Anthony J.M. Verberne

CORTICAL MODULATION OF THE CARDIOVASCULAR SYSTEM

Cortical modulation of central cardiovascular control mechanisms has been recognized for many decades. However, it is only recently that the mechanisms underlying cortical influences on circulatory function have been systematically examined. This review considers the view that certain regions of the cerebral cortex, including the medial prefrontal cortex (MPFC) and insular cortex (IC), participate in specific aspects of central circulatory control. Anatomical investigations indicate that these cortical areas are connected with hypothalamic, midbrain, pontine and medullary brain regions involved in cardiovascular control. Lesions of the MPFC and IC have demonstrated modulation of the activity of cardiovascular reflexes such as the baroreceptor heart rate reflex and involvement in conditioned cardiovascular responses. Electrophysiological studies have provided evidence that cortical regions are able to influence premotor sympathoexcitatory vasomotor neurons within the rostral ventrolateral medulla and subsequently alter sympathetic vasomotor tone. Cortical regions such as the IC receive visceral sensory information arising from baroreceptors and chemoreceptors within the cardiovascular system. In contrast, the MPFC receives afferents predominantly from limbic sources, although its outputs include structures associated with central sympathetic vasomotor control. Cortical modulation of circulatory function has been demonstrated in man and may underlie the cardiovascular components of a number of conditions. It is suggested that cortical areas involved in visceral sensory or visceral motor processes associated with circulatory function may be involved in generation of patterns of cardiovascular responses specific for certain behaviours.

Properties of C1 and other ventrolateral medullary neurones with hypothalamic projections in the rat

1 This study compared (i) the properties of C1 cells with those of neighbouring non‐C1 neurones that project to the hypothalamus and (ii) the properties of C1 cells that project to the hypothalamus with those of their medullospinal counterparts. 2 Extracellular recordings were made at three rostrocaudal levels of the ventrolateral medulla (VLM) in α‐chloralose‐anaesthetized, artificially ventilated, paralysed rats. Recorded cells were filled with biotinamide. 3 Level I (0‐300 μm behind facial nucleus) contained spontaneously active neurones that were silenced by baro‐ and cardiopulmonary receptor activation and virtually unaffected by nociceptive stimulation (firing rate altered by < 20%). These projected either to the cord (type I; 36/39), or to the hypothalamus (type II; 2/39) but rarely to both (1/39). 4 Level II (600‐800 μm behind facial nucleus) contained (i) type I neurones (n= 3) (ii) type II neurones (n= 11), (iii) neurones that projected to the hypothalamus and were silenced by baro‐ and cardiopulmonary receptor activation but activated by strong nociceptive stimulation (type III, n= 2), (iv) non‐barosensitive cells activated by weak nociceptive stimulation which projected only to the hypothalamus (type IV, n= 9), (v) cells that projected to the hypothalamus and responded to none of the applied stimuli (type V, n= 7) and (vi) neurones activated by elevating blood pressure which projected neither to the cord nor to the hypothalamus (type VI, n= 4). 5 Level III (1400‐1600 μm behind facial motor nucleus) contained all the cell types found at level II except type I. 6 Most of type I and II (17/26) and half of type III cells (4/8) were C1 neurones. Type IV‐V were rarely adrenergic (2/12) and type VI were never adrenergic (0/3). 7 All VLM baroinhibited cells project either to the cord or the hypothalamus and virtually all (21/23) C1 cells receive inhibitory inputs from arterial and cardiopulmonary receptors.

Medial prefrontal cortical lesions modulate baroreflex sensitivity in the rat

Previous neuroanatomical studies in rats have demonstrated that the medial prefrontal cortex sends projections to the nucleus of the solitary tract which also receives the bulk of baroreceptor information from primary afferents within the IXth and Xth cranial nerves. The present study examines the influence of the prefrontal cortex on baroreceptor heart rate reflex in conscious rats. Baroreceptor reflex activity was examined in rats with bilateral excitotoxin (N-methyl-D-aspartate)-induced lesions of the medial prefrontal cortex and in control rats (artificial cerebrospinal fluid). Seventeen to eighteen days after lesioning, reflex heart rate responses were recorded following intravenous bolus doses of the pressor agent phenylephrine and the depressor agent sodium nitroprusside. Baroreceptor reflex parameters i.e., maximum and average baroreceptor reflex gain (or sensitivity): minimum and maximum heart rate plateaus; heart rate range; upper and lower reflex thresholds, were determined by sigmoidal computerized curve-fitting. Lesioning the medial prefrontal cortex did not affect resting mean arterial pressure and heart rate. However, the lesion reduced maximum and average baroreceptor reflex gain and produced a small reduction in lower reflex threshold. The other parameters were unaffected by the lesion. These observations suggest that although the medial prefrontal cortex does not exert a tonic influence on brainstem vasomotor neurons, there may be a descending excitatory projection from this brain region to medullary neurones involved in the baroreceptor reflex arc.

