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Biomedical subjects

A V Ferguson

Publications and source records attributed to A V Ferguson.

At least 55 records · Page 3Linked to original sources
PubMed1995

Subfornical organ stimulation elicits drinking.

The subfornical organ is a specialized central nervous system structure known to be involved in the control of drinking. We report here that electrical activation of subfornical organ neurons (100 microA, 10 Hz, 1 ms pulse width, for 5 min.) induced drinking in 67% (six of nine) of animals. This effect was site-specific as none of the animals with electrode placements (n = 7) dorsal or rostral to the subfornical organ drank in response to electrical stimulation. In contrast, activity levels were increased significantly during stimulation in both the subfornical and nonsubfornical organ stimulated groups. These results suggest that electrical stimulation of the subfornical organ can elicit site-specific drinking behaviour and provide further support for the involvement of the subfornical organ in the control of drinking behaviour.

Animals↗
PubMed1995

Paraventricular nucleus neurons projecting to the spinal cord receive excitatory input from the subfornical organ.

The present study utilized electrophysiological techniques to determine the effects of subfornical organ (SFO) stimulation on the activity of neurons in the paraventricular nucleus (PVN) projecting to the spinal cord. Single-unit recordings were obtained from 79 PVN neurons antidromically identified as projecting to the intermediolateral cell column (IML). Antidromically evoked action potentials showed a mean latency of 94.6 +/- 5.3 ms and a mean threshold for activation of 1.58 +/- 0.11 mA. Electrical stimulation of SFO (100 microA-1.5 mA, 0.1 ms) resulted in excitatory responses in 18 of the 27 neurons tested (67%). Peristimulus histogram analysis of such effects demonstrated a duration of < 50 ms in 14 of the 18 cells so influenced (78%), whereas the remaining 4 cells (22%) showed excitatory responses with a longer duration. Systemic administration of the nonpeptidergic angiotensin II (ANG) type 1 (AT1) receptor antagonist losartan (3 mg/kg) blocked the long-duration excitatory responses in 100% (3 of 3) of the cells tested but was without effect on the short-duration excitations (0 of 5). Twenty-two identified PVN neurons were also tested for their responses to systemic ANG (20-500 ng), which had no observable effect on the activity of any of these cells. These data demonstrate that neurons in SFO provide excitatory input to PVN cells that project to the IML. One of the neurotransmitters responsible for communication in this pathway is ANG.

Angiotensin Receptor Antagonists↗
PubMed1995

Vasopressin actions on area postrema neurons in vitro.

The area postrema (AP) is a circumventricular organ located on the dorsal surface of the medulla. Substantial evidence suggests that the AP is an important site involved in cardiovascular regulation. Arginine vasopressin (AVP) is thought to act at the AP to increase the sensitivity of the baroreceptor reflex. We have therefore examined the effects of AVP on AP neurons with the use of extracellular single unit recordings in vitro. Coronal medullary brain slices (thickness = 400 microns) were obtained from male Sprague-Dawley rats and maintained in oxygenated artificial cerebrospinal fluid (aCSF). The slices were perfused with AVP (10(-8) to 10(-6) M), and the effect on single AP neurons was recorded. A total of 79 AP neurons was tested of which 50 (63.3%) were excited by AVP and 5 (6.3%) were inhibited, whereas the remaining 24 (30.3%) cells were unaffected. The excitatory effects of AVP were dose dependent: firing rate increased 92.6 +/- 25.8% at 10(-8) M, 289.4 +/- 53.9% at 10(-7) M, and 456.8 +/- 113.1% at 10(-6) M, respectively. We also examined whether these effects of AVP resulted from direct actions of this peptide on AP cells by testing if responses were retained during blockade of synaptic transmission (achieved by perfusion with a low Ca(2+)-high Mg2+ aCSF) in 11 cells excited by AVP. Nine of these cells were excited by AVP during such synaptic blockade. Finally, we demonstrated that the excitatory responses of five AP cells to AVP were all totally abolished by perfusion of slices with aCSF containing the V1 antagonist ([1-beta-mercapto-beta,beta-cyclopentamethylene propionic acid,2-(O-methyl)tyrosine]-Arg8-vasopressin; Peninsula Laboratories, 10(-6) M).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Modified cardiovascular sensitivity of the area postrema to vasopressin in spontaneously hypertensive rats.

