Jouji Horiuchi

Central mechanisms underlying short- and long-term regulation of the cardiovascular system.

1. Sympathetic vasomotor nerves play a major role in determining the level of arterial blood pressure and the distribution of cardiac output. The present review will discuss briefly the central regulatory mechanisms that control the sympathetic outflow to the cardiovascular system in the short and long term.

LONG-TERM REGULATION OF ARTERIAL BLOOD PRESSURE BY HYPOTHALAMIC NUCLEI: SOME CRITICAL QUESTIONS

1. The long‐term level of arterial pressure is dependent on the relationship between arterial pressure and the urinary output of salt and water, which, in turn, is affected by a number of factors, including renal sympathetic nerve activity (RSNA). In the present brief review, we consider the mechanisms within the brain that can influence RSNA, focusing particularly on hypothalamic mechanisms.

Functional organization of brain pathways subserving the baroreceptor reflex: studies in conscious animals using immediate early gene expression.

Abstract1. This paper reviews studies carried out in our laboratory in which we have used the c-fos functional mapping method, in combination with other methods, to determine the functional organization of central baroreceptor pathways as they operate in the conscious rabbit.2. First, we showed that periods of induced hypertension or hypotension each result in a specific and reproducible pattern of activation of neurons in the brainstem and forebrain. In particular, hypotension (but not hypertension) results in the activation of catecholamine neurons in the medulla and pons and vasopressin-synthesizing neurons in the hypothalamus.3. The activation of medullary cell groups in response to induced hypertension or hypotension in the conscious rabbit is almost entirely dependent on inputs from arterial baroreceptors, while the activation of hypothalamic vasopressin-synthesising neurons in response to hypotension is largely dependent on baroreceptors, although an increase in circulating angiotensin also appears to contribute.4. Discrete groups of neurons in the rostral ventrolateral medulla (RVLM) and A5 area in the pons are the major groups of spinally projecting neurons activated by baroreceptor unloading. In contrast, spinally projecting neurons in the paraventricular nucleus in the hypothalamus appear to be largely unaffected by baroreceptor signals.5. Direct afferent inputs to RVLM neurons in response to increases or decreases in arterial pressure originate primarily from other medullary nuclei, particularly neurons located in the caudal and intermediate levels of the ventrolateral medulla (CVLM and IVLM), as well as in the nucleus tractus solitarius (NTS).6. There is also a direct projection from barosensory neurons in the NTS to the CVLM/IVLM region, which is activated by baroreceptor inputs.7. Collectively, the results of our studies in conscious animals indicate that baroreceptor signals reach all levels of the brain. With regard to the baroreceptor reflex control of sympathetic activity, our studies are consistent with previous studies in anesthetized animals, but in addition reveal other previously unrecognized pathways that also contribute to this reflex regulation.

Role of angiotensin II receptors in the regulation of vasomotor neurons in the ventrolateral medulla.

1. There is a high density of angiotensin type 1 (AT1) receptors in various brain regions involved in cardiovascular regulation. The present review will focus on the role of AT1 receptors in regulating the activity of sympathetic premotor neurons in the rostral part of the ventrolateral medulla (VLM), which are known to play a pivotal role in the tonic and phasic regulation of sympathetic vasomotor activity and arterial pressure.

What Drives The Tonic Activity Of Presympathetic Neurons In The Rostral Ventrolateral Medulla

1. The present review discusses the mechanisms that maintain the tonic activity of presympathetic cardiovascular neurons in the rostral part of the ventrolateral medulla.

Activation of brain neurons following central hypervolaemia and hypovolaemia: contribution of baroreceptor and non-baroreceptor inputs

