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R B McCall

Publications and source records attributed to R B McCall.

At least 19 recordsLinked to original sources

8-OH-DPAT-induced inhibition of renal sympathetic nerve activity and serotonin neuronal firing.

The effects of the 5-HT1A receptor 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) administered i.v. on medullary 5-HT neuronal firing and renal sympathetic nerve activity were determined in spontaneously breathing anaesthetized cats. Low doses of 8-OH-DPAT (1-3 micrograms/kg) caused a similar reduction in 5-HT neuronal firing and renal nerve activity while high doses (10-30 micrograms/kg) completely inhibited neuronal firing but caused only 80% inhibition of renal nerve activity. These data are discussed in relationship to the mechanism of sympatholytic action of 8-OH-DPAT and the serotonergic regulation of sympathetic nerve activity.

8-Hydroxy-2-(di-n-propylamino)tetralin

Novel indolodioxanes with antihypertensive effects: potent ligands for the 5-HT1A receptor.

The synthesis and biological evaluation of a new family of tricyclic indolodioxanes is described. These compounds all contain the 2,3-dihydro-7H-1,4-dioxino[2,3-e]indole nucleus and bear substituents at the 2 and/or 8 positions. Thirteen members of this class were prepared and shown to be potent ligands for the 5-HT1A receptor, with several compounds displaying subnanomolar inhibition constants. These compounds also bind to the dopamine D-2 receptor, but generally with higher inhibition constants than those for 5-HT1A. Certain members of this novel structural class show in vivo activity in the mouse hypothermia assay. One of these compounds, U-86192A, has been shown to have antihypertensive effects in the cat, completely eliminating sympathetic nerve discharge at 1 mg/kg iv and lowering mean arterial pressure to 50% pretreatment levels. These effects can be reversed by the administration of spiperone, indicating that U-86192A is acting via a central serotonergic mechanism.

Animals

Evidence that the lateral tegmental field plays an important role in the central sympathoinhibitory action of 8-OH-DPAT.

We examined the effects of 8-OH-DPAT and 5-HT on three types of sympathetic-related neurons identified in the lateral tegmental field of anesthetized cats using spike-triggered averaging techniques. Based on their response to baroreceptor activation, these neurons could be classified as sympathoexcitatory, sympathoinhibitory, or baroreceptor activation unresponsive. 8-OH-DPAT administered intravenously was found to inhibit sympathoexcitatory neurons with a high degree of correlation to inhibition of sympathetic activity, and to excite sympathoinhibitory neurons in a dose-dependent manner. Iontophoretic application of 8-OH-DPAT and 5-HT to the majority of sympathoexcitatory neurons caused inhibition of spontaneous activity while iontophoretic application of 8-OH-DPAT to sympathoinhibitory neurons had variable effects although 5-HT consistently caused excitation. Baroreceptor unresponsive neurons were insensitive to iontophoretic 8-OH-DPAT and showed only limited response to 5-HT. It is concluded that the lateral tegmental field plays an important role in the sympathoinhibitory action of 8-OH-DPAT.

8-Hydroxy-2-(di-n-propylamino)tetralin

Responses of single units in the midline medulla to stimulation of the rostral ventrolateral medulla.

Single units in the midline medulla were characterized as sympathoexcitatory (SE), sympathoinhibitory (SI) or serotonin (5-HT) neurons. Post-stimulatory changes in the firing patterns of sympathoexcitatory, sympathoinhibitory and 5-HT units were observed during single shock stimulation of the pressor area of the rostral ventrolateral medulla (RVLM). Excitation, inhibition, or no change in cell firing patterns were observed for each cell type, but each cell showed only one type of response to stimulation. No midline neurons were antidromically activated by stimulation of the rostral ventrolateral medulla. These results are discussed in relation to neuronal pathways between the RVLM and the midline medulla involved in the generation of sympathetic activity.

Animals

Effects of muscular contraction on discharge patterns of neurons in the medullary raphe nuclei.

Cells of the medullary raphe nuclei were characterized as sympathoinhibitory (SI), sympathoexcitatory (SE) or serotonergic (5-HT). When muscular contraction (MC) was evoked by stimulation of the L7 and S1 ventral roots, putative SI cells were inhibited while putative SE cells were excited. 5-HT cells were unaffected by MC. These data are discussed in relation to integration of somatosensory and cardiovascular reflexes.

