elicited through baroreceptor reflexes but does not alter the slope relating change in heart rate to change in blood pressure.     

LEFT ATRIAL RECEPTOR INHIBITION OF CARDIAC EFFERENT VAGAL ACTIVITY IN THE DOG

1. The tachycardia produced by atrial receptor stimulation has been reported to be ‘solely’ due to an increased sympathetic activity, but not inhibitable by propranolol. We examined the effect of left atrial balloon inflation in chloralose-anaesthetized dogs on heart rate with and without propranolol (l. Omg/kg) and on the activity in single cardiac efferent fibres of the vagus nerve. 2. Propranolol reduced the cardiac response to balloon inflation by one-third, but did not abolish the tachycardia. Efferent cardiac vagal activity was 3.8 ± 0.4 spikes/s and 2.3 ± 0.7 spikes/s prior to and during balloon inflation respectively. 3. It was concluded that the left atrial receptors produce a tachycardia by decreasing cardiac parasympathetic and increasing sympathetic efferent activities.     

MODIFICATION BY DILTIAZEM, A CALCIUM ANTAGONIST, OF THE PULMONARY VAGAL AND CARDIAC SYMPATHETIC CHEMOREFLEXES IN THE DOG

1. Experiments were performed on anaesthetized, open-chest dogs to determine the effects of diltiazem on: the pulmonary vagal chemoreflex evoked by intravenous (i.v.) injection of capsaicin; cardiac sympathetic chemoreflexes activated by epicardial application of bradykinin or capsaicin; and baroreflex-mediated changes in heart rate resulting from both pressor and depressor effects produced by i.v. injections of noradrenaline and bradykinin, respectively. 2. Diltiazem infused i.v. at a rate of 10-30 micrograms/kg per min (mean cumulative dose 0.53 +/- 0.05 mg/kg, n = 9), did not affect basal heart rate, despite significant (P less than 0.001) reduction of resting blood pressure. 3. Diltiazem treatment did not affect the pressor responses to i.v. noradrenaline (0.3 micrograms/kg) or the hypotensive effects of i.v. bradykinin (0.3 micrograms/kg), but reduced significantly both the baroreflex-mediated bradycardia (P less than 0.01) and tachycardia (P less than 0.05) occurring with noradrenaline and bradykinin, respectively. 4. In contrast, diltiazem greatly enhanced reflex bradycardia (P less than 0.001) and systemic hypotension (P less than 0.01) resulting from activation of the afferent vagal pulmonary receptors by i.v. capsaicin (3-5 micrograms/kg). 5. Reflex pressor responses evoked by activation of the afferent cardiac sympathetic neurons by epicardial application of bradykinin (1 microgram) or capsaicin (10-20 micrograms) were not affected by diltiazem, but the corresponding reflex increases in heart rate evoked by both substances were significantly (P less than 0.01) reduced. 6. The results indicate that diltiazem, while reducing the influence of sinoaortic baroreceptors on heart rate, facilitates the reflex vagal control of the cardiac pacemaker by the afferent cardiopulmonary vagal receptors. These nervous reflex mechanisms, which include attenuation of positive chronotrophic effects that may result from ischaemia-induced activation of the afferent cardiac sympathetic neurons, may play an important role in the protective action of diltiazem in ischaemic heart disease.     

CARDIAC BAROREFLEXES AND HYPERTENSION

1. The role of cardiac reflexes in baroreflex control mechanisms and the changes that occur in chronic hypertension is reviewed. The rapid resetting properties of the arterial baroreceptors ensures its role in short-term rather than long-term control of blood pressure. 2. In hypertensive humans and animals, the baroreceptor-heart rate reflex has diminished sensitivity due mainly to reduced maximum capacity of the cardiac vagal component rather than a change to the sympathetic. 3. The development of this vagal deficit in spontaneously hypertensive rats (SHR) coincides with the onset of cardiac hypertrophy rather than vascular hypertrophy. A combination of chronic perindopril treatment regimens in young and older SHR showed that the vagal deficit was better correlated with the degree of cardiac hypertrophy than with other variables such as blood pressure, hypertension or indices of vascular hypertrophy. Similar results have been shown for renovascular hypertension in rats. 4. The bradycardia produced by electrical stimulation of the vagus in urethane anaesthetized young SHR was enhanced compared to Wistar-Kyoto rats (WKY) while responses observed in adult SHR and WKY were similar, suggesting that the vagal deficit in hypertensive rats is not due to a defect in the efferent arm of the baroreflex. 5. The association of the vagal deficit with cardiac hypertrophy, but not with the vagal efferent pathways, suggests an important role for cardiac afferents in hypertension in mediating the baroreflex deficit. 6. A diminished baroreflex and also a reduced heart rate variability is an independent risk factor for sudden death following myocardial infarction. Thus, antihypertensive therapy, which more effectively reduces cardiac hypertrophy, should have a desirable effect on baroreceptor reflexes and therefore in reducing blood pressure variability.     

