Susan M. Barman

Serotonin and Blood Pressure Regulation

5-Hydroxytryptamine (5-HT; serotonin) was discovered more than 60 years ago as a substance isolated from blood. The neural effects of 5-HT have been well investigated and understood, thanks in part to the pharmacological tools available to dissect the serotonergic system and the development of the frequently prescribed selective serotonin-reuptake inhibitors. By contrast, our understanding of the role of 5-HT in the control and modification of blood pressure pales in comparison. Here we focus on the role of 5-HT in systemic blood pressure control. This review provides an in-depth study of the function and pharmacology of 5-HT in those tissues that can modify blood pressure (blood, vasculature, heart, adrenal gland, kidney, brain), with a focus on the autonomic nervous system that includes mechanisms of action and pharmacology of 5-HT within each system. We compare the change in blood pressure produced in different species by short- and long-term administration of 5-HT or selective serotonin receptor agonists. To further our understanding of the mechanisms through which 5-HT modifies blood pressure, we also describe the blood pressure effects of commonly used drugs that modify the actions of 5-HT. The pharmacology and physiological actions of 5-HT in modifying blood pressure are important, given its involvement in circulatory shock, orthostatic hypotension, serotonin syndrome and hypertension.

Presence of vasomotor and respiratory rhythms in the discharge of single medullary neurons involved in the regulation of cardiovascular system

We analyzed the discharges of 77 single neurons located in the rostral ventrolateral medulla (RVLM, n = 25), caudal ventrolateral medulla (CVLM, n = 18), lateral tegmental field (LTF, n = 19) and caudal raphe nuclei (n = 15). These recordings were made from 36 vagotomized and sinoaortic denervated cats that were either decerebrate (n = 27) or anesthetized with urethane (n = 9) and from 3 decerebrate cats with intact sinoartic and vagal nerves. These neurons were classified as sympathetic-related (n = 61) if spike triggered averaging showed that their naturally occurring discharges were correlated to either the cardiac related (2-6 Hz) or a faster (10 Hz) oscillation in inferior cardiac sympathetic nerve discharge. Neurons were classified as sympathetic-unrelated (n = 16) if they lacked these characteristics. We used autoregressive spectral techniques to detect additional slower oscillations hidden in the variability of neuronal discharge and possibly correlated to the oscillations of systolic arterial pressure (SAP). This analysis revealed the existence of a low frequency (LF) oscillation (0.12 +/- 0.02 Hz) in the discharges of 36 sympathetic-related and 9 sympathetic-unrelated neurons. In relation to 35 neurons in 21 animals there was also an LF component in SAP variability. In 29 instances the LF neuronal discharges and SAP variabilities were significantly correlated. In addition, there was a high frequency (HF) oscillation (0.34 +/- 0.06 Hz) in the discharges of 59 medullary neurons. In 56 cases the HF in neuronal discharge variability cohered to that in SAP variability. These data are the first to demonstrate the existence of an LF component in the discharges of individual medullary neurons, at least some of which were likely to be involved in the regulation of the cardiovascular system. Since these oscillations were evident in cats with section of sinoaortic and vagal nerves, they likely reflect central rhythmogenic properties.

Rapid rhythmic discharges of sympathetic nerves: sources, mechanisms of generation, and physiological relevance.

Like virtually all other physiological control systems, the sympathetic nervous system controlling cardiovascular function is characterized by the presence of rhythmic activity. These include slow rhythms with frequencies at or below that of the respiration and rapid rhythms with frequencies at or above that of the heart beat. The rapid rhythms are the subject of this review. The specific questions entertained are as follows: (1) Are the rapid cardiac-related and 10-Hz rhythms inherent to central sympathetic networks, or are they imposed on sympathetic nerve discharge (SND) by extrinsic periodic inputs? (2) Does basal SND arise from an anatomically circumscribed “vasomotor center” composed of pacemaker neurons in the rostral ventrolateral medulla or from an anatomically distributed network oscillator composed of different types of brainstem neurons, none of which necessarily have intrinsic pacemaker properties? (3) Are the rapid rhythms generated by single circuits or by systems of coupled oscillators, each with a separate target? (4) Are the rapid rhythms in SND simply by-products of the sympathetic generating mechanisms, or do they subserve selective and special functions, such as the formulation of differential patterns of spinal sympathetic outflow that support particular behaviors? The controversial aspects of these issues and the state-of-the-art analytical methods used to study them are stressed in this review.