Vasopressin has been shown to act at the area postrema to increase the sensitivity of the baroreceptor reflex. We have previously demonstrated that microinjection of vasopressin into the area postrema of Sprague-Dawley rats elicits pressor effects. We report here that vasopressin microinjection into the area postrema of spontaneously hypertensive rats is without effect on blood pressure, whereas microinjection into age-matched Wistar-Kyoto controls results in significant increases in blood pressure at 50 and 100 pg. These results suggest an altered sensitivity of the area postrema to vasopressin in this genetic model of hypertension.

Animals↗
PubMed1994

Angiotensin II neurotransmitter actions in paraventricular nucleus are potentiated by a nitric oxide synthase inhibitor.

There is increasing evidence that nitric oxide (NO) plays a role within the central nervous system as a novel messenger. Neuronal culture work suggests NO to be involved specifically in mediating actions of angiotensin II (ANG). The present study examined the potential role of NO within the paraventricular nucleus (PVN), a structure involved in mediating the cardiovascular changes initiated by activation of the subfornical organ (SFO). The pressor response to stimulation of SFO, which can be divided into a short (SD) and long duration (LD) component was enhanced following administration of an NO synthase inhibitor (L-NAME) (SD control: 101 +/- 4 vs. post L-NAME: 145 +/- 10 mmHg.s (P < 0.05); LD control: 387 +/- 167 vs. post L-NAME: 1737 +/- 617 mmHg.s (P < 0.05)). This effect was specific to activation of SFO efferents as the blood pressure responses to either, stimulation of PVN, or systemic administration of vasopressin were not potentiated by administration of L-NAME. These findings suggest that NO may be acting within PVN to inhibit further release of ANG, thereby attenuating the cardiovascular response to stimulation of SFO.

Amino Acid Oxidoreductases↗
PubMed1994

Circulating vasopressin influences area postrema neurons.

Extracellular single-unit recordings were obtained from 107 area postrema and 74 nucleus tractus solitarius neurons in sodium pentobarbital anaesthetized rats. Systemic administration of vasopressin (1-10 ng) decreased the firing frequency of 45.8% of area postrema neurons and 58.1% of nucleus tractus solitarius neurons tested while the firing frequency of 38.3% of area postrema neurons and 21.6% of nucleus tractus solitarius neurons was increased by this peptide. To determine whether these neurons were specifically influenced by vasopressin or the accompanying pressor response, the effects of alpha-adrenergic agonists on neuronal activity were also determined. Cells that responded similarly to vasopressin and the change in blood pressure elicited by alpha-adrenergic agonists were classified as "blood pressure-sensitive", whereas those neurons that responded differently to both agents were classified as "vasopressin-sensitive" neurons. The majority (85.2%) of area postrema cells that decreased firing frequency in response to vasopressin were determined to be "vasopressin-sensitive", while 68.8% of area postrema neurons responding to vasopressin with increases in firing frequency were classified as "blood pressure-sensitive". In contrast, 78.6% of nucleus tractus solitarius neurons that decreased firing frequency in response to vasopressin and 55.5% of those that increased firing frequency were classified as "blood pressure-sensitive" neurons. To determine whether the actions of vasopressin in the area postrema were mediated by V1 receptors the effect of vasopressin after V1 receptor blockade was examined in seven "vasopressin-sensitive" area postrema neurons. All seven neurons tested showed no response to vasopressin after such V1 receptor blockade. These data suggest that there exists a population of area postrema neurons specifically responsive to circulating vasopressin as a result of actions of this peptide at V1 receptors. They also implicate these neurons in the physiological mechanisms through which circulating vasopressin acts in the area postrema to influence baroreceptor reflex sensitivity.

Animals↗
PubMed1994

Cardiovascular and single-unit responses to subfornical organ stimulation are abolished by pentobarbital anesthesia.

