Network interactions within the canine intrinsic cardiac nervous system: implications for reflex control of regional cardiac function.

The aims of the study were to determine how aggregates of intrinsic cardiac (IC) neurons transduce the cardiovascular milieu versus responding to changes in central neuronal drive and to determine IC network interactions subsequent to induced neural imbalances in the genesis of atrial fibrillation (AF). Activity from multiple IC neurons in the right atrial ganglionated plexus was recorded in eight anaesthetized canines using a 16-channel linear microelectrode array. Induced changes in IC neuronal activity were evaluated in response to: (1) focal cardiac mechanical distortion; (2) electrical activation of cervical vagi or stellate ganglia; (3) occlusion of the inferior vena cava or thoracic aorta; (4) transient ventricular ischaemia, and (5) neurally induced AF. Low level activity (ranging from 0 to 2.7 Hz) generated by 92 neurons was identified in basal states, activities that displayed functional interconnectivity. The majority (56%) of IC neurons so identified received indirect central inputs (vagus alone: 25%; stellate ganglion alone: 27%; both: 48%). Fifty per cent transduced the cardiac milieu responding to multimodal stressors applied to the great vessels or heart. Fifty per cent of IC neurons exhibited cardiac cycle periodicity, with activity occurring primarily in late diastole into isovolumetric contraction. Cardiac-related activity in IC neurons was primarily related to direct cardiac mechano-sensory inputs and indirect autonomic efferent inputs. In response to mediastinal nerve stimulation, most IC neurons became excessively activated; such network behaviour preceded and persisted throughout AF. It was concluded that stochastic interactions occur among IC local circuit neuronal populations in the control of regional cardiac function. Modulation of IC local circuit neuronal recruitment may represent a novel approach for the treatment of cardiac disease, including atrial arrhythmias.

Presynaptic imidazoline receptors. New developments in characterization and classification.

Presynaptic imidazoline receptors (IRs) which inhibit norepinephrine (NE) release from sympathetic nerve endings have been identified in cardiovascular tissue of man, rabbit, rat, and guinea pig. They do not belong to one of the classical presynaptic inhibitory receptor classes such as alpha 2-adrenoceptors or H3 histamine receptors, and there is also no relation to I1- and I2-imidazoline binding sites. Segments of human right atrial appendages preincubated with [3H]NE were used to determine unknown pharmacologic properties of the presynaptic IRs. In the presence of 1 microM rauwolscine, S23230, the (-)-enantiomer of the racemic oxazoline derivative S22687 (5-(2(methyl-phenoxy-methyl)-1,3-oxazoline-2-yl)amine) exhibited low potency in inhibiting the electrically evoked [3H]NE release (pIC30% = 4.96), whereas the (+)-enantiomer S23229 and the racemate S22687 were ineffective. The IR-mediated inhibitory effect of the imidazoline BDF 6143 (4-chloro-2-(2-imidazolin-2-ylamino)-isoindoline) and the guanidine aganodine on evoked [3H]NE release from sympathetic nerves in human atrial appendages was counteracted by rauwolscine (with very low potency) and by the cannabinoid CB1-receptor antagonist SR141715A (N-[piperdin-1-yl]-5-[4-chlorophenyl]-2,4-dichlorophenyl]-4- methyl-1H-pyrazole-3-carboxamide). The inhibitory effect of moxonidine on evoked [3H]NE release (which is exclusively mediated via activation of alpha 2-autoreceptors) was antagonized with high potency by rauwolscine, but not by SR141716A. The cannabinoid CB1 receptor agonists CP55,940([(-)-Cis-3-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl] -trans-4- (3-hydroxy-propyl)cyclohexane]) and anandamide inhibited evoked [3H]NE release. Inhibition by CP55,940 and anandamide was abolished by 1 microM SR141716A as well as by 30 microM rauwolscine. In radioligand binding experiments on membranes from human atrial appendages (alpha 2- and sigma-binding sites were masked), cannabinoid receptor ligands and IR agonists displaced the radiolabeled guanidine derivative [3H]DTG (1,3-di-o-tolyguanidine, an agonist at presynaptic IRs) from its binding sites. Comparison of the potencies of these drugs determined in the competition experiments with [3H]DTG with those in inhibiting NE release via activation of the presynaptic IRs in the same tissue revealed a correlation. The present results suggest, e.g., that the presynaptic IRs may have certain binding domains in common with presynaptic cannabinoid receptors or that both receptors are different proteins which interact with each other in an unknown manner.

