Cardiogenic reflexes after immune injury of the heart

Afferent and efferent spike activity from the parasympathetic (vagus) and sympathetic cardiac nerves were recorded simultaneously with ECG, and indices of heart function were measured in acute experiments on anesthetized dogs, which allowed us to study the modifications of cardio-cardiac reflex influences after a local immune heart injury. After an injury nidus has been formed in the heart, cardiogenic depressor reflexes evoked by an intracoronary application of veratrine or bradykinin were considerably suppressed or even abolished, and afferent spike activity in the vagus cardiac nerves noticeably decreased. At the same time, both the facilitation of activity in sympathetic afferent fibers and pressor reflex effects were preserved after the heart injury. Different localization of vagus and sympathetic afferent structures in the heart and their specialized sensitivity to the biologically active substances are suggested as the factors determining the pattern of cardiogenic reflex influences after a heart injury.Neirofiziologiya/Neurophysiology, Vol. 27, No. 1, pp. 18–25, January–February, 1995.     

Effect of indomethacin-induced inhibition of arachidonic acid metabolism on the development of cardiogenic reflexes

In acute experiments on anesthetized cats, afferent spike activity from the parasympathetic (vagal) and sympathetic cardiac nerves, ECG, and cardiodynamic indices were recorded. The effects of indomethacin-induced blockade of cyclo-oxygenase pathway in metabolism of arachidonic acid on the development of cardiogenic reflex responses after intracoronary injections of veratrine, bradykinin, or prostacyclin were tested. It was found that after indomethacin injection depressor cardiogenic vagal reflexes, evoked by veratrine or bradykinin administrations, became significantly suppressed or practically disappeared. This was accompanied by a drop in the frequency of afferent vagal activity in the cardiac nerves. This effect could be observed throughout the entire period of influence of indomethacin (about 2 h after its injection). Veratrine or bradykinin, being injected simultaneously with prostacyclin, provided faster partial recovery of depressor responses (at 1 h) and promoted some activation of vagal cardiac nerves, despite the effect of indomethacin. Injection of indomethacin did not change the pattern of sympathetic afferent activity. It is suggested that the main derivative of cyclo-oxygenase pathway of arachidonic acid metabolism, prostacyclin, is able to modulate vagal nervous activity at the level of afferent structures in the heart. Prostacyclin may appear a humoral component of cardiogenic depressor reflexes of a vagal nature.Neirofiziologiya/Neurophysiology, Vol. 28, No. 1, pp. 53–61, January–February, 1996.     

Role of NO in coronary and systemic vasodilation following cardiogenic reflexes

In acute experiments on anesthetized dogs under closed-chest conditions, we used the technique of double lumen catheterization of coronary vessels and peripheral vessel bed. We studied the role of endothelium-dependent relaxing factor/nitric oxide (EDRF/NO) in the development of parasympathetic coronary vasodilation after excitation of cardiac receptors. Under conditions of pharmacological stimulation of cardiac receptors of the left ventricle and short-lasting episodes of local myocardial ischemia, we also examined the effects of inhibition of NO synthesis on the development of cardiogenic depressor reflexes (hypotension and peripheral vasodilation). It was found that the reflex coronary dilatation following excitation of the cardiac (left ventricular) receptors significantly decreased after systemic NO synthase inhibition. Thus, NO production is one of the effector mechanisms of the development of coronary vessel dilatation; this conclusion is confirmed by changes in the dilatation level after blockade of this process with L-NNA (nitro-ω-L-arginine). We pioneered in demonstrating that after the blockade of NO synthesis peripheral vessel vasodilation decreases or disappeas altogether when cardiogenic reflexes are realized following pharmacological excitation of cardiac receptors with veratrine or catecholamine injections, and vasoconstrictor responses evoked by myocardial ischemia are significantly intensified. It is suggested that the influences of NO-dependent mechanisms exert a dual effect on sympathic control-mediated peripheral vasodilation during cardiogenic reflexes. Such mechanisms reduce central sympathetic tone and/or concurrently provide peripheral inhibition of neural sympathetic influences; in the latter case, NO-dependent cardiogenic reflexes play a crucial role in compensatory reactions after an injury to the heart.     