The nature of reflex cardiovascular responses to electrical stimulation in the central nervous system has been suggested to be influenced by anesthetic. We report here that pressor responses to subfornical organ stimulation observed in urethane-anesthetized rats (n = 4) are absent, or reversed in animals under pentobarbital anesthesia (n = 5; Student's t test, p < 0.01, compared with urethane anesthesia. Single-unit recordings from identified hypothalamic neurons (n = 60) showed that the activation of these cells, by subfornical organ efferents, with systemic angiotensin observed in urethane-anesthetized animals (29 of 39 cells tested), was not observed under pentobarbital anesthesia (2 of 21 cells tested). Bicuculline treatment of pentobarbital-anesthetized rats (n = 5) restores small pressor responses to subfornical organ stimulation (t test, p < 0.05), suggesting that potentiated GABA inhibition underlies this modified state under pentobarbital anesthesia.

Angiotensin II↗
PubMed1994

Autonomic pathways in development of neural stimulation-induced gastric mucosal damage.

Gastric mucosal erosions can be induced by electrical stimulation of either vagus nerves (5 Hz, 5 V, 1 ms) or the paraventricular nucleus (PVN) of the hypothalamus (200 microA, 60 Hz, 100-microseconds pulse width). We have utilized various pharmacological and surgical interventions to determine the contributions of different components of the autonomic nervous system to the development of this neurally induced gastric damage in urethan-anesthetized Sprague-Dawley rats. In all experiments damage was assessed macroscopically and scored blindly on a 0 (normal) to 3 (severe) scale with samples sectioned for subsequent histological assessment of damage at the light microscopic level. Animals pretreated with either hexamethonium (30 mg/kg iv) or atropine (2 mg/kg iv) demonstrated reduced gastric damage scores after vagal stimulation compared with untreated control animals (P < 0.05). In contrast animals that underwent cervical cord transection exhibited gastric damage after both vagal and PVN stimulation that was not significantly different compared with animals with an intact cord undergoing similar stimulation (P > 0.05). Such cord transection itself did not cause any significant change to the gastric mucosa in the time period studied. These data emphasize the importance of the autonomic nervous system, in particular the parasympathetic component in the development of vagal stimulation-induced gastric damage. In addition, the present studies suggest that neither vagal nor PVN stimulation-induced gastric damage is dependent on neural projections to sympathetic preganglionic neurons of the intermediolateral cell column of the spinal cord.

Animals↗
PubMed1994

Nitric oxide actions in paraventricular nucleus: cardiovascular and neurochemical implications.

We have examined potential functions of nitric oxide (NO) within the paraventricular nucleus (PVN) in urethan-anesthetized male Sprague-Dawley rats. Initial experiments demonstrated microinjection of 50 pmol of the NO donor, sodium nitroprusside (SNP), directly into the PVN resulted in significant decreases in mean blood pressure (BP) (-3,312 +/- 1,189 mmHg/s over 300-s response time; P < 0.05). To determine whether such effects were attributable to SNP-induced NO release, NO was administered into PVN directly by bilateral microdialysis of NO-containing artificial cerebrospinal fluid (NO-aCSF), a process that results in delivery of approximately 50 pmol NO.PVN-1 x min-1. Such microdialysis resulted in significant decreases in BP (-5,121 +/- 817 mmHg/s over 1,200-s response time; P < 0.005), while aCSF microdialysis was without effect (1,298 +/- 1,071 mmHg/s over 1,200-s response time; P > 0.1). Amino acid concentrations were measured in dialysates collected during perfusion of the same PVN sites with either aCSF or NO-aCSF by high-performance liquid chromatography (HPLC) analysis. NO-aCSF induced significant increases in aspartate (aCSF 31 +/- 7 pmol/30 min; NO-aCSF 134 +/- 33 pmol/30 min; P < 0.05), glutamate (aCSF 36 +/- 5 pmol/30 min; NO-aCSF 417 +/- 108 pmol/30 min; P < 0.02), gamma-aminobutyric acid (aCSF 4.1 +/- 0.7 pmol/30 min; NO-aCSF 104 +/- 29 pmol/30 min; P < 0.02), and taurine (aCSF 34 +/- 3 pmol/30 min; NO-aCSF 117 +/- 24 pmol/30 min; P < 0.01) concentrations, while alanine, glutamine, and serine concentrations were unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1993

Angiotensin II responsiveness of rat paraventricular and subfornical organ neurons in vitro.