Human brain alpha rhythm: nonlinear oscillation or filtered noise?

The mechanism for generation of the alpha rhythm is controversial. In the current study, analysis in the time and frequency domains revealed that the alpha rhythm recorded from the scalp overlying the human occipital cortex can be entrained to the second or third harmonic of low frequency light flashes. These results support the view that the alpha rhythm is generated by a nonlinear oscillator rather than a narrow-band transmission system acting as a filter.

Medullary lateral tegmental field: an important synaptic relay in the baroreceptor reflex pathway of the cat

This study was designed to test the hypothesis that the medullary lateral tegmental field (LTF) is an important synaptic relay in the baroreceptor reflex pathway controlling sympathetic nerve discharge (SND) of urethan-anesthetized cats. We determined the effects of blockade of excitatory amino acid-mediated neurotransmission in the LTF on three indexes of baroreceptor reflex function: cardiac-related power in SND, strength of linear correlation (coherence value) of SND to the arterial pulse (AP), and inhibition of SND during increased arterial pressure produced by abrupt obstruction of the abdominal aorta. Bilateral microinjection ofd-(-)-2-amino-5-phosphonopentanoic acid, an N-methyl-d-aspartate (NMDA) receptor antagonist, abolished cardiac-related power and coherence of SND to the AP, and it prevented inhibition of SND during aortic obstruction. These data support the view that NMDA receptor-mediated neurotransmission in the LTF is critical for baroreceptor reflex control of SND. Bilateral microinjection of 1,2,3,4-tetrahydro-6-nitro-2,3-dioxobenzo-[ f]-quinoxaline-7-sulfonamide, a non-NMDA receptor antagonist, decreased cardiac-related power and total power in the 0- to 6-Hz band of SND; however, the AP-SND coherence value remained high, and inhibition of SND during aortic obstruction was preserved. These data imply that non-NMDA receptor-mediated neurotransmission in the LTF is involved in setting the level of excitatory drive to sympathetic nerves.

A 10-Hz rhythm reflects the organization of a brainstem network that specifically governs sympathetic nerve discharge

Coherence analysis revealed that the 10-Hz rhythm in sympathetic nerve discharge (SND) was not correlated to that either in inferior olivary activity of decerebrate cats or in neocortical spindles of urethane-anesthetized cats. Also the discharges of some ventrolateral medullary and raphe neurons contained a 10-Hz rhythm that was not correlated to that in SND. These data support the hypothesis that a 10-Hz rhythm reflects the organization of a brainstem network that specifically governs sympathetic outflow.

Responses of neurons in the rostral ventrolateral medulla to whole body rotations: comparisons in decerebrate and conscious cats

The responses to vestibular stimulation of brain stem neurons that regulate sympathetic outflow and blood flow have been studied extensively in decerebrate preparations, but not in conscious animals. In the present study, we compared the responses of neurons in the rostral ventrolateral medulla (RVLM), a principal region of the brain stem involved in the regulation of blood pressure, to whole body rotations of conscious and decerebrate cats. In both preparations, RVLM neurons exhibited similar levels of spontaneous activity (median of ∼17 spikes/s). The firing of about half of the RVLM neurons recorded in decerebrate cats was modulated by rotations; these cells were activated by vertical tilts in a variety of directions, with response characteristics suggesting that their labyrinthine inputs originated in otolith organs. The activity of over one-third of RVLM neurons in decerebrate animals was altered by stimulation of baroreceptors; RVLM units with and without baroreceptor signals had similar responses to rotations. In contrast, only 6% of RVLM neurons studied in conscious cats exhibited cardiac-related activity, and the firing of just 1% of the cells was modulated by rotations. These data suggest that the brain stem circuitry mediating vestibulosympathetic reflexes is highly sensitive to changes in body position in space but that the responses to vestibular stimuli of neurons in the pathway are suppressed by higher brain centers in conscious animals. The findings also raise the possibility that autonomic responses to a variety of inputs, including those from the inner ear, could be gated according to behavioral context and attenuated when they are not necessary.