In the present study we have used the detection of Fos, the protein product of c-fos, to determine the distribution of neurons in the medulla and hypothalamus that are activated by changes in central blood volume. Experiments were conducted in both barointact and barodenervated conscious rabbits, to determine the contribution of arterial baroreceptors to the pattern of Fos expression evoked by changes in central blood volume, induced either by intravenous infusion of an isotonic modified gelatin solution, or by partial occlusion of the vena cava. These procedures resulted in a significant increase and decrease, respectively, in right atrial pressure over a 60 min period. In control experiments, barointact and barodenervated rabbits were subjected to the identical procedures except that no changes in central blood volume were induced. In comparison with the control observations, central hypervolaemia produced a significant increase in the number of Fos-immunoreactive neurons in the nucleus tractus solitarius, area postrema, the caudal, intermediate and rostral parts of the ventrolateral medulla, supraoptic nucleus, paraventricular nucleus, arcuate nucleus, suprachiasmatic nucleus and median preoptic nucleus. The overall pattern of Fos expression induced by central hypervolaemia did not differ significantly between barointact and barodenervated animals. Similarly, the overall pattern of Fos expression induced by central hypovolaemia did not differ significantly between barointact and barodenervated animals, but did differ significantly from that produced by hypervolaemia. In particular, central hypovolaemia produced a significant increase in Fos expression in the same regions as above, but also in the subfornical organ and organum vasculosum lamina terminalis. In addition, compared with central hypervolaemia, hypovolaemia produced a significantly greater degree of Fos expression in the rostral ventrolateral medulla and supraoptic nucleus. Furthermore, double-labelling for tyrosine hydroxylase immunoreactivity demonstrated that neurons in the ventrolateral medulla that expressed Fos following hypovolaemia were predominantly catecholamine cells, whereas following hypervolaemia they were predominantly non-catecholamine cells. Finally, double-labelling for vasopressin immunoreactivity demonstrated that the number of Fos/vasopressin immunoreactive cells in the supraoptic nucleus was approximately 10 times greater following hypovolaemia compared with hypervolaemia, but there were very few such double-labelled neurons in the paraventricular nucleus in response to either stimulus. The results demonstrate that central hypervolaemia and hypovolaemia each induces reproducible and specific patterns of Fos expression in the medulla and hypothalamus. The degree and pattern of Fos expression was unaffected by arterial baroreceptor denervation, indicating that it is primarily a consequence of inputs from cardiac receptors, together with an increase in the level of circulating hormones such as atrial natriuretic peptide, angiotensin II or vasopressin. Furthermore, the pattern of Fos expression produced by central hypervolaemia and hypovolaemia is distinctly different from that evoked by hypertension and hypotension, respectively [Li and Dampney (1994) Neuroscience 61, 613-634], particularly in hypothalamic regions. These findings therefore indicate that the central pathways activated by changes in blood volume are, at least in part, separate from those activated by changes in arterial pressure.

Distribution of neurons projecting to the rostral ventrolateral medullary pressor region that are activated by sustained hypotension

Hypotension produces a reflex increase in the activity of sympathetic vasomotor and cardiac nerves. It is believed that the reflex sympathoexcitation is due largely to disinhibition of sympathoexcitatory neurons in the rostral ventrolateral medulla, but it is possible that it may also be mediated by excitatory inputs from interneurons that are activated by a fall in blood pressure. The aim of this study in conscious rabbits was to identify and map neurons with properties that are characteristic of interneurons conveying excitatory inputs to the rostral ventrolateral medullary pressor region in response to hypotension. In a preliminary operation, a retrogradely-transported tracer, fluorescent-labelled microspheres, was injected into the functionally-identified pressor region in the rostral ventrolateral medulla. After a waiting period of at least one week, a moderate hypotension (decrease in arterial pressure of approximately 20 mmHg) was induced in conscious rabbits for 60 min by the continuous infusion of sodium nitroprusside. In confirmation of a previous study from our laboratory, [Li and Dampney (1994) Neuroscience 61, 613634] hypotension resulted in the expression of Fos (the protein product of c-fos, a marker of neuronal activation) in many neurons in several distinct regions in the brainstem and hypothalamus. Some of these regions (nucleus tractus solitarius, area postrema, caudal and intermediate ventrolateral medulla, parabrachial complex in the pons, and paraventricular nucleus in the hypothalamus) also contained large numbers of retrogradely-labelled cells. Approximately 10% of the Fos-positive neurons in the nucleus tractus solitarius, and 15-20% of Fos-positive neurons in the caudal and intermediate ventrolateral medulla were also retrogradely-labelled from the rostral ventrolateral medullary pressor region. In other brain regions, very few double-labelled neurons were found. In previous studies from our laboratory, we have determined the distribution of neurons in the brainstem that project to the rostral ventrolateral medullary pressor region and that are also activated by hypertension [Polson et al. (1995) Neuroscience 67, 107-123] or by hypoxia. [Hirooka et al. (1997) Neuroscience 80, 1209-1224] Comparison of the present results with those from these previous studies indicate that although hypotension and hypoxia both elicit powerful reflex sympathoexcitatory responses, the central pathways subserving these effects in conscious animals are fundamentally different. Hypoxia activates rostral ventrolateral medullary sympathoexcitatory neurons mainly via a major direct excitatory projection from the nucleus tractus solitarius, as well as from the Kölliker-Fuse nucleus in the pons, while in contrast the activation of these neurons in response to hypotension appears to be due mainly to disinhibition, mediated via inhibitory interneurons. In addition, however, inputs originating from excitatory interneurons in the nucleus tractus solitarius and caudal and intermediate parts of the ventrolateral medulla appear to contribute to the hypotension-evoked activation of sympathoexcitatory neurons in the rostral ventrolateral medulla.

