Rapid and long duration tolerance to the vagal bradycardic effects of 5-HT1A receptor agonists.

Administration of a single dose of the 5-HT1A receptor high intrinsic agonist U-93385E (either 0.3, 1.0 or 3.0 mg/kg, i.v.) results in a 20-30% decrease in heart rate. In contrast, cumulative dosing of U-93385E (0.01-3.0 mg/kg, i.v.) failed to lower heart rate in the spinal cat. Similarly, infusion of 1 mg/kg of U-93385E over a 2 h period failed to lower heart rate and prevented a bradycardic effect of a single bolus dose of U-93385E or flesinoxan. In contrast, the alpha 2-receptor agonist clonidine decreased heart rate in animals receiving the U-93385E infusion. Single bolus doses of flesinoxan or U-93385E failed to decrease heart rate in cats treated for 7 days with U-93385E (3 mg/kg, b.i.d.) and then saline for 3 days. Similarly, U-93385E failed to lower heart rate 12 days following a 14 day infusion of U-93385E (1 mg/kg per day). These data indicate that a rapid and long duration tolerance develops to the vagal bradycardia produced by 5-HT1A receptor agonists.

Tolerance development to the vagal-mediated bradycardia produced by 5-HT1A receptor agonists.

The purpose of this study was to characterize the bradycardic effects of 5-hydroxytryptamine (5-HT)1A receptor agonists in the chloralose-anesthetized spinal cat and to determine if tolerance develops to the bradycardia produced by these drugs. 5-HT1A receptor agonists studied included 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), buspirone, gepirone, flesinoxan and U-93385E (cis-(3aR)-(-)-2,3,3a,4,5,9b-hexahydro-3-propyl-1H-benz[e]indole-9 - carboxamide). These compounds reduced heart rate by 20 to 30% in the spinal cat and lowered arterial blood pressure. The hypotension resulted from a decrease in cardiac output. Atropine reversed and vagotomy prevented the bradycardia produced by a single dose of U-93385E. The decrease in heart rate produced by i.v. bolus doses of flesinoxan or U-93385 was reversed by administration of the 5-HT1A receptor antagonists spiperone or WAY 100135. Administration of a single dose of U-93385E (either 0.3, 1.0 or 3.0 mg/kg i.v.) resulted in a 20 to 30% decrease in heart rate. In contrast, cumulative dosing of U-93385E (0.01-3.0 mg/kg i.v.) failed to lower heart rate in the spinal cat. Similarly, infusion of 1 mg/kg of U-93385E over a 2-hr period failed to lower heart rate and prevented a bradycardic effect of a single bolus dose of U-93385E or flesinoxan. In contrast, the alpha-2 receptor agonist clonidine decreased heart rate in animals receiving the U-93385E infusion. Finally, single bolus doses of flesinoxan or U-93385E failed to decrease heart rate in cats treated for 7 days with U-93385E and then saline for 3 days.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

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.

Effects of serotonin1 and serotonin2 receptor agonists and antagonists on blood pressure, heart rate and sympathetic nerve activity.

Previous studies indicate that serotonin (5-HT) neurons provide a tonic excitatory input to central sympathetic neurons. The purpose of the present study was to utilize a number of 5-HT agonists in order to provide insights into the general function of the serotonergic system in the regulation of central sympathetic pathways. The 5-HT1A agonists 8-hydroxy-dipropylaminotetralin and p-aminophenyl-ethyl-m-trifluoromethylphenyl piperazine produced a dose-related inhibition of sympathetic nerve discharge (SND) recorded from either the postganglionic inferior cardiac nerve or the preganglionic splanchnic nerve in chloralose-anesthetized cats. The sympatholytic effects of 8-hydroxy-dipropylaminotetralin and p-aminophenyl-ethyl-m-trifluoromethylphenyl piperazine were accompanied by hypotension and bradycardia. The effects of 5-HT1A agonists were reversed by the 5-HT1A antagonist spiperone. In contrast, spiperone alone produced decreases in blood pressure, heart rate and SND. The 5-HT1B agonists 1[3(trifluoromethyl) phenyl]-piperazine, 1-(3-chlorophenyl) piperazine and 1-(2-methoxyphenyl) piperazine all produced variable effects on SND. In some experiments, SND was increased by these agents, whereas it was decreased in others. The 5-HT2 agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane produced a marked increase in SND. A second 5-HT2 agonist, MK212, produced similar effects. The role of 5-HT receptor subtypes in mediating the 5-HT excitation of sympathetic neurons is discussed. It is suggested that 5-HT1A agonists inhibit SND through a process of disfacilitation by inhibiting the firing rate of 5-HT neurons. Possible mechanisms by which 5-HT2 agonists increase SND are proposed.