Chemical stimulation of vagal afferent neurons and sympathetic vasomotor tone

Vagal afferents innervate a diverse range of structures of the thoracic and abdominal viscera. While a proportion of these afferents function as mechanoreceptors and respond to changes in intramural tension within the structures that they innervate, many also sense a broad range of chemical substances ranging from peptides, sugars and lipids present in the intraluminal contents of the gastrointestinal tract, as well as tissue prostanoids, cytokines and monoamines in the cardiopulmonary circulation. This review examines the effects of chemical stimulation of vagal afferents on circulatory and sympathetic vasomotor function. Notably, the von Bezold-Jarisch reflex is a cardiorespiratory reflex produced by chemical activation of cardiopulmonary vagal afferents. Classical stimulants of the von Bezold-Jarisch reflex include the Veratrum alkaloids and 5-HT(3) receptor agonists. Atrial natriuretic peptides are agents which also produce a von Bezold-Jarisch reflex-like response or a sensitisation of this reflex via an action on vagal afferents. Cholecystokinin (CCK) activates abdominal visceral vagal afferents, which apart from a clear role in mediation of satiety, also produces selective sympathetic vasomotor inhibition probably by inhibition of sub-groups of presympathetic vasomotor neurons of the rostral ventrolateral medulla. These actions of CCK may constitute a novel gastrointestinal-cardiovascular reflex. The afferent vagus transmits a diverse array of signals to the central nervous system, influencing sympathetic vasomotor and cardiomotor function, gastrointestinal function, neuroimmune function and endocrine function.

Regional haemodynamic responses to activation of the medial prefrontal cortex depressor region

Electrical or chemical stimulation of the medial prefrontal cortex (MPFC) produces depressor and sympathoinhibitory responses. To characterise the MPFC depressor response more fully, we determined the regional haemodynamic changes which occurred in response to stimulation of the MPFC. In halothane-anaesthetised rats, we recorded arterial blood pressure and renal, superior mesenteric, and iliac arterial vascular conductance using miniaturised Doppler flow probes. Electrical stimulation of the MPFC (50-100 microA) was used to map the location of the depressor region. Increases in vascular conductance (or increases in blood flow) were recorded from the renal (+2.3+/-0.5 kHz/mmHgx10(3)), mesenteric (+4.4+/-0.4 kHz/mmHgx10(3)), and iliac (+8.3+/-1.0 kHz/mmHgx10(3)) vascular beds in response to stimulation of the MPFC depressor region coinciding with the ventral infralimbic (IL) and dorsal peduncular (DP) cortical areas. Similar responses were obtained after microinjection of the chemical excitant L-glutamate (n=3, 100 nl, 100 mM), indicating that the responses were due to excitation of cell bodies and not due to axons traversing the area. Administration of the nitric oxide synthesis inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 25 micromol/kg, i.v., n=5) significantly reduced the MPFC depressor response (51%, 12.5+/-1.2 to 6.1+/-2.5 mmHg). The increases in conductance in the hindquarter and mesenteric vascular beds were significantly reduced after L-NAME treatment (mesenteric by 77%, iliac by 70%), but there was no significant reduction of renal flow (35%). These observations indicate that the depressor region of the MPFC is localised to ventral regions (IL and DP) and that the depressor response is mediated by increased conductance in the hindquarters and mesenteric vascular beds. Furthermore, the depressor response may be mediated, in part, by release of nitric oxide in these vascular beds.

Impaired arterial baroreceptor reflex and cardiopulmonary vagal reflex in conscious spontaneously hypertensive rats.

The activity of baroreceptor reflexes and cardiopulmonary reflexes was examined in conscious spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) rats. The baroreceptor heart rate reflex, elicited by phenylephrine- and nitroprusside-induced changes in blood pressure, had a reduced range and lower heart rate plateau in SHR than in WKY rats, which suggests impaired vagal control of the heart rate in SHR. Cardiopulmonary receptor reflex activity was assessed by intravenous injections of phenyldiguanide which evoke the Bezold-Jarisch reflex. Phenyldiguanide elicited dose-dependent bradycardic and hypotensive responses in WKY rats, but these were significantly attenuated in SHR. This is the first demonstration of impaired Bezold-Jarisch responses in conscious SHR and provides evidence of both impaired vagally mediated arterial baroreceptor activity and impaired cardiopulmonary receptor activity in this rat strain.

Heterogeneous responses of nucleus incertus neurons to corticotrophin‐releasing factor and coherent activity with hippocampal theta rhythm in the rat

•  The nucleus incertus (NI) is a stress and arousal responsive, hindbrain region involved in ascending control of septohippocampal theta rhythm. •  NI neurons express high levels of the neuropeptide relaxin‐3 and corticotrophin‐releasing factor (CRF) receptor‐1 (CRF‐R1). •  We report the first in‐depth characterization of NI neurons, using in vivo and in vitro electrophysiological techniques, which reveal a population of relaxin‐3‐containing NI neurons activated by CRF via postsynaptic CRF‐R1 and a non‐relaxin‐3 neuron population inhibited or unaffected by CRF. •  Relaxin‐3 NI neurons exhibit strong phase‐locked firing with the ascending phase of hippocampal theta oscillations. •  These findings suggest the NI is a heterogeneous neuronal population and key site of CRF action with the capacity to modulate cognition in response to stress.