Animals

The effects of 8-OH-DPAT on medullary 5-HT neurons and sympathetic activity in baroreceptor-denervated animals.

The effects of the 5HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on medullary 5-hydroxy-tryptamine (5-HT) neuronal firing and inferior cardiac sympathetic nerve activity were simultaneously determined in baroreceptor-denervated cats. 5-HT neuronal firing was inhibited by 50% at a 1 microgram/kg i.v. dose of 8-OH-DPAT in the baroreceptor-denervated animal. Unit firing was completely inhibited by a 3 microgram/kg dose. In contrast, 8-OH-DPAT inhibited inferior cardiac nerve activity between 10 and 100 micrograms/kg i.v. A similar relationship between the 8-OH-DPAT-induced inhibition of 5-HT unit activity and sympathetic nerve activity was observed in sham-operated control animals. These data suggest that the sympatholytic effects of 8-OH-DPAT cannot be explained on the basis of an autoreceptor effect of the drug.

8-Hydroxy-2-(di-n-propylamino)tetralin

Sympatholytic action of yohimbine mediated by 5-HT1A receptors.

The present study determined the mechanism by which yohimbine inhibits sympathetic nerve activity in the anesthetized cat. Low i.v. doses of yohimbine increased inferior cardiac nerve discharge as a result of the alpha 2-adrenoceptor antagonist properties of the drug. Higher doses of yohimbine (0.8-1.6 mg/kg) inhibited sympathetic nerve discharge. The inhibition of nerve activity was reversed by i.v. administration of the 5HT1A receptor antagonist spiperone. Similarly we have previously observed spiperone reversal of the sympatholytic effects of the 5-HT1A agonist 8-OH-DPAT (8-hydroxy-2-(di-n-propylamino)tetralin) but failed to affect nerve activity when given alone. Spiperone failed to reverse the sympatholytic effect of clonidine. These data indicate that high doses of yohimbine inhibit sympathetic nerve activity via a 5HT1A agonist action.

8-Hydroxy-2-(di-n-propylamino)tetralin

Effects of clonidine on sympathoexcitatory neurons in the rostral ventrolateral medulla.

The effects of intravenous and iontophoretic clonidine were determined on the firing rates of sympathoexcitatory neurons in the rostral ventrolateral medulla of the cat. As previously reported in the rat, we found that sympathoexcitatory neurons could be differentiated based on their sensitivity in clonidine. Approximately 50% of the neurons were inhibited by clonidine. There was only a weak correlation between the inhibition of unit activity and whole sympathetic nerve activity. The discharge rates of the remaining neurons were either not altered or were increased by clonidine. Unlike the rat, these two groups of neurons could not be further differentiated on the basis of axonal conduction velocity or discharge frequency. These data are discussed and the effects of clonidine and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) on sympathoexcitatory neurons are compared.

Animals

Pharmacological characterization of medullary serotonin neurons.

In the present study we investigated the characteristics of medullary raphe serotonergic neurons. Specifically, we sought to examine further the similarities between medullospinal 5-HT neurons and the more extensively studied neurons of the dorsal raphe. Intravenous administration of 5-methoxy-dimethyltryptamine (5-MeODMT) produced a dose-related inhibition of the firing of midline medullary 5-HT neurons. Microiontophoretically applied 5-MeODMT also inhibited medullary 5-HT neurons. The inhibitory potency of 5-MeODMT was nearly identical to that observed for dorsal raphe 5-HT neurons. Microiontophoretic or intravenous administration of the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) did not alter the firing rate of medullary 5-HT neurons. Intravenous administration of the alpha 1-receptor antagonist prazosin resulted in an inhibition of the medullary 5-HT neuronal firing. The discharge of medullary 5-HT neurons increased during iontophoresis of norepinephrine. These data are discussed in relation to the identification and characterization of medullary 5-HT neurons. In addition, the data suggest that the firing rate of medullary 5-HT neurons is regulated in part by a tonic excitatory noradrenergic input.

Amphetamines

Effect of chronic treatment on the cardiovascular and behavioral responses of 8-OH-DPAT in conscious normotensive rats.