Reflex bradycardia induced by hydralazine in sino-aortic deafferented conscious rats

1. It is generally recognized that the vasodilator hydralazine produces hypotension accompanied by baroreflex-mediated tachycardia. In some experimental conditions, however, the accompanying heart rate change is bradycardia, a paradoxical response which has not been satisfactorily explained. The present study examined the possibility of hydralazine-induced bradycardia being mediated by vagal or sympathetic afferents activated by changes in left ventricular pressure. 2. Systolic blood pressure and heart rate responses to hydralazine were recorded in conscious normotensive intact rats by a tail cuff method and compared with responses in animals subjected to previous sino-aortic deafferentation (SAD) to remove the influence of the arterial baroreflex. Responses were also obtained after blockade of myocardial afferent vagal C-fibres with urethane, of efferent vagal impulses to the heart with methylatropine, of positive inotropic effects of hydralazine with atenolol, and of prostanoid sensitization of myocardial nerve fibres with indomethacin. 3. Hydralazine produced hypotension and tachycardia in intact rats, and hypotension and bradycardia in SAD animals. In intact rats, this pattern was not affected by any of the pretreatments, while in SAD rats, all pretreatments reversed the bradycardia to hydralazine. 4. The present results indicate that suppression of the arterial baroreflex by SAD propitiates the appearance of a bradycardiac response to hydralazine. This reaction probably results from activation of a vagal cardiodepressant reflex originating in the heart, as suggested by its blockade by drugs acting at various sites along the reflex arch.     

Cardiovascular effects of 3-mercaptopropionic acid and levels of GABA in regions of the brain of guinea-pigs

3-Mercaptopropionic acid (3-MP), an inhibitor of the synthesis of gamma-aminobutyric acid (GABA), was administered to anesthetized rats and guinea-pigs in order to examine the relationship between the effect of this agent on regional levels of GABA in the brain and cardiovascular function. After a latent period, 3-mercaptopropionic acid (0.16 ml/kg, i.p.) produced initial increases in blood pressure and heart rate in rats followed by vagal bradycardia and hypotension. Guinea-pigs treated with 3-mercaptopropionic acid developed one of three patterns of cardiovascular changes. The type I response consisted of a period of sympathetically-mediated hypertension and tachycardia followed by vagal bradycardia. Type II animals exhibited increased arterial pressure and heart rate, but no vagal activation. Type III and control animals exhibited no significant cardiovascular changes following administration of 3-mercaptopropionic acid or appropriate vehicle. Regional levels of GABA in brain, measured at 90 min after treatment were significantly lower than control in type I and II animals in 3 of 4 areas of the brain measured, but not in type III guinea-pigs. When decreases in levels of GABA were compared to the changes in cardiovascular parameters for individual animals, the decrease in heart rate at the time of sacrifice was directly correlated with the decrease in medullary levels of GABA in type I animals. Conversely, in type II guinea-pigs, decreases in hypothalamic levels of GABA correlated inversely with heart rate at sacrifice. These results suggest that activation of cardiac sympathetic and parasympathetic nervous pathways following the administration of 3-mercaptopropionic acid may result from decreased levels of GABA in different regions of the brain.     

