Structural changes in large arteries are often considered the predominant mechanism responsible for decreased baroreflex sensitivity and baroreceptor resetting in hypertension, atherosclerosis, and aging. Recent work has demonstrated that "functional" mechanisms, both at the level of the peripheral sensory endings and within the central nervous system, contribute significantly to altered baroreflex responses. We have conducted both reductive studies of mechanoelectrical transduction in cultured baroreceptor neurons and integrative studies with in vivo recordings of the activity of baroreceptor afferent fibers and efferent sympathetic nerves. Results suggest that the primary mechanism of mechanical activation of baroreceptor neurons involves opening of stretch-activated ion channels susceptible to blockade by gadolinium. Baroreceptor nerve activity is modulated by the activity of potassium channels and the sodium-potassium pump and by paracrine factors, including prostacyclin, oxygen free radicals, and factors released from aggregating platelets. Endothelial dysfunction and altered release of these paracrine factors contribute significantly to the decreased baroreceptor sensitivity in hypertension and atherosclerosis. The central mediation of the baroreflex depends on the pulse phasic pattern of afferent baroreceptor discharge. Baroreflex-mediated inhibition of sympathetic nerve activity is well maintained during pulse phasic afferent activity. Continuous, nonphasic baroreceptor discharge or a rapid (> 1.5 Hz) pulse phasic discharge results in disinhibition of sympathetic activity. This disinhibition during continuous baroreceptor input is exaggerated with aging. Thus, a defect in central mediation of the baroreflex may be a major cause of the impaired baroreflex and sympathoexcitation in the elderly. In summary, functional neural mechanisms, in addition to structural vascular changes, contribute importantly to altered baroreflex responses in normal and pathophysiological states.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiopulmonary afferents, baroreceptor afferents, or atrial natriuretic peptide binding to circumventricular organs may mediate the central response to volume expansion, a condition common to pregnancy, exercise training, and congestive heart failure. This study used Fos immunocytochemistry to examine brain regions activated by volume expansion. Male Sprague-Dawley rats were infused with isotonic saline equal to 10% of their body weight in 10 min followed by a maintenance infusion of 0.5 ml/min for 110 min. Control animals received 2-h infusions at 0.01 ml/min. Five minutes after the start of volume expansion, central venous pressure of expanded animals was significantly greater than control animals. The volume-expanded group exhibited significantly greater Fos activation ( P < 0.05) in the area postrema, nucleus of the solitary tract, caudal ventrolateral medulla, paraventricular nucleus, supraoptic nucleus, and perinuclear zone of the supraoptic nucleus. Double labeling indicates that oxytocinergic neurons in the supraoptic nucleus are activated. Neurons in brain regions known to inhibit both sympathetic activity and vasopressin release show increased Fos expression following isotonic volume expansion.

The mechanisms underlying mechanotransduction in baroreceptor neurons (BRNs) are undefined. In this study, we specifically identified aortic baroreceptor neurons in primary neuronal cell cultures from nodose ganglia of rats. Aortic baroreceptor neurons were identified by labeling their soma with the fluorescent dye 1,1'-dioleyl-3,3,3',3'-tetramethylin-docarbocyanine (DiI) applied to the aortic arch. Using Ca2+ imaging with fura 2, we examined these BRNs for evidence of Ca2+ influx and determined its mechanosensitivity and voltage dependence. Mechanical stimuli were produced by ejecting buffer from a micropipette onto the cell surface with a pneumatic picopump, producing a shift in the center of mass of the cell that was related to intensity of stimulation. Ninety-three percent of DiI-labeled neurons responded to mechanical stimulation with an increase in [Ca2+]i. The magnitude of the increases in [Ca2+]i was directly related to the intensity of the stimulus and required the presence of external Ca2+. The trivalent cations Gd3+ or La3+ in equimolar concentrations (20 mumol/L) eliminated the K(+)-induced rises in [Ca2+]i, demonstrating that both trivalent cations are equally effective at blocking voltage-gated Ca2+ channels in these baroreceptor neurons. In contrast, the mechanically induced increases in [Ca2+]i were blocked by Gd3+ (20 mumol/L) only and not by La3+ (20 mumol/L). Stretch-activated channels (SACs) have been shown in other preparations to be blocked by Gd3+ specifically. Our data demonstrate that (1) BRNs, specifically identified as projecting to the aortic arch, have ion channels that are sensitive to mechanical stimuli; (2) mechanically induced Ca2+ influx in these cells is mediated by a Gd(3+)-sensitive ion channel and not by voltage-gated Ca2+ channels; (3) the magnitude of the Ca2+ influx is dependent on the intensity of the stimulus and the degree and duration of deformation; and (4) repeated stimuli of the same intensity result in comparable increases in [Ca2+]i. We conclude that mechanical stimulation increases Ca2+ influx into aortic BRNs independent of voltage-gated Ca2+ channels. The results suggest that Gd(3+)-sensitive SACs are the mechanoelectrical transducers in baroreceptors.

1. Precise control over the cardiovascular system requires the integration of both neural and humoral signals related to blood volume and blood pressure. Humoral signals interact with neural systems, modulating their control over the efferent mechanisms that ultimately determine the level of pressure and volume. 2. Peptide hormones such as angiotensin (Ang)II and arginine vasopressin (AVP) act through circumventricular organs (CVO) to influence cardiovascular regulation. 3. The area postrema (AP), a CVO in the brainstem, mediates at least some of the central actions of these peptides. Vasopressin appears to act in the AP to cause sympathoinhibition and a shift in baroreflex control of the sympathetic nervous system (SNS) to lower pressures. These effects of AVP and the AP appear to be mediated by alpha2-adrenoceptor and glutamatergic mechanisms in the nucleus tractus solitarius. 4. In contrast to AVP AngII has effects in the AP to blunt baroreflex control of heart rate and cause sympathoexcitation. The effects of chronic AngII to increase activity of the SNS may be due to AP-dependent activation of neurons in the rostral ventrolateral medulla.

The goal of this study was to identify the source of baroreceptor-related noradrenergic innervation of the diagonal band of Broca (DBB). Male Sprague-Dawley rats underwent sinoaortic denervation (SAD, n = 13) or sham SAD surgery (n = 13). We examined Fos expression produced by baroreceptor activation and dopamine-beta-hydroxylase immunofluorescence in hindbrain regions that contain noradrenergic neurons. Baroreceptors were stimulated by increasing blood pressure >40 mmHg with phenylephrine (10 microgram. kg(-1). min(-1) iv) in sham SAD and SAD rats. Controls were infused with 0.9% saline. Only the locus ceruleus (LC) demonstrated a baroreceptor-dependent increase in Fos immunoreactivity in dopamine-beta-hydroxylase-positive neurons. In a second experiment, normal rats received rhodamine-labeled microsphere injections in the DBB (n = 12) before phenylephrine or vehicle infusion. In these experiments, only the LC consistently contained Fos-positive cells after phenylephrine infusion that were retrogradely labeled from the DBB. Finally, we lesioned the LC with ibotenic acid and obtained extracellular recordings from identified vasopressin neurons in the supraoptic nucleus. LC lesions significantly reduced the number of vasopressin neurons that were inhibited by acute baroreceptor stimulation. Together, these results suggest that noradrenergic neurons in the LC participate in the baroreflex activation of the DBB and may thus be important in the baroreflex inhibition of vasopressin-releasing neurons in the supraoptic nucleus.