Vasomotor and respiratory responses evoked from the dorsolateral periaqueductal grey are mediated by the dorsomedial hypothalamus

Activation of neurons in the dorsomedial hypothalamus (DMH) evokes increases in mean arterial pressure (MAP), sympathetic activity, heart rate (HR) and respiratory activity. Results of previous studies suggest that the DMH‐evoked increases in MAP and HR are mediated by neurons within the periaqueductal grey (PAG), but a recent study has proposed that the converse is also true, i.e. that increases in MAP and HR evoked from the PAG depend upon neuronal activity in the DMH. In this study in anaesthetized rats, we examined the functional relationship between the DMH and PAG in regulating renal sympathetic nerve activity (RSNA) and respiratory activity (determined by measuring phrenic nerve activity (PNA)). Bilateral microinjections of the neuronal inhibitor muscimol into the DMH virtually abolished the increases in MAP, RSNA and PNA burst rate and amplitude evoked from the dorsolateral (dl) PAG. In contrast, multiple bilateral injections of much larger (10 times) doses of muscimol or of the local anaesthetic lignocaine into sites in the dlPAG at three different rostrocaudal levels did not reduce the magnitude or duration of the sympathetic vasomotor and respiratory responses evoked by disinhibition of neurons in the DMH. Thus, sympathetic vasomotor and respiratory responses generated from the dlPAG are dependent upon neuronal activity in the DMH, but not the converse. The results of this study together with those of previous studies indicate that the PAG regulates cardiovascular and respiratory function via both ascending projections to the DMH and descending projections to the ventral medulla, that originate from different PAG subregions.

Sympathoinhibition after angiotensin receptor blockade in the rostral ventrolateral medulla is independent of glutamate and γ-aminobutyric acid receptors

Bilateral blockade of angiotensin (Ang) receptors in the rostral ventrolateral medulla (RVLM) causes a profound fall in arterial pressure. In this study, we tested whether this effect is due to an interaction between Ang receptors and either glutamatergic or gamma-aminobutyric acidergic (GABAergic) synaptic inputs to RVLM sympathoexcitatory neurons. In urethane-anaesthetised rats, bilateral microinjections of the Ang receptor antagonists [Sar1,Thr8]Ang II or [Sar1,Ile8]Ang II into the RVLM pressor region caused large decreases in arterial pressure, heart rate and renal sympathetic nerve activity (RSNA). These responses were not significantly altered following bilateral microinjections into the RVLM of the glutamate receptor antagonist kynurenic acid (4.5 nmol). Furthermore, bilateral injections of kynurenic acid plus the GABA(A) receptor antagonist bicuculline (200 pmol) into the RVLM increased the baseline arterial pressure and RSNA, but did not alter the percentage decreases in these variables evoked by bilateral microinjections of [Sar1,Ile8]Ang II. However, the level of arterial pressure and RSNA following bilateral injections of kynurenic acid, bicuculline and [Sar1,Ile8]Ang II were similar to the levels before injection of any of these compounds. The effectiveness of the microinjections of kynurenic acid and bicuculline into the RVLM was demonstrated by the observation that they virtually abolished the somato-sympathoexcitatory and baroreceptor-sympathoinhibitory reflexes, which are mediated by glutamatergic and GABAergic synapses, respectively, in the RVLM. These results indicate that (1) blockade of Ang receptors greatly reduces the firing rate of RVLM sympathoexcitatory neurons via a mechanism that is independent of glutamatergic or GABAergic neurotransmission, and (2) in the absence of inputs mediated by ionotropic glutamate, GABA(A) and Ang receptors, there are other mechanisms which generate a level of tonic activity in RVLM sympathoexcitatory neurons sufficient to maintain a normal level of sympathetic vasomotor activity.

DIFFERENTIAL CONTROL OF CARDIAC AND SYMPATHETIC VASOMOTOR ACTIVITY FROM THE DORSOMEDIAL HYPOTHALAMUS

1 The dorsomedial hypothalamus (DMH) plays a crucial role in mediating the cardiovascular responses to different stressors, including acute psychological stress and cold stress. Activation of neurons in the DMH evokes increases in arterial pressure and in the activity of sympathetic nerves innervating the heart, blood vessels and brown adipose tissue. The descending pathways from the DMH to the spinal sympathetic outflow include synapses with neurons in medullary nuclei and possibly other brain stem regions. 2 Recent studies from our and other laboratories have indicated that neurons in the rostral ventrolateral medulla (RVLM) and in the region of the raphe pallidus (RP) in the medulla are important components of the descending pathways that mediate the cardiovascular response to activation of the DMH. Neurons in the RP primarily mediate the sympathetic cardiac components of the DMH‐evoked response, whereas the RVLM neurons primarily mediate the sympathetic vasomotor component. 3 Activation of DMH neurons not only increases heart rate and sympathetic vasomotor activity, but also resets the baroreceptor reflex such that it remains effective, without any decrease in sensitivity, over a higher operating range of arterial pressure. 4 Activation of 5‐hydroxytryptamine 5‐HT1A receptors in the medulla oblongata leads to a selective suppression of cardiac and sympathetic vasomotor components of the DMH‐evoked response, but does not affect sympathetic reflex responses evoked from baroreceptors or chemoreceptors. Thus, central 5‐HT1A receptors modulate cardiovascular responses evoked from the DMH in a highly potent but selective fashion.