Methods of analysis and physiological relevance of rhythms in sympathetic nerve discharge

1 Like virtually all other physiological control systems, the sympathetic nervous system controlling cardiovascular function is characterized by the presence of rhythmic activity. Despite the prevalence of rhythms, their function is often not obvious, which leads to the question, what can one learn about the neural control of autonomic function by studying sympathetic nervous system rhythms? 2 Sympathetic nerve discharge (SND) is characterized by a mixture of periodicities ranging between approximately 0.04 and 10 Hz, depending on the physiological conditions, type of nerve being analysed and the species. The present article illustrates why frequency domain (power density spectral) analysis is more suitable than time domain (autocorrelation) analysis to quantify a complex signal (i.e. one with multiple frequency components) such as SND. 3 The present article entertains the possibilities that rhythmic activity may lead to more effective activation of sympathetic neurons than randomly occurring activity, that rhythmicity is important for coordinating activity in different sympathetic nerves and in formulating complex cardiovascular response patterns and that sympathetic rhythmicity may help maintain homeostasis.

STUDIES ON THE ORIGIN AND GENERATION OF SYMPATHETIC NERVE ACTIVITY

This paper summarizes the efforts of our laboratory to define the substrates and mechanisms for generation of one of the primary components in sympathetic nerve discharge (SND) of the cat, the 2- to 6-Hz rhythm. Using spike-triggered averaging, we have identified single brain stem neurons with naturally occurring activity correlated to the 2- to 6-Hz rhythm in SND. Such neurons were found in three regions--the rostral ventrolateral medulla (RVLM), medullary raphe (R) and medullary lateral tegmental field (LTF). RVLM neurons were inhibited in parallel to SND when carotid sinus pressure was raised while R neurons were excited. These observations suggest that RVLM neurons exert sympathoexcitatory (SE) actions while R neurons mediate sympathoinhibitory (SI) effects. Both SE and SI neurons were found in the LTF. Antidromic mapping revealed that the axons of RVLM-SE and R-SI neurons innervate the thoracic spinal intermediolateral nucleus. In contrast, LTF neurons do not project to the spinal cord. Rather, the axons of LTF-SE neurons project to the RVLM while those of LTF-SI neurons project to R. We hypothesize that the aforementioned cell groups comprise a network oscillator responsible for the 2- to 6-Hz rhythm in SND.

Tonic sympathoinhibition in the baroreceptor denervated cat.

Summary Lesions of those portions of the paramedian reticular, raphe obscurus and raphe pallidus nuclei which extend 0-2 mm rostral to the obex increased renal SND without affecting the baroreceptor reflexes in cats with intact carotid sinus, aortic depressor, and vagus nerves. Lesions of these medial medullary structures in baroreceptor dener-vated cats produced an equivalent increase in SND. The effect of medial medullary lesions on SND, however, was prevented by prior decerebration. These results indicate that tonic sympathoinhibition involving the medial medulla is of nonbaroreceptor origin and is dependent upon the integrity of forebrain-medullary connections. The increase in SND produced by medial medullary lesions was not significantly different from that produced by section of the baroreceptor nerves or by ablation of the medullary nucleus of baroreceptor fiber termination (i.e., NTS). Thus, the nonbaroreceptor sympathoinhibitory system of the medial medulla is potentially as important as the baroreceptor reflexes in the control of SND in the anesthetized cat. Finally, this study also demonstrated that sympathoinhibitory elements in NTS are not tonically active in the absence of baroreceptor nerve input.