The responsiveness of neurons in the hypothalamic paraventricular nucleus to angiotensin II was investigated using extracellular single unit recording techniques in rat brain slices. Bath application of angiotensin II at a concentration of 3 x 10(-7) M for 2-5 min resulted in excitatory responses in 50.4% of 141 paraventricular cells tested. The mean increase in firing rate was 2.12 +/- 0.20 (mean +/- S.E.M.) spikes/s, which represents a mean increase in activity of 149.8 +/- 16.5%. Angiotensin II-sensitive neurons usually displayed irregular, phasic, or very slow spontaneous activity, with the majority of these neurons located in the magnocellular region. Under physiological blockade of synaptic transmission with low Ca2+/high Mg2+ medium, neuronal responses to this peptide remained in 12 (92.3%) of 13 cells tested. Application of three successive doses of angiotensin II ranging from 3 x 10(-9)-3 x 10(-7) M showed that neuronal responses were dose-dependent with an estimated threshold of 10(-8) M. In comparison with angiotensin III, angiotensin II not only stimulated more paraventricular cells, but usually induced larger excitatory responses. Angiotensin II subtype 1 receptor antagonist losartan completely blocked angiotensin II responsiveness in each of 14 paraventricular cells tested whereas PD 123319, an angiotensin II subtype 2 receptor antagonist, exhibited a partial inhibitory effect in about one half of another 13 cells. In addition, single unit in vitro subfornical organ recordings demonstrate that angiotensin II evokes greater excitatory responses than in the paraventricular nucleus and that these effects are abolished by losartan application. These results support the hypothesis that within both the paraventricular nucleus and subfornical organ angiotensin II is a bioactive peptide which modulates neuronal activity and thus may exert significant control over neuroendocrine and autonomic functions.

Action Potentials↗
PubMed1993

Functional evidence that the angiotensin antagonist losartan crosses the blood-brain barrier in the rat.

Losartan is a novel nonpeptidergic antagonist of angiotensin (ANG) II subtype 1 (AT1) receptors, which effectively lowers blood pressure in high-renin hypertensive rat and blocks the pressor response to systemic ANG II. It is well known that high densities of ANG II receptors exist in the hypothalamic paraventricular nucleus (PVN). In addition, activation of putative angiotensinergic afferents to the PVN originating in subfornical organ (SFO) elevates blood pressure and facilitates the activity of PVN neurons. We report here that systemic administration of losartan (3 mg/kg) significantly attenuates the pressor response to electrical stimulation of SFO. The excitatory responses of PVN neurons to SFO stimulation or local pressure microinjection of ANG II were also significantly inhibited in 58.8% and 88.9% of PVN cells, respectively, by intravenous administration of losartan. These pharmacological effects were rapid and reversible, and were accompanied by little change of basal arterial blood pressure or spontaneous neuronal activity. These observations suggest that systemic losartan crosses the blood-brain barrier (BBB) and acts at AT1 receptors within the PVN.

Afferent Pathways↗
PubMed1993

Subfornical organ efferents to paraventricular nucleus utilize angiotensin as a neurotransmitter.

In this study, we have utilized electrophysiological single unit recordings to evaluate the effects of nonpeptidergic angiotensin II (ANG II) antagonists on neural responses of hypothalamic paraventricular nucleus (PVN) neurons to either electrical stimulation in subfornical organ (SFO) or direct application of ANG II. Electrical stimulation (200-400 microA; 0.1 ms) in the SFO resulted in excitatory responses in 36 of 50 PVN neurons tested. Peristimulus histogram analysis of such excitatory effects demonstrated latencies of < 30 ms and variability of response times of approximately 50 ms in 14 of these 36 neurons. In view of previous anatomic and electrophysiological studies such inputs were therefore considered to be monosynaptically mediated by direct neural inputs from the SFO. The remaining 22 cells excited by such SFO stimulation showed responses of longer latency and duration suggestive of a different underlying synaptic mechanism. Local pressure ejection of ANG II into the PVN resulted in increased neural activity in 50% (9 of 18) of the neurons tested. After systemic (3 mg/kg iv) or local (2 x 10(-2) M; 1-25 s; 2-40 psi) microinjection of the nonpeptidergic angiotensin II1 (AT1) receptor antagonist losartan, SFO excitations were attenuated in 63.9% (23 of 36) of the PVN neurons tested, such pharmacologically blocked excitatory responses being reduced by 68.3 +/- 5.2% from control stimulation effects (P < 0.001). Similar losartan-induced attenuations of both short latency (presumed monosynaptic) (50.0%) and longer latency (72.7%) responses were observed. In addition, losartan also abolished the excitatory effects of local administration of ANG II on 77.8% (7 of 9) of ANG II-sensitive neurons in PVN tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1993