Sympathetic alterations after midline medullary raphe lesions.

The present study was designed to determine the functional importance of the midline medullary raphe nuclei in the autonomic regulation of the cardiovascular system in the anesthetized cat. Baroreceptor and somatosympathetic reflexes as well as the effects of electrical stimulation of vagal afferents and pressor and depressor sites in the hypothalamus and spinal trigeminal tract were determined before and after midline medullary lesions that extended from 2 to 7 mm rostral to the obex. Midline medullary lesions failed to affect baroreceptor reflexes as judged by the lack of effect on the sympathoinhibition associated with the pressor response to phenylephrine and the degree of slow-wave locking of sympathetic activity to the cardiac cycle. However, the lesion did significantly increase spontaneous sympathetic activity recorded from the inferior cardiac nerve. Blood pressure and heart rate were not altered by midline lesions. In addition, the computer-summed sympathoexcitatory response to electrical stimulation of somatic afferents in the sciatic nerve and the sympathoinhibitory response to stimulation of vagal afferent fibers were not affected by midline lesions. In contrast, the decrease in blood pressure and inhibition of sympathetic nerve activity elicited by electrical stimulation of the spinal trigeminal tract were completely abolished by the lesion. Depressor responses evoked from the anteroventral third ventricle region of the hypothalamus but not pressor responses elicited from the posterior hypothalamus were eliminated following midline medullary lesions. Finally, the sympathoinhibitory actions of the serotonin antagonist methysergide were blocked by medullary raphe lesions. These data indicate that neural elements in the medial medullary area function to provide a tonic inhibition of sympathetic nerve activity that is of nonbaroreceptor origin. Depressor responses evoked from the anterior hypothalamus and the spinal trigeminal tract also are mediated through this area of the medulla. Finally, the data support our contention that medullary serotonergic neurons have a sympathoexcitatory function.

Characterization of the central sympathoinhibitory action of ketanserin.

The present study was designed to determine whether the central sympatholytic effects of ketanserin result from the ability of the drug to block serotonin2 or alpha-1 adrenergic receptors. Ketanserin produced a dose-related inhibition of sympathetic nerve discharge recorded from the inferior cardiac nerve in chloralose-anesthetized cats. Administration of a large dose of prazosin (1 mg/kg i.v.) decreased arterial blood pressure and inhibited sympathetic activity for several hours. Additional doses of prazosin failed to further inhibit sympathetic nerve discharge. Pretreatment with prazosin (1 mg/kg i.v.) also blocked the ability of ketanserin to inhibit sympathetic activity. Conversely, pretreatment with ketanserin blocked the central sympatholytic action of prazosin. In contrast, the alpha-2 adrenergic agonist clonidine inhibited sympathetic activity in animals pretreated with prazosin. The highly selective serotonin2 antagonist, LY 53857, failed to affect arterial blood pressure, heart rate or sympathetic activity recorded from the inferior cardiac nerve. These data, along with earlier results from our laboratory, provide strong evidence to indicate that ketanserin produces a centrally mediated inhibition of sympathetic nerve discharge as a result of the ability of the drug to block alpha-1 adrenergic receptors.

GABA-serotonergic interactions in the regulation of central sympathetic pathways.

Methysergide, a serotonin antagonist, and clonidine, an alpha 2-adrenoceptor agonist, lowered arterial blood pressure, heart rate and inferior cardiac sympathetic nerve activity in the anesthetized cat. Picrotoxin, a GABA antagonist, caused a reduction in the inhibition of sympathetic activity produced by methysergide. In contrast, picrotoxin did not effect the reduction of sympathetic nervous discharge resulting from administration of clonidine. These observations suggest that an interaction exists between GABAergic and serotonergic neurons which regulates central sympathetic pathways, possibly by a tonic GABAergic inhibition of serotonergic sympathoexcitatory pathways.