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Notes: Summary Horseradish peroxidase was injected into the biceps brachii muscle of rats at various stages of development, from 10 days to 50 weeks. The retrogradely labeled neurons were found in the ipsilateral ventro-lateral column of the cervical cord, C4–C8, of all stages studied, but the number of labeled neurons decreased according to exponential curve as the age advanced. A striking finding was that the contralateral ventral horn cells were also labeled in the 10- and 14-day-old rats.

Notes: Summary The origin of the spinal cord noradrenaline (NA) has been investigated by means of the horseradish peroxidase (HRP) method, combined with monoamine oxidase staining (Glenner) to identify the NA neurons. Following the injection of HRP to the various levels of rat spinal cord, cervical to sacral cord, A1–3, 5–7 NA neuron groups were labeled with HRP. They showed almost the same distribution pattern regardless of difference in the injected segment. Labeled NA neurons in A6 were concentrated in the ventral division of the locus coeruleus, which continued to the labeled NA neurons in the subcoeruleus area. The HRP positive neurons in the pons outnumbered those of the medulla oblongata. As the NA neurons described above were considered to be the source of NA in the forebrain, such as the hypothalamus and preoptic area, the possibility that the same NA neurons might innervate both the forebrain and spinal cord has been presented.

Notes: Summary Combination of glyoxylic acid perfusion and postfixation in permanganate was used in an electron microscopic study of the locus coeruleus (LC) of the rat to give good preservation of fine structure and a reproducible demonstration of noradrenaline (NA) storage granules. Medium-sized LC cells (18 × 30 μm) contained a moderate number of small granular vesicles (SGV) and a few large granular vesicles (LGV), mainly near the Golgi apparatus. Dendritic branches were identified by their SGV content up to the tip. Dendrites were occasionally in close contact with each other or with the soma of LC cells, forming dendro-dendritic or dendro-somatic contacts. Numerous axon terminals containing many SGV and some LGV were observed in the neuropil, and they tended to contact dendrites and somata of LC cells or dendrites of unknown origin. These neuronal contacts were devoid of synaptic specializations except for an array of dense perpendicular lines between the juxtaposed membranes. Small oval cells (10 × 15 μm) devoid of SGV occurred frequently in the peripheral part of the nucleus, and they were occasionally in direct contact with LC cells.

Notes: Summary Attempts were made to determine the afferent projections to the anterior hypothalamus including the preoptic area from the lower brain stem by means of the horseradish peroxidase method combined with monoamine oxidase staining to identify noradrenaline (NA) neurons. In addition to this technique, a histofluorescence analysis was performed. NA fibers in the medial part of the anterior hypothalamus were mainly supplied by A1 and A2 NA neuron groups, while the lateral part and periventricular zone received NA terminals from both pontine and medulla oblongata NA neuron groups. Furthermore, the present study indicated that there were direct projections to the anterior hypothalamus from non-noradrenergic neurons in the lower brain stem: nuclei raphe dorsalis, centralis superior, cells in the mesencephalic and pontine central gray matter, nuclei parabrachialis lateralis and medialis, cells around fasciculus longitudinalis medialis.

Notes: 1. The effects of SK&F 24260 administered intravenously or intraduodenally on the coronary sinus outflow, coronary arteriovenous oxygen difference (A-V O2), myocardial oxygen consumption (MVO2), systemic blood pressure, heart rate and atrioventricular (AV) conduction time were examined in open-chest dogs.2. SK&F 24260 in doses of 0.3–10 μg/kg, i.v., caused a dose-dependent increase in coronary sinus outflow, but the increase was smaller with 30 μg/kg, i.v., than with 10μg/kg, i.v.3. SK&F 24260 (0.3–30μg/kg, i.v.) decreased A-V O2 and MVO2 in a dose-dependent manner.4. SK& F 24260 (0.3–30μg/kg, i.v.) decreased systemic blood pressure and heart rate, and increased AV conduction time.5. Intraduodenal administration of SK&F 24260 (1 mg/kg) produced almost the same effects on coronary sinus outflow, A-V O2, MVO2, systemic blood pressure, heart rate and AV conduction time as did the intravenous administration of the compound (10μg/kg).6. The property of SK&F 24260 to increase the coronary blood flow and to moderately decrease MVO2, systemic blood pressure and heart rate indicates that this agent is a potential antianginal drug.