Cardiovascular consequences of microinjection of vasopressin and angiotensin II in the area postrema.

Microinjection of angiotensin II (ANG II) into the area postrema (AP) of urethan-anesthetized male Sprague-Dawley rats elicited statistically significant increases in mean arterial blood pressure at doses ranging from 10 pg to 500 ng (10 pg, mean +/- SE, 10.8 +/- 1.1 mmHg, P < 0.001; 250 ng, 15.2 +/- 2.6 mmHg, P < 0.001). Heart rate was also significantly increased at doses > 10 pg, although these increases were not dose dependent. Systemic administration of losartan (Dup-753), an AT1 antagonist, was able to significantly reduce the pressor response to 250 ng ANG (post-losartan: 81.9 +/- 9.5% reduction in blood pressure response, P < 0.0001), whereas PD123319, an AT2 antagonist, was without significant effect (P > 0.1). Microinjection of vasopressin (VP) (10 pg-500 ng) into the AP also resulted in statistically significant increases in blood pressure at doses ranging from 10 to 100 pg (10 pg, 7.0 +/- 1.5 mmHg, P < 0.05) and 100-500 ng (250 ng, 12.2 +/- 1.8 mmHg, P < 0.0001). Small but significant changes in heart rate were observed only at 100 pg and 100 ng. Systemic administration of a V1 antagonist significantly attenuated the increases in blood pressure in response to 50, 100, and 250 ng VP (250 ng, post-V1 antagonist: 66.4 +/- 8.6% reduction in blood pressure response, P < 0.001), whereas [desamino,D-Arg8]vasopressin (DDAVP), a V2 agonist, had a depressor effect when microinjected directly into the AP (250 ng, -9.9 +/- 1.6 mmHg, P < 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1992

Angiotensin II actions in paraventricular nucleus: functional evidence for neurotransmitter role in efferents originating in subfornical organ.

Angiotensin II (ANG) has been suggested to be the neurotransmitter utilised by subfornical organ (SFO) efferents projecting to the paraventricular nucleus (PVN). The PVN has been shown to be involved in mediating the cardiovascular response elicited by electrical stimulation of SFO. The possible role of ANG as a neurotransmitter in these pathways has been examined in the present study. The cardiovascular effects of ANG microinjection into the PVN were examined in urethane anaesthetized, male Sprague-Dawley rats. Microinjection of 20 ng or 50 ng ANG into PVN resulted in mean increases in blood pressure of 12.8 +/- 0.6 mmHg (P < 0.0005), and 16.2 +/- 1.4 mmHg (P < 0.0001) respectively, without effect on heart rate. These responses were significantly attenuated following systemic administration of losartan, an ANG type 1 receptor (AT1) antagonist (Control, +12.8 +/- 0.6 mmHg; post-losartan, +5.6 +/- 1.7 mmHg), but were unaffected by the AT2 receptor antagonist, PD123319 (Control, +10.8 +/- 1.6 mmHg; post-PD123319, +11.6 +/- 2.4 mmHg). Initial and later components of the biphasic pressor response elicited by electrical stimulation of SFO (200 microA, 10 Hz, 1 ms pulse width, 10 s) were also significantly attenuated by losartan, but unaffected by PD123319. The short latency increase in mean arterial pressure was 16.6 +/- 2.3 mmHg in comparison to a post-losartan increase of 9.3 +/- 1.6 mmHg (P < 0.001). Similarly, the secondary response consisted of a control increase of 9.6 +/- 1.3 mmHg and a post-losartan increase of 3.4 +/- 0.9 mmHg (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1992

Endothelin acts at the subfornical organ to influence the activity of putative vasopressin and oxytocin-secreting neurons.