Vagal involvement in the pressor responses to cranial artery infusions of bradykinin in anaesthetised greyhounds

In anaesthetised greyhounds, vertebral and carotid artery infusions of bradykinin increased blood pressure whereas intravenous infusions caused a decrease. With each route of administration, heart rate and cardiac output increased while total peripheral resistance fell. With cranial artery infusions, the consecutive pretreatments of propranolol, phentolamine and vagal cooling resulted in a progressive reduction in the heart rate responses and conversion of the pressor to depressor responses. The responses to intravenous infusions of bradykinin were little changed. In contrast, when the initial pretreatment was interruption of vagal transmission, cranial artery infusions of bradykinin were at once depressor and the depressor response to intravenous infusions immediately enhanced. Subsequent propranolol and phentolamine were without further effect on the blood pressure responses although propranolol did reduce the tachycardia responses. It is concluded that while the tachycardia induced by cranial artery infusions of bradykinin has both cardiac sympathetic and vagal withdrawal components, the hypertensive action is mediated by an increase in cardiac output due largely to withdrawal of cardiac vagal tone.     

The peripheral sympathetic nervous system is the major target of cannabinoids in eliciting cardiovascular depression

Our objective was to identify the sites of interaction of cannabinoids with cardiovascular sympathetic regulation in the rat. Effects on sympathetic tone were first determined in anaesthetised animals following i.v. administration of the drugs. Central effects were evaluated in anaesthetised rats receiving microinjections of cannabinoids into brain stem nuclei. Peripheral effects were identified in pithed rats with electrically stimulated sympathetic outflow.In anaesthetised and artificially ventilated rats, i.v. injection of the cannabinoid agonists WIN55212-2 and CP55940 decreased mean arterial pressure, heart rate and the plasma noradrenaline concentration. These effects were antagonized by the CB(1) cannabinoid receptor antagonist SR141716A. The bradycardia was abolished by the muscarinic acetylcholine receptor antagonist methylatropine. The decreases in mean arterial pressure and heart rate caused by cannabinoids in ventilated rats were much less pronounced than in spontaneously breathing rats. Microinjection of WIN55212-2 into the nucleus tractus solitarii had no effect. Microinjected into the rostral ventrolateral medulla oblongata, WIN55212-2 lowered mean arterial pressure slightly without changing other parameters. In pithed rats, WIN55212-2 inhibited the increases in mean arterial pressure, heart rate and the plasma noradrenaline concentration evoked by electrical stimulation of the sympathetic outflow.Our results show that activation of CB(1) cannabinoid receptors induces sympathoinhibition and enhancement of cardiac vagal tone, leading to hypotension and bradycardia. Presynaptic inhibition of noradrenaline release from terminals of postganglionic sympathetic neurons is the major component of the sympathoinhibition, but an effect in the rostral ventrolateral medulla oblongata may also contribute. The cannabinoid-evoked cardiovascular depression depends strongly on the respiratory state of the animals.     

Reflexly evoked coactivation of cardiac vagal and sympathetic motor outflows: observations and functional implications

1. The purpose of the present review is to highlight the pattern of activity in the parasympathetic and sympathetic nerves innervating the heart during their reflex activation. 2. We describe the well-known reciprocal control of cardiac vagal and sympathetic activity during the baroreceptor reflex, but point out that this appears to be the exception rather than the rule and that many other reflexes reviewed herein (e.g. peripheral chemoreceptor, nociceptor, diving response and oculocardiac) involve simultaneous coactivation of both autonomic limbs. 3. The heart rate response during simultaneous activation of cardiac autonomic outflows is unpredictable because it does not simply reflect the summation of opposing influences. Indeed, it can result in bradycardia (peripheral chemoreceptor, diving and corneal), tachycardia (nociceptor) and, in some circumstances, can predispose to malignant arrhythmias. 4. We propose that this cardiac autonomic coactivation may allow greater cardiac output during bradycardia (increased ventricular filling time and stronger contraction) than activation of the sympathetic limb alone. This may be important when pumping blood into a constricted vascular tree, such as is the case during the peripheral chemoreceptor reflex and the diving response.     

Cardiovascular effects in the Sprague-Dawley rat of 8-hydroxy-2(di-N-propylamino) tetralin, a selective 5-hydroxytryptamine receptor agonist

The intravenous administration of 8-hydroxy-2(di-N-propylamino) tetralin, a selective 5-HT receptor agonist, caused a biphasic blood pressure response and bradycardia in Sprague-Dawley rats. The initial pressor response involved peripheral alpha 1-adrenoceptors since it was present in pithed rats and was antagonized by prazosin. Though the intracerebroventricular route of administration was not more effective the hypotension and bradycardia were probably of central origin. The bradycardia was prevented by pretreatment with atropine and propranolol suggesting an involvement of vagal as well as sympathetic activity. These results support the view that central 5-HT receptor activation reduces the blood pressure and heart rate.     