The mechanisms of the formation of cardiogenic afferent effects after the development of local immune damage to the heart]

Sensitivity of cardiac receptors to several substances after local immune heart damage and the nature of cardiogenic influences on the circulation were studied in acute experiments o anesthetized dogs. The depressor reflexes from the heart were shown to disappear during 30 min. after immune heart damage, and vagal afferent impulse activity decreased. After immune heart damage, cardiac sympathetic afferent fibres were more sensitive to endogenous biological substances than to vagal ones. The sympathetic cardiac afferent system is found to be more sensitive to chemical agents, which is a decisive factor in formation of cardiogenic influences on the circulation during pathological processes in the heart.     

家兔Bezold—Jarisch反射时区域性交感神经传出放电的变化

在46只麻醉兔,记录了经冠脉内注射尼古丁诱发Bezold-Jarisch反射时不同区域交感神经传出放电的变化。肾神经、心脏神经、脾神经、星状神经节-颈神经交通支和颈前神经节的颈外动脉支五个部位的交感性传出放电,在冠脉内注射尼古丁后均减少,其中以肾神经、心脏神经和脾神经的减少更为显著。此结果表明,交感神经传出放电减少所致的总外周阻力降低,在Bezold-Jarisch反射诱发的低血压中起着重要作用。     

Pharmacological investigation on the neurohumoral transmission of the vasomotor regulation.

Renal efferent sympathetic activity and its changes due to stimulation of the central stump of the vagal, sciatic and ulnar nerves were investigated. In addition, the effect on basal activity and sympathetic reflexes of drugs with well defined site of action was studied (diazepam, tofizopam, phentolamine, dihydroergotamine, chlorpromazine, reserpine, clonidine, atropine, methysergide and phenindamine). The sympathetic efferent activity and the changes in sympathetic reflexes allowed conclusions to be drawn as to the functional state of the vasomotor centre. Neither methysergide nor phenindamine inhibited efferent sympathetic activity or influenced sympathetic reflexes. These findings exclude the possibility of serotonin or histamine being the transmitter substance in the vasomotor neurone. Experiments with atropine revealed that the muscarinic action of acetylcholine does not figure in the sympathetic inhibitory or excitatory reflex processes. Of the drugs investigated only diazepam and clonidine inhibited efferent sympathetic activity. Clonidine was more selective and acted in much lower doses (20 micrograms/kg) than diazepam (0.5--1 mg/kg). The alpha blocking agents inhibited the viscero-sympathetic inhibitory reflex arch more intensely than the somato-sympathetic inhibitory one. The transmitter is presumably noradrenaline. The sympathetic excitatory reflexes were decreased by diazepam and tofizopam and increased by clonidine and phentolamine. The other substances were ineffective. As to the transmitter substance figuring in the sympathetic excitatory reflexes no unequivocal answer could be obtained in the present experiments.     

Protective influence of phosphocreatine (Neoton) on the neural structures of the heart and brain

In acute experiments on dogs, we demonstrated that local immunogenic injury to the heart resulting from injection of anticardial cytotoxic serum is accompanied by suppression of a vagus-mediated depressor reflex evoked by intracoronary injection of 5 μg veratrine. Preliminary i.v. injection of 250 mg/kg phosphocreatine to a significant extent prevented the development of immunogenic heart injury and served to normalize the cardiogenic depressor reflex (we measured the heart rate, systemic arterial pressure, pressure in the left ventricle, and its first derivative, and also recorded the afferent activity in the cardial branches of the vagus nerve). These data are indicative of a protective effect of phosphocreatine on the receptor and afferent structures in the heart. At the same time, a parallel study of the effects of application of phosphocreatine on the spike activity of single neurons and on evoked potentials in the neocortex of rats showed that phosphocreatine increases the excitability of cortical neurons by facilitating the processes of synaptic transmission. This was manifested in an increase in the frequency of background spike activity of the neurons and in facilitation of the development of epileptiform reactions evoked by surface application of penicillin after preliminary applications of phosphocreatine.     

Biocybernetic studies on reflectory heart modification in the rabbit]

In rabbits the depressor nerves and cardiac vagal branches were stimulated. Their actions on heart rate, atrio-ventricular conduction time, myocardial action potential and mean central blood pressure were recorded. The frequency-effect characteristics of the chronotropic, dromotropic and electrotropic actions on the heart, resulting from afferent and efferent nerve stimulation, are compared. The participation of each of the depressor nerves in their total effects on heart rate and blood pressure is studied. Time courses of heart rate and blood pressure decrease by afferent and efferent nerve stimulation with sinusoidally modulated pulse rates are presented. The results are discussed with respect to the different dynamics of blood pressure and heart rate control. It is concluded that at least two mechanisms are involved in blood pressure control by the depressor nerves: 1. Decrease of vascular resistance by lowering the sympathetic tone. 2. Decrease of heart rate by enhancing the cardiac vagal activity. It is suggested that the parasympathetic control unit compensates rapid disturbances, whereas the slow-acting sympathetic vascular mechanism exerts a long-time pressure control of high efficiency.     