Presynaptic imidazoline receptors mediate inhibition of noradrenaline release from sympathetic nerves in rat blood vessels.

In rat vena cava and aorta preincubated with [3H]noradrenaline the involvement of imidazoline receptors in modulation of [3H]noradrenaline release from sympathetic nerves was investigated. In the vena cava, the guanidine 1,3-di(2-tolyl)guanidine (DTG) inhibited the electrically evoked [3H]noradrenaline release; the inhibitory effect was more pronounced in the presence than in the absence of the alpha 2-adrenoceptor antagonist rauwolscine. The concentration-response curves of BDF 6143 [4-chloro-2-(2-imidazolin-2-ylamino)-isoindoline], and idazoxan for their facilitatory effect on electrically evoked [3H]noradrenaline release was bell-shaped; in the presence of rauwolscine, BDF 6143 inhibited the evoked [3H]noradrenaline release, whereas idazoxan did not. After blockade of alpha 2-autoreceptors by rauwolscine, the electrically evoked [3H]noradrenaline release from vena cava was inhibited not only by DTG and BDF 6143 but also by aganodine, clonidine and cirazoline; the rank order of potency of most of the drugs was similar to that found at the presynaptic imidazoline receptors in the rabbit aorta and pulmonary artery as well as in human atrial appendages. In the presence of rauwolscine, clonidine-induced inhibition of electrically evoked [3H]noradrenaline release was counteracted by 1 microM of the selective CB1 receptor antagonist SR141716A (N-[piperidin-1-yl]-5-[4-chlorophenyl]-1-[2,4-dichlorophenyl] -4-methyl-1H-pyrazole-3-carboxamide). In the aorta, BDF 6143 and cirazoline did not modify [3H]noradrenaline release in the absence of alpha 2-adrenoceptor blockade; in the presence of rauwolscine, the electrically evoked [3H]noradrenaline release from aorta was inhibited by BDF 6143, cirazoline, aganodine and clonidine with a rank order of potency similar to that in the vena cava. SR141716A 1 microM antagonized the inhibitory effect of BDF 6143 and clonidine (in the presence of rauwolscine). In conclusion, noradrenaline release in rat vena cava and aorta is inhibited via presynaptic imidazoline receptors which appear to be related to those previously characterized in rabbit and human cardiovascular tissue.

Noradrenergic hyperinnervation in the caval vein of stroke-prone spontaneously hypertensive rats.

1. The distribution of fluorescent noradrenergic (NA) nerve fibres in the caval vein, which originate from the coeliac ganglion, was examined by glyoxylic acid method in stroke-prone spontaneously hypertensive rats (SHRSP) aged 10, 30, 60, 90 and 180 days. The results were compared with those in age-matched normotensive Wistar Kyoto (WKY) rats. 2. The distribution pattern of NA nerve fibres in the caval vein in both strains changed from a meshwork pattern at 10 days of age to a wavelike line arrangement after 30 days of age. 3. The densities of NA fibres of the caval veins in SHRSP were significantly higher (P < 0.01, Student's t-test, 6 d.f.) than those of WKY at all ages examined. The difference in NA fibre density between SHRSP and WKY showed double peaks at 10 and 90 days of age. 4. The present study suggests that hyperinnervation of the caval vein based on the hyperfunction of the coeliac ganglion is an important factor in the development of hypertension and also may participate in increasing cardiac output because the heart of SHR causes marked hypertrophy from 90 days of age.

Structure of autonomic neuromuscular junctions in the sinus venosus of the toad.

The structure of cholinergic and adrenergic neuromuscular junctions in the sinus venosus of the toad, Bufo marinus, was determined by electron microscopy. From random sections of sinus venosus tissue it appeared that there were variable separations between cholinergic or adrenergic varicosities and the nearest sinus venosus muscle cell. However, when the structure of complete cholinergic and adrenergic varicosities was determined by examining serial electron micrographs, virtually all varicosities that lost their covering of Schwann cell were found to form an area of close apposition with an adjacent muscle cell. At the region of close apposition, the neuromuscular cleft was filled with a single layer of basal lamina to give a neuromuscular separation of about 70 nm. Synaptic vesicles within a varicosity were usually found to be concentrated towards the region of close apposition. These observations are discussed in relationship to the idea that when transmission occurs at these neuromuscular junctions the transmitters act on discrete pools of specialized subsynaptic receptors.