Cardiovascular and behavioral responses induced by intravenous administration of the serotonin (5-HT)1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), were studied in conscious normotensive rats either after a single administration, after repeated subcutaneous treatments (1 mg/kg daily for 3 days), or after chronic intravenous infusion (200 micrograms/kg per h for 72 h). In naive rats, a single intravenous treatment with 10, 30 or 100 micrograms/kg 8-OH-DPAT produced a blood pressure reduction of approximately 10% and a heart rate reduction of 15-20%. The duration of blood pressure and heart rate reduction was dose-dependent. Behavioral responses were observed (i.e. reciprocal forepaw treading, flat body posture, hind limb abduction and headweaving), the severity and duration of which were also dose-dependent. Subcutaneous pretreatment with 8-OH-DPAT greatly reduced the behavior responses but did not alter the hypotensive or the heart rate response to a single intravenous administration of 8-OH-DPAT. Blood pressure and behavior were not monitored during the subcutaneous pretreatment period. Intravenous infusion of 8-OH-DPAT attenuated both the cardiovascular and behavioral effects to post-infusion intravenous treatment. The differential tolerance development to these responses suggests that 8-OH-DPAT may exert its blood pressure response and its behavior response through two distinct mechanisms.

8-Hydroxy-2-(di-n-propylamino)tetralin

Studies on the site and mechanism of the sympatholytic action of 8-OH DPAT.

Studies in our laboratory indicate that the 5-HT1A agonist 8-OH DPAT acts in the central nervous system at postsynaptic receptor sites to inhibit sympathetic nerve activity and lower arterial blood pressure. The present study was designed to investigate possible postsynaptic sites on central sympathetic neurons where 8-OH DPAT might produce its sympatholytic action in anesthetized cats. The sympatholytic effect of 8-OH DPAT was compared in midcollicular transected and sham operated control animals. Administration of 8-OH DPAT (0.01-1.0 mg/kg, i.v.) inhibited sympathetic activity and decreased blood pressure in both the transected and sham animals to a similar degree. The effects of microiontophoretically applied 8-OH DPAT and 5-HT on antidromically identified sympathetic preganglionic neurons were determined. Microiontophoretically applied 5-HT consistently increased the firing rate of sympathetic preganglionic neurons. Iontophoretic 8-OH DPAT failed to affect the firing of sympathetic preganglionic neurons but blocked the excitatory effects of 5-HT. The effects of 8-OH DPAT and 5-HT on the firing of sympathoexcitatory neurons located in the rostral ventrolateral medulla were also determined. Sympathoexcitatory neurons were identified using spike triggered averaging techniques and by their response to baroreceptor activation. Intravenous administration of 8-OH DPAT inhibited the firing of sympathoexcitatory neurons in the rostral ventrolateral medulla. The inhibition of unit firing produced by 8-OH DPAT was exactly paralleled by the shutoff of inferior cardiac nerve activity. Microiontophoretic application of 8-OH DPAT and 5-HT onto sympathoexcitatory neurons in the rostral ventrolateral medulla failed to affect the firing rate of these neurons.(ABSTRACT TRUNCATED AT 250 WORDS)

8-Hydroxy-2-(di-n-propylamino)tetralin

Studies on the site and mechanism of the sympathoexcitatory action of 5-HT2 agonists.

Intravenous administration of the selective 5-HT2 agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), produced an increase in sympathetic activity recorded from the inferior cardiac nerve in chloralose-anesthetized cats. Microiontophoretically applied 5-HT increased the firing rate of antidromically identified sympathetic preganglionic neurons. Microiontophoretic DOI failed to affect the firing of sympathetic preganglionic neurons. The effect of DOI was also studied on medullospinal sympathoexcitatory neurons located in the rostral ventrolateral medulla. Intravenous DOI increased the firing of sympathoexcitatory neurons and sympathetic nerve discharge to a similar extent. Microiontophoretic application of DOI failed to affect the firing of sympathoexcitatory neurons. The data are discussed in relation to the site and mechanism of the sympathoexcitatory action of 5-HT2 agonists.

Action Potentials

Role of neurotransmitters in the central regulation of the cardiovascular system.