Study on the functional development of the sympathetic nervous system of fetal heart in rats

The drugs acting on the autonomic nervous system were administered intravenously to dams or intraperitoneally to the 20-day-old fetuses maintained by umbilical and placental circulation. The fetal heart rates were accelerated by the administration of isoproterenol, epinephrine, norepinephrine, tyramine and dopamine to fetuses, and they were decelecated by the injection of propranolol and methacholine to fetuses. However, the tachycardia caused by the fetal injection of isoproterenol and the bradycardia by methacholine were inhibited by the pretreatment of propranolol and atropine. The fetal bradycardia and hypoxia caused by the administration of epinephrine under the pretreatment of propranolol to fetuses were inhibited by the injection of alpha-adrenergic receptor blockers such as phentolamine and yohimbine. Furthermore, the tyramine treatment to fetuses produced significant acceleration of the fetal heart rate on day 19-20 of gestation, but not on day 18. These findings suggest that fetal cardiac beta-adrenergic, muscarine-cholinergic receptors and vascular postsynaptic alpha-adrenergic receptor may be sensitive enough to respond to sympathomimetic and sympatholytic drugs, and the fetal cardiac sympathetic innervation between the adrenergic nerve terminal and synapse effector cells may be developed on day 18-19 of gestation.     

The role of cardiac receptors in clonidine-induced vagal bradycardia.

In chloralosed, spinalized and beta-blocked cats, clonidine, 10 microgram/kg i.v. caused a vagally mediated bradycardia which was further analysed with particular attention to cardiopulmonary receptors. Cardiovascular deafferentiation, with preservation of vagal cardiac efferents, abolished the bradycardia. However, in animals with arterial baroreceptors denervated but with vagal cardiopulmonary pathways intact, clonidine decreased heart rate simultaneously with an increase in left atrial pressure to an extent known to activate cardiac receptors with unmyelinated vagal efferents. Clonidine somewhat enhanced the bradycardia to efferent vagal stimulation and also had a slight positive chronotropic effect on the non-innervated heart. The reflex bradycardia from electrical stimulation of unmyelinated cardiac afferents was augmented by the drug but not more than could be accounted for by the changed neuroeffector sensitivity. The data suggest that clonidine can reflexly augment vagal tone on the heart by an increased activity in vagal cardiac afferents, secondary to the drug's peripheral vasoconstrictor action, whereas no evidence for any central facilitation of these reflexes has been found.     

Influence of endogenous neuropeptide Y (NPY) on the sympathetic-parasympathetic interaction in the canine heart

The purpose of this study was to examine the sympathetic-parasympathetic interactions on heart rate through release of neuropeptide Y (NPY) and its action on prejunctional NPY Y2 receptors on vagal and sympathetic nerve fibers. In other studies on various preparations and in various organs, attenuation of transmitter release has in fact been demonstrated through activation of the NPY Y2 receptor. In the present study on anesthetized dogs we examine, however, for the first time if vagal bradycardia is attenuated by endogenous NPY released during intense cardiac sympathetic stimulation. In addition, we explore if sympathetic transmitter release and heart rate, during moderate sympathetic stimulation, are affected through this receptor system. The significance of the NPY Y2 receptor was revealed by performing experiments before and after administration of its specific receptor antagonist BIIE0246. We found that attenuation of the bradycardia during vagal nerve stimulation was dose-dependently counteracted by BIIE0246 and that the tachycardia elicited by sympathetic stimulation remained unaffected after NPY Y2 receptor blockade. Thus, endogenous NPY appears to attenuate vagal bradycardia by stimulating prejunctional NPY Y2 receptors on cardiac vagal nerve terminals and, less efficiently, to attenuate transmitter release and tachycardia through a feedback loop on the cardiac sympathetic nerve fibers.     