脑室注射高低渗NaCl溶液对血浆肾素活性及肾交感神经活动的影响

第三脑室注射高渗NaCl溶液可引起肾交感神经活动(RSNA)减弱和血浆肾素活性(PRA)降低,低渗NaCl的作用则相反,引起KSNA及PRA升高。PRA和RSNA变化呈一定的正相关,切除肾神经后高、低渗NaCl对PRA的影响减弱或消失,表明脑室内Na~ 浓度改变后主要经肾交感神经的传出通路影响肾素释放。     

Specific baroreceptor control of vertebral and cardiac sympathetic activity.

The effect of bilateral carotid occlusion (BCO) on the activity of the vertebral and cardiac sympathetic efferent nerves was studied in gallamine-immobilized and artificially ventilated cats under chloralose-urethane anaesthesia. Electrical activity of the vertebral and cardiac nerves (VNA and CNA), their integram, arterial blood pressure and respiration were recorded. BCO led to an increase in VNA persisting throughout the occlusion period, while merely a transient increase took place in CNA. When blood pressure was kept at a constant level or the depressor nerves was transected, CNA responded to BCO with a lasting increase. Electrical stimulation of the central stump of the left depressor nerve inhibited CNA much more than VNA. It is assumed that the selective inhibition of CNA, after a transient increase, arises as a consequence of a rise in blood pressure, i.e. of consecutive aortic baroreceptor excitation.     

Differential responses of regional sympathetic activity and blood flow to visceral afferent stimulation

The sympathetic nervous system is essential for the cardiovascular responses to stimulation of visceral afferents. It remains unclear how the reflex-evoked sympathetic output is distributed to different vascular beds to initiate the hemodynamic changes. In the present study, we examined changes in regional sympathetic nerve activity and blood flows in anesthetized cats. Cardiovascular reflexes were induced by either electrical stimulation of the right splanchnic nerve or application of 10 microg/ml of bradykinin to the gallbladder. Blood flows were measured using colored microspheres or the Transonic flow meter system. Sympathetic efferent activity was recorded from the left splanchnic, inferior cardiac, and tibial nerves. Stimulation of visceral afferents decreased significantly blood flows in the celiac (from 49 +/- 4 to 25 +/- 3 ml/min) and superior mesenteric (from 35 +/- 4 to 23 +/- 2 ml/min) arteries, and the vascular resistance in the splanchnic bed was profoundly increased. Consistently, stimulation of visceral afferents decreased tissue blood flows in the splanchnic organs. By contrast, activation of visceral afferents increased significantly blood flows in the coronary artery and portal vein but did not alter the vascular resistance of the femoral artery. Furthermore, stimulation of visceral afferents increased significantly sympathetic efferent activity in the splanchnic (182 +/- 44%) but not in the inferior cardiac and tibial nerves. Therefore, this study provides substantial new evidence that stimulation of abdominal visceral afferents differentially induces sympathetic outflow to the splanchnic vascular bed.     

The efferent sympathetic activity of the rabbit renal nerve during local application of adrenaline to the carotid sinus]

Adrenalin solution (1:1000) administered at the carotid sinus, through excitation of the depressoric C-fibre system of the carotid nerve, induces a strong, lasting reflectoric decrease of arterial pressure with slowing heart rate, associated with an almost complete inhibition of the efferent sympathetic activity of the renal nerve. The efferent sympathetic activity, arterial blood pressure and heart rate, both at the onset and at the height of adrenalin action, show corresponding activity changes: the relative inhibition of the sympathetic nerve is strongest correlated with the depressoric blood-pressure effect, while the decrease of heart rate, related to the initial activity, is least pronounced.     