Cocaine‐ and amphetamine‐regulated transcript in catecholamine and noncatecholamine presympathetic vasomotor neurons of rat rostral ventrolateral medulla

Presympathetic vasomotor adrenergic (C1) and nonadrenergic (non‐C1) neurons in the rostral ventrolateral medulla (RVLM) provide the main excitatory drive to cardiovascular sympathetic preganglionic neurons in the spinal cord. C1 and non‐C1 neurons contain cocaine‐ and amphetamine‐regulated transcript (CART), suggesting that CART may be a common marker for RVLM presympathetic neurons. To test this hypothesis, we first used double‐immunofluorescence staining for CART and tyrosine hydroxylase (TH) to quantify CART‐immunoreactive (‐IR) catecholamine and noncatecholamine neurons in the C1 region. Next, we quantified the proportion of CART‐IR RVLM neurons that expressed Fos in response to a hypotensive stimulus, using peroxidase immunohistochemistry for Fos and dual immunofluorescence for CART and TH. Finally, we fluorescently detected CART immunoreactivity in electrophysiologically identified, juxtacellularly labeled RVLM presympathetic neurons. In the RVLM, 97% of TH‐IR neurons were CART‐IR, and 74% of CART‐IR neurons were TH‐IR. Nitroprusside infusion significantly increased the number of Fos‐IR RVLM neurons compared with saline controls. In nitroprusside‐treated rats, virtually all Fos/TH neurons in the RVLM were immunoreactive for CART (98% ± 1.3%, SD; n = 7), whereas 29% ± 8.3% of CART‐positive, TH‐negative neurons showed Fos immunoreactivity. Six fast (2.8–5.8 m/second, noncatecholamine)‐, two intermediate (2.1 and 2.2 m/second)‐, and five slow (<1 m/second, catecholamine)‐conducting RVLM presympathetic vasomotor neurons were juxtacellularly labeled. After fluorescent detection of CART and biotinamide, all 13 neurons were found to be CART‐IR. These results suggest that, in rat RVLM, all catecholamine and noncatecholamine presympathetic vasomotor neurons contain CART. J. Comp. Neurol. 476:19–31, 2004.

Neural pathways that control the glucose counterregulatory response

Glucose is an essential metabolic substrate for all bodily tissues. The brain depends particularly on a constant supply of glucose to satisfy its energy demands. Fortunately, a complex physiological system has evolved to keep blood glucose at a constant level. The consequences of poor glucose homeostasis are well-known: hyperglycemia associated with uncontrolled diabetes can lead to cardiovascular disease, neuropathy and nephropathy, while hypoglycemia can lead to convulsions, loss of consciousness, coma, and even death. The glucose counterregulatory response involves detection of declining plasma glucose levels and secretion of several hormones including glucagon, adrenaline, cortisol, and growth hormone (GH) to orchestrate the recovery from hypoglycemia. Low blood glucose leads to a low brain glucose level that is detected by glucose-sensing neurons located in several brain regions such as the ventromedial hypothalamus, the perifornical region of the lateral hypothalamus, the arcuate nucleus (ARC), and in several hindbrain regions. This review will describe the importance of the glucose counterregulatory system and what is known of the neurocircuitry that underpins it.

Rostroventrolateral medullary neurons modulate glucose homeostasis in the rat

Several lines of evidence support the view that the premotor sympathetic input to the adrenal gland arises from the rostroventrolateral medulla (RVLM). The aim of this study was to determine whether RVLM neurons play a role in glucose homeostasis. We identified RVLM neurons that control epinephrine secretion by searching for medullospinal neurons that responded to neuroglucoprivation induced by systemic 2-deoxyglucose (2-DG) administration. We tested the effect of disinhibition of the RVLM on arterial blood pressure and plasma glucose concentration. RVLM medullospinal barosensitive neurons (n = 17) were either unaffected or slightly inhibited by 2-DG. In contrast, we found a group (n = 6) of spinally projecting neurons that were excited by 2-DG administration. These neurons were not barosensitive and had spinal conduction velocities in the unmyelinated range (<1 m/s). These neurons may mediate epinephrine secretion and participate in the counterregulatory responses to neuroglucoprivation. To test the hypothesis that activation of the RVLM leads to adrenomedullary activation and subsequent hyperglycemia, we applied the GABA(A) antagonist bicuculline to the RVLM and measured blood pressure, heart rate, and blood glucose in rats with intact adrenals or after bilateral adrenalectomy. Disinhibition of the RVLM resulted in hypertension, tachycardia, and hyperglycemia (4.9 ± 0.3 to 14.7 ± 0.9 mM, n = 5, P < 0.05). Adrenalectomy significantly reduced the hyperglycemic response but did not alter the cardiovascular responses. These data suggest that the RVLM is a key component of the neurocircuitry that is recruited in the counterregulatory response to hypoglycemia.