Modulation of the cardiac autonomic transmission of pithed rats by presynaptic opioid OP4 and cannabinoid CB1 receptors

We studied the effects of nociceptin, the endogenous ligand of the opioid OP4 receptor, and of two cannabinoid receptor agonists WIN 55,212-2 and CP-55,940 (0.001-1 micromol/kg each) on the neurogenic tachycardia and bradycardia in pithed rats. Electrical stimulation (1 Hz, 1 ms, 50 V for 10 s) of the preganglionic sympathetic nerve fibres and injection of nicotine 2 micromol/kg or isoprenaline 0.5 nmol/kg increased heart rate by about 70 beats/min (bpm) in pithed rats pretreated with atropine 1.5-2 micromol/kg. The electrically induced tachycardia was reduced dose dependently by nociceptin, WIN 55,212-2 and CP-55,940 (by 60, 30 and 20% at the highest dose, respectively). The OP4 and cannabinoid receptor agonists diminished the nicotine- but not the isoprenaline-stimulated increase in heart rate. In pithed rats pretreated with propranolol 3 micromol/kg, vagal stimulation (5 Hz, 1 ms, 15 V for 10 s) or injection of methacholine (5-10 nmol/kg) decreased heart rate by about 30 bpm. Nociceptin, but not WIN 55,212-2 or CP-55,940 decreased the vagal bradycardia dose dependently (the inhibitory effect of 1 micromol/kg was about 40%). Nociceptin failed to modify the methacholine-induced decrease in heart rate. The OP4 receptor antagonists naloxone benzoylhydrazone 5 micromol/kg and/or [Phe1Psi(CH2-NH)Gly2]-nociceptin(1-13)NH2 0.7 micromol/kg, but not the OP(1-3) receptor antagonist naloxone 10 micromol/kg, diminished the inhibitory action of nociceptin on the neurogenic tachycardia and bradycardia. The inhibitory effect of both cannabinoid receptor agonists on the neurogenic tachycardia was abolished by the CB1 receptor antagonist SR 141716 0.1 micromol/kg. The present data suggest that the postganglionic sympathetic nerve fibres innervating the rat heart are endowed with presynaptic opioid OP4 and cannabinoid CB1 receptors, activation of which inhibits the neurogenic tachycardia. The parasympathetic nerve fibres innervating the heart and causing bradycardia are endowed with presynaptic opioid OP4 but not cannabinoid receptors.     

TIME COURSE OF CHANGES IN BARORECEPTOR REFLEX CONTROL OF HEART RATE IN CONSCIOUS SHR AND WKY: CONTRIBUTION OF THE CARDIAC VAGUS AND SYMPATHETIC NERVES

1. The aim of this study was to assess the vagal and sympathetic nerve contribution to the relationship between mean arterial pressure (MAP) and heart rate (HR) at 6, 9, 14 and 20 weeks of age in conscious Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR) with methoxamine- and nitroprusside-induced steady-state changes in blood pressure. 2. MAP increased with age in both strains but was 17-23% higher in SHR. 3. By contrast baroreflex parameters (HR range: difference between upper and lower HR plateaus, and gain: average slope between inflection points of the logistic MAP-HR relationship) decreased with age in SHR but increased in WKY. 4. After methylatropine, no differences in the cardiac sympathetic baroreflex range or gain parameters were observed between strains or ages. 5. It was concluded that older SHR have normal sympathetic but reduced vagal capacity to control HR in response to changes in MAP, but that this deficit was not dependent on the absolute level of blood pressure. 6. Because the differences were confined to one effector, SHR may have different central rather than arterial baroreceptor afferent mechanisms.     

INFLUENCE OF VARIATION IN DIETARY SODIUM INTAKE ON BIOCHEMICAL INDICES OF SYMPATHETIC ACTIVITY IN NORMAL MAN

The effects of variation in dietary sodium intake on biochemical indices of sympathetic activity were investigated in normal subjects. Sodium restriction for 7 days (mean urinary sodium excretion 21 mmol/day, s.e.m. = 4) increased supine plasma noradrenaline concentration significantly (1.78 nmol/l, s.e.m. = 0.23) compared to levels during medium sodium intake (1.31 nmol/l, s.e.m. = 0.14) and high sodium intake (1.35 nmol/l, s.e.m. = 0.25), when urinary sodium excretion averaged 186 (s.e.m. = 24) and 310 (s.e.m. = 43) mmol/l respectively. Plasma adrenaline concentrations did not vary significantly. During sodium restriction, the apparent release rate of noradrenaline increased significantly; noradrenaline clearance remained unchanged. No changes were observed in the heart rate response after beta-adrenoceptor stimulation with isoprenaline, suggesting that increased sympathetic activity during sodium restriction did not necessarily alter cardiac beta-receptor sensitivity. The responses to cardiac autonomic blockade with propranolol and atropine did not vary with sodium intake. These observations suggest that the sympathetic response to sodium restriction may not be generalized, excluding, in particular, the sympathetic nerves to the heart.     