肾脏去神经化在心力衰竭治疗中的研究进展

生理情况下,心脏和肾脏在血流动力学和神经激素等调节中相互作用,对于循环系统的稳态维持起重要作用。但在充血性心力衰竭的病理情况下,心脏和肾脏之间存在明显的调节紊乱。首先,急性失代偿性心力衰竭的患者住院治疗的研究结果证明其有一定程度的肾脏失调。其次,慢性充血性心力衰竭时肾脏交感神经系统也起到重要作用:肾脏交感纤维活性增强可导致肾素的释放、钠水潴留、肾血流的降低、血管阻力增加、左心室重塑、左心功能失调等。众所周知,肾脏交感神经切除术可以减低血压和改善心脏功能,但是由于有创的手术方式限制了其应用。过去两年间,随着新的导管消融肾脏去神经化技术的日益完善,其有望成为治疗高血压病和心力衰竭的手段。在此,本文综述了心力衰竭时肾脏交感传入神经和传出神经的发病机理,对目前进行的经导管肾脏去神经化治疗慢性心力衰竭的基础及临床试验进行安全性及有效性评价。提示我们经导管肾脏去神经化有望成为心力衰竭治疗的新靶点。     

Non-Markov negative correlation between interspike intervals in mammalian sympathetic efferent discharges

The background discharge of sympathetic efferent fibres in the hypogastric and splanchnic nerves of the cat was analyzed. Stationary discharges were renewal or had significant negative first order serial correlation coefficients. Negatively correlated discharges were non-Markov and the post-spike depression persisted for up to 5 s, covering the same time course as the prolonged inhibitory phenomena of sympathetic reflexes.     

Experimental studies on the effects of vibration and noise on sympathetic nerve activity in skin

Multi-unit sympathetic activity was recorded at elbow level from median nerve fascicles supplying glabrous skin of the left hand in five healthy subjects. The resultant vasomotor responses accompanying the neural activity were monitored by simultaneous recordings of skin blood flow using the laser doppler method and skin temperature in the innervation zones. No significant change in sympathetic activity was observed during handgrip exercise of the right hand under a constant gripping force of 2 kg. Subjects maintained the same gripping force of the right hand during exposure in random order to local vibration and/or noise, each type of exposure lasting 5 min with intervals of 20 min. A two-peaked significant increase in outflow from sympathetic nerves was observed during local exposure of the right hand to vibration with a frequency of 60 Hz and an acceleration of 50 m.s-2, followed by a postexposure period which revealed a relative suppression of sympathetic nerve activity and a significant increase in blood flow. Noise at 100 dB(A) showed only an initial effect on skin sympathetic nerve activity (SSA), whereas when combined with local vibration at 60 Hz, a pronounced increase in neural activity was noticed, indicating a combined effect of vibration and noise. These results from direct recordings of SSA suggest a sympathetic vasomotor reflex mechanism triggered by local vibration stimuli to the hand.     

Functional and anatomical variability of canine cardiac sympathetic efferent pathways: implications for regional denervation of the left ventricle

To further elucidate the functional anatomy of canine cardiac innervation as well as to assess the feasibility of producing regional left ventricular sympathetic denervation, the chronotropic and (or) regional left ventricular inotropic responses produced by stellate or middle cervical ganglion stimulation were investigated in 22 dogs before and after sectioning of individual major cardiopulmonary or cardiac nerves. Sectioning the right or left subclavian ansae abolished all cardiac responses produced by ipsilateral stellate ganglion stimulation. Sectioning a major sympathetic cardiopulmonary nerve, other than the right interganglionic nerve, usually reduced, but seldom abolished, regional inotropic responses elicited by ipsilateral middle cervical ganglion stimulation. Sectioning the dorsal mediastinal cardiac nerves consistently abolished the left ventricular inotropic responses elicited by right middle cervical ganglion stimulation but minimally affected those elicited by left middle cervical ganglion stimulation. In contrast, cutting the left lateral cardiac nerve decreased the inotropic responses in lateral and posterior left ventricular segments elicited by left middle cervical ganglion stimulation but had little effect on the inotropic responses produced by right middle cervical ganglion stimulation. In addition, the ventral mediastinal cardiac nerve was found to be a significant sympathetic efferent pathway from the left-sided ganglia to the left ventricle. These results indicate that the stellate ganglia project axons to the heart via the subclavian ansae and thus effective sympathetic decentralization can be produced by cutting the subclavian ansae; the right-sided cardiac sympathetic efferent innervation of the left ventricle converges intrapericardially in the dorsal mediastinal cardiac nerves; and the left-sided cardiac sympathetic efferent innervation of the left ventricle diverges to innervate the left ventricle by a number of nerves including the dorsal mediastinal, ventral mediastinal, and left lateral cardiac nerves. Thus consistent denervation of a region of the left ventricle can not be accomplished by sectioning an individual cardiopulmonary or cardiac nerve because of the functional and anatomical variability of the neural components in each nerve, as well as the fact that overlapping regions of the left ventricle are innervated by these different nerves.     