Heterogeneity of presynaptic serotonin receptors on sympathetic neurones in blood vessels.

Presynaptic serotonin (5-HT) receptors on the postganglionic sympathetic nerves, which mediate inhibition of noradrenaline release in blood vessels of various species and which interact with the presynaptic alpha 2-autoreceptors, are heterogeneous. In the rat vena cava, they are of the 5-HT1B subtype, in the pig coronary artery they belong to a novel, so far unknown class of 5-HT receptors, and in the human saphenous vein they could be classified as 5-HT1D. These results point to marked species differences and the need to carry out experiments in human vascular preparations. Presynaptic 5-HT receptors may be involved in the mechanism of action of the new antimigraine drug sumatriptan.

[Age and changes in the nerve supply of the superior and inferior venae cavae in man]. / Vozrastnye izmeneniia nervnogo apparata verkhnei i nizhnei polykh ven cheloveka.

The superior and inferior venae cavae have been studied in 51 human being at various age, beginning from newborns using histochemical methods. After birth concentration of neural plexuses in the venae cavae increases up to the period of puberty, and then after 40years of age, certain rarefication of adrenergic and then cholinergic neural plexuses is noted. Choline- and adrenergic innervation is revealed in myocardial fibers penetrating the walls of the superior and inferior venae cavae.

Effect of carotid pressoreceptor stimulation on integrated systemic venous bed.

In 9 mongrel dogs, venous return was completely drained from the caval veins to an oxygenator and returned to the femoral arteries with a roller pump. Perfusion rate of systemic circulation and blood pressures in both caval veins were kept constant. Changes in the oxygenator weight were recorded and reflected reciprocal changes in integrated systemic venous blood volume. The vagal nerves were dissected. The carotid sinuses were separately perfused with blood by means of a pump. In 25 experiments, increases in carotid sinus pressure of 15 to 74 mm Hg resulted in decreases in systemic arterial pressure of 10 to 57 mm Hg and increases in systemic venous blood volume of 1.1 to 4.7 ml/kg. On an average, systemic venous blood volume was changed by 1.25 +/- 0.08 ml/kg when the change in systemic arterial pressure was 10 mm Hg. It is concluded that the carotid sinus pressoreceptor reflex considerably alters the systemic venous capacity which in tern alters venous return and cardiac output. These changes in cardiac output are expected to be small, but sufficient to alter the arterial pressure considerably. Thus, they might contribute nearly as much as the reflex effect on total peripheral resistance to the reflex control of arterial pressure.

[Ultrastructural analysis of preparations impregnated with silver salts]. / Ultrastrukturnyi analiz preparatov, impregnirovannykh soliami serebra

The work was devoted to the ultrastructural analysis of the neurohistological preparations. Sections of the tissue from the precardial parts of the pulmonary and caval dog veins were impregnated with silver salts after Campos and embedded in the araldite by a special method. Electronmicroscopi studies showed reduced silver adsorbed by the tissue of the impregnated preparations to exhibit a granular structure (the granules were 30-400 A in size). The largest of them were revealed in the axoplasm of the myelinated and unmyelinated nerve conductors, whereas the smaller ones found in various cellular and fibrous formations of the tissue substrate; silver granules were as a rule absent within the thickness of the myelin sheath. The noted regularities of adsorption and distribution of the silver granules in the impregnated preparations caused a morphologically expressed phenomenon of argentophilia.

[State of the receptors in the wall of the large arteries and veins following the action of impulse acceleration in the organism]. / Sostoianie retseptorov v stenke krupnykh arterii i ven posle vozdeistviia impul'snykh uskorenii na organizm

The state of receptors in the wall of the vena cava and pulmonary veins, the pulmonary trunk and the aorta arc was studied in cats subjected to single impulse accelerations within the limits of 8-70 gravitation units during 20-25 msec. Myelinated nerve fibres underwent reactive changes in the form of increased argirophilia, swelling, varicosities. In bushy receptors there appeared the same reactive changes in their preterminal part as well as an excessive growth of terminals. A small part of myelinated fibres and bushy receptors regenerated. Regeneration of the receptor terminals was noted.