Dual activation of cardiac sympathetic and parasympathetic components during conditioned fear to context in the rat

1. The present study investigates the contribution of the sympathetic and vagal parasympathetic systems to the tachycardic response of long-lasting (40 min) conditioned fear responses to context. 2. The conditioned fear response evoked by re-exposure to a footshock chamber was tested 10 min after intravenous injection of the beta-adrenoceptor antagonist propranolol (2 mg/kg) or the muscarinic antagonist atropine methyl nitrate (2 mg/kg) in rats implanted with radiotelemetric probes. 3. Compared with saline controls, the drugs did not change the behavioural component of the response (freezing, 22 kHz ultrasonic vocalizations) or its pressor component (+28 mmHg). 4. Propranolol abolished the tachycardic response of fear, whereas atropine more than doubled it (from +75 to +175 b.p.m. above resting baseline). 5. The results demonstrate that both sympathetic and vagal parasympathetic outflows to the heart are strongly activated during conditioned fear. The vagal activation may act to hold back cardiac acceleration while the animal waits for the aversive stimulus to come.     

Pharmacological studies of lycorenine, an alkaloid of Lycoris radiata Herb.: Vasodepressor mechanism in rats

Vasodepressor mechanism of lycorenine (an alkaloid of Lycoris radiata Herb.) was investigated in anesthetized rats. Lycorenine (1--10 mg/kg i.v.) produced dose-related decreases in blood pressure and heart rate and tachyphylaxis developed with repeated injections. In the blood-perfused rat hindquarters, lycorenine (62.5--500 micrograms i.a.) produced dose-related decreases both in mean blood pressure and in perfusion pressure, and the lycorenine-induced decrease in perfusion pressure was abolished by phenoxybenzamine or hexamethonium. Lycorenine (more than 1 mg/kg i.v.) blocked the pressor response to sympathetic nerve stimulation, but failed to block the tachycardia induced by sympathetic nerve stimulation. Lycorenine (7.5 or 15 mg/kg i.v.) reduced the spontaneous splanchnic nerve activity. Lycorenine when given intracerebroventricularly produced decreases in blood pressure and heart rate only in large doses (over 500 micrograms). The maximal bradycardia induced by lycorenine was abolished by bilateral vagotomy. It is suggested that lycorenine may produce a decrease in blood pressure as the result of alpha-adrenergic blockade in conjunction with the reduction of the spontaneous sympathetic nerve activity, and produce bradycardia by modifying vagal activity.     

Corticotropin-releasing factor receptor-1: a therapeutic target for cardiac autonomic disturbances

Corticotropin-releasing factor (CRF), a neuropeptide involved in triggering a myriad of responses to fear and stress, is favourably positioned in the CNS to modulate the sympathetic and parasympathetic branches of the cardiac autonomic nervous system. In vivo studies suggest that central CRF inhibits vagal output and stimulates sympathetic activity. Therefore, CRF may function to inhibit exaggerated vagal activation that results in severe bradycardia or even vasovagal syncope. On the other hand, CRF receptor-1 (CRF₁) antagonists increase cardiac vagal and decrease sympathetic activity, thereby also implicating CRF₁ as a therapeutic target for autonomic disturbances resulting in elevated sympathetic activity, such as hypertension and coronary heart disease. The central distribution of CRF₁ and the cardiovascular effects of CRF₁ agonists and antagonists, suggest it mediates CRF-induced autonomic changes. However, there is insufficient information regarding the autonomic effects of CRF₂-selective compounds to rule out CRF₂ contribution. This review provides an update on the autonomic effects of CRF and the neuronal projections thought to mediate these cardiovascular responses.