The effect of acute rise in intracranial pressure on the sympathetic cardiac, vertebral and phrenic nerve activities.

A transient rise of intracranial pressure in cats under chloralose-urethane anaesthesia increased the activity of the sympathetic vertebral nerve, cardiac nerve and in the first phase phrenic nerve. If the vagus nerves were intact this rise in sympathetic activity was associated with bradycardia. These effects developed with a delay, as a rule after abatement of the transient intracranial pressure rise. The authors suggest that Cushing's reaction is caused by medullary ischaemia and development of local metabolic acidosis activating simultaneously the sympathetic and parasympathetic neurons in the medulla oblongata.     

Effect of Inhibition of NO Synthases on Cardiogenic Depressor Reflexes in Different Animal Species

We studied the role of the nitric oxide (NO) system in the realization of cardiogenic depressor reflexes evoked by stimulation of cardiac receptors by veratrine (reproduction of the Bezold–Jarish reflex). Acute experiments were performed on anesthetized dogs and rats: we tested the effects of inhibition of dissimilar isoforms of NO synthase (NOS) and paid special attention to possible species-related differences in realization of the reflex responses. We found that systemic inhibition of NOS by L-nitro-N-arginine (L-NNA, 30 mg/kg, i.v.) significantly decreased the depressor reflex reaction in dogs. Vasomotor dilatatory reactions of the peripheral vessels underwent considerable modifications and in some cases were converted into vasoconstrictory responses. Selective inhibition of neuronal NOS (nNOS) by 7-nitroindazole (7-NI, 25 mg/kg, i.p.) exerted no effect on the development of cardiogenic depressor reflexes in dogs. At the same time, systemic inhibition of NOS in the course of reproduction of cardiogenic depressor reflexes in rats resulted in intensification of depressor responses, while inhibition of nNOS decreased these reactions. Thus, we first demonstrated the role of NO in the realization of cardiogenic depressor reflexes under in vivo conditions and described species-related peculiarities of the involvement of the NO system in the development of these reflexes. We also demonstrated the dependence of formation of cardiogenic depressor reflexes on the predominant involvement of one NOS type or another.     

Cardiac, respiratory, and renal responses to stimulation of the external cuneate nucleus

The cardiac, respiratory, and renal responses of electrical stimulation and microinjection of excitatory amino acids into the external cuneate nucleus were investigated in 57 cats anesthetized with pentobarbital sodium, paralyzed, and artificially ventilated. Trains of rectangular cathodal pulses of 40-100 microA at 50 Hz and 0.1 ms duration were delivered through monopolar glass microelectrodes with a tip diameter of 10-20 micron, filled with indium-Woods metal alloy. Electrical stimulation at 232 histologically identified sites within the external cuneate nucleus could evoke changes in arterial blood pressure, heart rate, and efferent renal sympathetic nerve activity. In a further set of experiments, a change in respiration was observed at 74 identified sites. An increase or decrease in all parameters measured could be elicited at different stimulus sites within the external cuneate nucleus. Repositioning of the electrode (0.2-0.4 mm) in depth or laterally could result in a different response with stimulation. Microinjections of D,L-homocysteic acid or glutamate could mimic the evoked changes in blood pressure, heart rate, efferent renal sympathetic nerve activity, and respiration. This suggests that the external cuneate nucleus contains cell bodies that may modulate components of various cardiac, respiratory and renal reflexes. It is proposed that the external cuneate nucleus may be involved in the integration of somato-autonomic reflex responses.     

The effect of an alerting acoustic stimulus on the heart rate, sympathetic activity and aortic baroreceptor discharge in conscious rabbits before and after naloxone administration

Blood pressure, heart rate, aortic nerve activity and cervical sympathetic discharge were recorded simultaneously in 10 rabbits. Chronic recordings were made with electrodes implanted to the uncut aortic and cervical sympathetic nerves. 1. The alerting acoustic stimulus produced a short lasting decrease in sympathetic activity with a transient bradycardia. 2. In 6 out of 8 rabbits i.v. administration of naloxone chloride (100 mg/kg) diminished or abolished early inhibitory effects evoked by acoustic stimulus. 3. The sympatho-inhibitory system involved in the startling response appears to be independent of the baroreceptor inhibitory reflex and has opposite responsiveness to naloxone. 4. A decrease in efferent sympathetic activity with no accompanying change in the aortic nerve activity suggests some central resetting of the baroreceptor-sympatho-inhibitory reflex. 5. We suggest that the observed autonomic effects following an alerting stimulus are typical for a fear-anxiety drive.