The last decade has seen tremendous progress in determining the nature of the neurotransmitters which regulate central nervous system pathways involved in the regulation of blood pressure. Investigations are now pursuing the identity and functional importance of neurotransmitters contained within pathways shown to be important in cardiovascular regulation. In addition, several key components of the brain stem networks involved in the control of sympathetic activity have been identified. For example, numerous studies indicate the importance of neurons located in the rostral ventrolateral medulla in the regulation of SPN. Indeed, this area contains medullospinal sympathoexcitatory neurons which represent the final site of integration of many brain stem and reflex pathways involved in the regulation of sympathetic nerve activity. The neurotransmitter which is utilized by this medullospinal pathway remains unknown. Epinephrine, substance P and glutamate have all been hypothesized as primary chemical mediators in the descending pathway from the brain stem to SPN. Interestingly, lesions of, or antagonists to, epinephrine, substance P, glutamate and 5-HT neurons all abolish sympathetic activity and reduce blood pressure to a level similar to that in a spinal animal. Clearly, not all these transmitters are primary mediators of sympathetic information carried from the brain stem to the spinal cord. It is likely that monoamines and neuropeptides act in the IML, as in other area of the central nervous system, as neuromodulators to set the level of excitability of SPN rather than relaying sympathetic information over a functionally specific medullospinal pathway. This conclusion is supported by the observation that midline medullary 5-HT neurons provide a tonic excitatory input to SPN, but receive no afferent inputs from other central sympathetic or baroreceptor pathways. However, the firing of 5-HT neurons appears to relate to the state of vigilance of the animal. This suggests that 5-HT neurons may lower the threshold of SPN to sympathetic inputs during states of wakefulness. In addition, the time course of the norepinephrine-mediated slow EPSPs and IPSPs in SPN is consistent with a gain-setting function. By analogy, epinephrine is likely to act as a neuromodulator in the IML rather than to serve as the primary mediator of sympathetic information descending from the rostral ventrolateral medulla.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals

Studies on the mechanism of the sympatholytic effect of 8-OH DPAT: lack of correlation between inhibition of serotonin neuronal firing and sympathetic activity.

Previous studies indicate that the selective 5-HT1A agonist, 8-OH DPAT, acts in the central nervous system to inhibit sympathetic nerve activity. Based on the observations that: (1) 8-OH DPAT acts at serotonin (5-HT) autoreceptors to inhibit 5-HT neuronal firing; and (2) medullary 5-HT neurons provide a tonic excitatory input to sympathetic preganglionic neurons, we have hypothesized that 8-OH DPAT produces its sympatholytic effects by inhibiting medullary 5-HT neuronal firing and thereby removing an excitatory input to sympathetic preganglionic neurons. The present study was designed to critically test this hypothesis. The sympatholytic effects of 8-OH DPAT were compared in intact animals and in animals which received large electrolytic lesions in the midline area of the lower brainstem. These lesions extended from the obex rostral through the level of the facial motor nucleus and encompassed the brain stem from the dorsal to the ventral surface. The sympatholytic effect of 8-OH DPAT was identical in intact animals and in animals receiving the lesion. The inhibitory effects of 8-OH DPAT on activity recorded simultaneously from the inferior cardiac sympathetic nerve and from medullospinal 5-HT neurons were determined. Medullary 5-HT neurons were identified using criteria modeled after the electrophysiological and pharmacological characteristics previously described for dorsal raphe 5-HT neurons. Medullary 5-HT neuronal activity was more sensitive to the inhibitory effects of 8-OH DPAT than was sympathetic activity. Indeed, low doses of 8-OH DPAT completely suppressed the firing of medullary 5-HT neurons but had little effect on sympathetic nerve activity. These data fail to support the hypothesis that inhibition of 5-HT neuronal firing is responsible for the central sympatholytic effects of 8-OH DPAT. Rather, the data suggest that 8-OH DPAT acts postsynaptically on 5-HT1A receptors located on central sympathetic neurons to inhibit sympathetic nerve activity.

8-Hydroxy-2-(di-n-propylamino)tetralin

Identification of serotonergic and sympathetic neurons in medullary raphe nuclei.