Notes: 1. In anaesthetized, open-chest dogs, 2-nicotinamidoethyl nitrate (SG-75) administered intravenously (0.3–1 mg/kg) or intraduodenally (3 mg/kg) produced decreases in systemic blood pressure, coronary resistance, heart rate and an increase in coronary sinus outflow, but virtually no change in myocardial oxygen consumption and atrioventricular conduction. The effects of SG-75 administered intraduodenally emerged within a few minutes after dosing and lasted over about 1 h.2. In isolated, blood-perfused sino-atrial node preparations of the dog SG-75 administered into the sinus node artery decreased slightly sinus rate at the dose which doubled blood flow through the artery.3. In isolated, blood-perfused atrioventricular node preparations of the dog SG-75 administered into the atrioventricular node artery did not impair atrioventricular conduction even in doses which increased blood flow through the artery to more than twice the basal level.4. In isolated, blood-perfused papillary muscle preparations of the dog SG-75 administered into the anterior septal artery scarcely affected force of contraction of the papillary muscle at the dose which doubled blood flow through the artery, although in further large doses it produced a transient decrease in the force of contraction. In extremely large doses it produced ventricular fibrillation.5. In anaesthetized, open-chest dogs in which cardiac input was kept constant SG-75 (0.01–1 mg/kg) administered into the ascending aorta increased venous return without changing systemic output.6. 2-Nicotinamidoethyl alcohol, a denitrated compound of SG-75, had no vasodilator action in doses comparable to those of the parent compound.7. These results indicate SG-75 to be a potential antianginal drug having no cardiodepressant actions but having properties uncharacteristic of the nitrates.

Notes: Summary 1. The present experiments were attempted to determine whether the (+)-enantiomer of verapamil would act predominantly as an inhibitor of the slow calcium channel or the fast sodium channel. For this purpose the effect of (+)-verapamil on atrioventricular (AV) conduction was compared with those of (-)-verapamil, a relatively pure inhibitor of the slow calcium channel, and of tetrodotoxin (TTX), a relatively pure inhibitor of the fast sodium channel by the use of the isolated, blood-perfused AV node preparation of the dog. To obtain a clue to settle the above question, their effects on blood flow through the nutrient arteries of the preparation were also investigated. 2. In the dog heart the upper part of the AV node is perfused through the posterior septal artery (PSA), whereas the more distal conduction system and the myocardium of the ventricular septum are supplied by the anterior septal artery (ASA). In conduction of cardiac impulses the slow calcium channel plays an important role in the upper part of the AV node whereas the fast sodium channel does so in the distal conduction system. 3. The isolated, blood-perfused AV node preparation consists of the right atrium and ventricular septum and permits administration of drugs individually into the PSA and the ASA. Changes in AV conduction time obtained with injection of drugs into the PSA reflect the effect on the slow calcium channel, whereas those obtained with injection into the ASA reflect the action on the fast sodium channel. 4. Single injections of (+)-verapamil (0.1–10 μg) into the PSA produced a dose-dependent increase in AV conduction time, and in high doses it caused a second or third degree block of AV conduction. Prolongation of AV conduction time was due entirely to that of the intervals between bipolar electrograms of the right atrium and those of the right bundle branch (A-B interval). 5. Single injection of (-)-verapamil (0.1–3 μg) into the PSA produced an effect on AV conduction qualitatively similar to that of (+)-verapamil. (-)-Verapamil was about 6 times more potent and far longer-acting than (+)-verapamil. 6. Single injection of (+)-verapamil (0.1–30 μg) into the ASA affected neither AV conduction time nor the shape of bipolar electrograms of the right bundle branch and of the underlying ventricular myocardium. 7. Essentially similar negative results were obtained with (-)-verapamil (0.1–30 μg) injected into the ASA. 8. TTX (1–30 μg) injected into the PSA or the ASA equally produced a dose-dependent increase in AV conduction time. Prolongation of AV conduction time caused by TTX injected into the PSA was due entirely to that of the A-B intervals, whereas that produced by injection into the ASA was due exclusively to that of intervals between bipolar electrograms of the right bundle branch and those of the underlying ventricular myocardium (B-V interval). The latter change was associated with alteration of the shape of bipolar electrograms of the right bundle branch and those of the ventricular septum. 9. Thus, it is unlikely that (+)-verapamil acts as an inhibitor of the fast sodium channel but rather likely that it acts as an inhibitor of the slow calcium channel like its (-)-enantiomer. Difference in action between them was only quantitative. 10. The results also suggest that in addition to the dominant slow calcium channel the fast sodium channel plays a subsidiary role in conduction through the AV node. 11. Both enantiomers of verapamil injected into the PSA or the ASA produced a dose-dependent increase in blood flow through the respective artery. In this regard (-)-verapamil was about 3 times as potent as (+)-verapamil. 12. Intra-arterial TTX was entirely ineffective in increasing blood flow through the PSA or the ASA. 13. The above results support the conlusion that (+)-verapamil is an inhibitor of the slow calcium channel.