Systemic endothelin-1 (ET-1) enhances the activity of subfornical organ (SFO) neurons with identified projections to the paraventricular nucleus of the hypothalamus (PVN). The present electrophysiological experiments were undertaken to examine the mechanisms through which systemic ET influences vasopressin secretion. Systemic ET-1 (50-100 pmol) was found to influence the excitability of antidromically identified vasopressin and oxytocin-secreting neurons in the PVN or supraoptic nucleus (SON) of urethane-anaesthetized rats. Long-term stable recordings from 95 antidromically identified neurons showed 56% of putative vasopressin- (n = 41), and 37% of putative oxytocin- (n = 54) secreting neurons were activated by ET-1. Such effects normally demonstrated a short latency (less than 10 s), with a duration ranging between 10 and 300 s. In contrast, unidentified neurons in the vicinity of PVN and SON (n = 27) were unaffected by ET-1. The inability of peptides to cross the normal blood-brain barrier suggested that such effects of ET-1 result from actions of this peptide at the SFO which lacks this barrier and sends efferent neural projections to both SON and PVN. This hypothesis was tested by obtaining similar recordings from animals in which this structure was destroyed prior to experimentation. In these studies recordings from 15 putative vasopressin- and 29 putative oxytocin-secreting neurons showed that only 7% and 14%, respectively, were excited by systemic ET-1 in lesioned animals. These data show that increases in circulating levels of ET have predominantly excitatory effects on vasopressin- and oxytocin-secreting neurons in SON and PVN. The modified responsiveness of these neurons to ET-1 in SFO-lesioned animals suggests this as a likely CNS site at which this peptide acts within the central nervous system to elicit such effects.

Animals↗
PubMed1992

Actions of endothelin at the subfornical organ.

Endothelin (ET), a potent vasoconstrictor peptide, is believed to have central sites of action and potential neurohormonal effects relating to body fluid homeostasis and blood-pressure regulation. Systemic endothelin binds to receptors at circumventricular organs and has been shown to increase plasma concentrations of vasopressin and increase the firing frequency of neurohypophysial vasopressin and oxytocin neurons. In the present study we have examined the effects of ET on blood-pressure following micro-injection into the subfornical organ (SFO). Micro-injection of 0.5 and 5.0 pmol of endothelin into SFO caused significant increases (10.1 +/- 1.1 and 10.2 +/- 2.1, respectively) in blood pressure, while lower doses were without effect. In addition, we have used single unit recording techniques to evaluate the effects of systemic ET on the activity of SFO neurons. Extracellular recordings from SFO neurons, antidromically identified as projecting to PVN, showed predominantly excitatory responses to systemic ET (21/35 cells). The data demonstrate that ET has excitatory actions on SFO neurons, and further raise the possibility that one of the functional consequences of such effects is an increase in arterial blood pressure.

Animals↗
PubMed1992

Central actions of angiotensin in cardiovascular control: multiple roles for a single peptide.

Angiotensin II (ANG II) acts peripherally as a hormone, with actions on the vasculature, adrenals, and kidney. In addition, certain actions of ANG II in the central nervous system are directed toward cardiovascular control and fluid volume homeostasis. Dense binding sites for ANG II are found at circumventricular organs, which apparently have the ability to relay information to cardiovascular centers via neural circuitry. Microinjection of ANG II into the subfornical organ (SFO) or area postrema (AP) produces site-specific increases in blood pressure. In addition, electrophysiological studies demonstrate profound effects of ANG II, acting at the SFO, on activity of neurohypophysial neurons and release of oxytocin and vasopressin, which can be antagonized by ANG II blockers or attenuated by SFO lesions. Evidence from microinjection, electrophysiological, and lesion studies indicate a complex interaction between central sites involved in mechanisms of cardiovascular control: the SFO, AP, organum vasculosum of the lamina terminalis, and paraventricular and supraoptic nuclei of the hypothalamus. Not only is ANG II a humoral messenger in this central scenario, but evidence suggests it acts as a neurotransmitter or neuroendocrine substance within specific CNS pathways, suggesting multiple roles for this peptide in central cardiovascular control.

Angiotensin II↗