The purpose of the present study was to identify midline medullary serotonin (5-HT) neurons and to determine if these neurons were distinct from previously identified sympathoinhibitory and sympathoexcitatory neurons. Identification of medullary 5-HT neurons was based on electrophysiological and pharmacological similarities to dorsal raphe 5-HT neurons. Sympathoinhibitory and sympathoexcitatory neurons were characterized by an irregular discharge pattern which was temporally related to inferior cardiac sympathetic nerve discharge (SND) and to the cardiac cycle. Sympathoinhibitory neurons increased their discharge rate and the discharge of sympathoexcitatory neurons decreased during baroreceptor reflex activation. A third type of neuron fired in an extremely regular fashion (as judged by interspike interval analysis), fired at a rate of 1.1 spikes/s and had spike durations of approximately 2 ms. The discharges of regularly firing neurons were not temporally related to SND and were not affected during baroreceptor reflex activation. Regularly firing neurons and sympathoinhibitory neurons could be antidromically activated by electrical stimulation of the intermediolateral cell column of the spinal cord. Axonal conduction velocity of sympathoinhibitory neurons (2.4 m/s) was significantly greater than that for regularly firing neurons (1.3 m/s). Regularly firing neurons were completely inhibited by low doses of the 5-HT1A agonist 8-hydroxy-dipropylamino-tetralin (8-OH-DPAT) (i.e. 2 micrograms/kg, i.v.) while much higher doses of the drug failed to affect the discharges of sympathoinhibitory and sympathoexcitatory neurons. Microiontophoretic application of 5-HT and 8-OH-DPAT profoundly depressed the firing of regularly discharging neurons. Based on the striking similarities between regularly firing medullary neurons and dorsal raphe 5-HT neurons it is concluded that the regularly firing neurons were 5-HT-containing neurons. Furthermore, these medullary 5-HT neurons are distinct from sympathoinhibitory and sympathoexcitatory neurons.

Action Potentials

Characterization of midline medulla role in the trigeminal depressor response.

The purpose of the present investigation was to determine the role of the midline medulla in mediating the trigeminal depressor response. Previously we found that lesions of the midline medulla abolished the decrease in blood pressure resulting from electrical stimulation of the spinal trigeminal complex. Electrical stimulation (5 Hz) of the spinal trigeminal tract elicited a decrease in arterial blood pressure that was associated with an inhibition of sympathetic nerve activity recorded from the inferior cardiac nerve of anesthetized cats. The effect of single shocks applied to the trigeminal complex on sympathetic activity was determined using computer-averaging techniques. Single shock stimulation consistently elicited an excitation of sympathetic activity that was followed by an inhibition of sympathetic nerve discharge. The gamma-aminobutyric acid antagonist picrotoxin blocked the depressor response elicited by electrical stimulation of the midline medulla but not by stimulation of the spinal trigeminal complex. Extracellular recordings of the discharges of midline medullary neurons were made to determine the effects of trigeminal stimulation on sympathoinhibitory, sympathoexcitatory, and serotonin neurons. Sympathoinhibitory and sympathoexcitatory neurons were identified by the relationship between unitary discharges and sympathetic nerve activity and by their response to baroreceptor reflex activation. Serotonin (5-HT) neurons were identified using criteria previously developed in our laboratory. These included 1) a slow regular discharge rate, 2) sensitivity to the inhibitory action of the 5-HT1A agonist 8-OH 8-hydroxy-2-(di-n-propylamino)tetralin, 3) failure to respond to baroreceptor reflex activation, and 4) the discharges of the 5-HT neurons were not related to sympathetic activity. Stimulation of the spinal trigeminal complex typically inhibited the discharges of sympathoinhibitory neurons. In contrast, stimulation of the trigeminal complex consistently excited both sympathoexcitatory and 5-HT neurons. These results are discussed in relationship to the role of the midline medulla in mediating the trigeminal depressor response.

Animals

5-HT2 receptor agonists increase spontaneous sympathetic nerve discharge.

The selective 5-HT2 agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) produced a marked increase in spontaneous sympathetic nerve discharge recorded from the inferior cardiac nerve in chloralose anesthetized cats. DOI (0.01-1.0 mg/kg i.v.) increased sympathetic nerve discharge to a maximum of 1750% of control values. The increase in sympathetic nerve discharge produced by DOI was reversed by the 5-HT2 antagonists ketanserin and LY 53857. In addition, pretreatment with ketanserin, but not prazosin, completely prevented the increase in sympathetic nerve discharge produced by DOI. These data are discussed in relationship to the role of serotonin in the regulation of activity in central sympathetic pathways.

Amphetamines