In this investigation we have evaluated whether blockade of endothelin receptors influenced the renal haemodynamic and excretory responses to a period of ischaemia and reperfusion in the anaesthetised rat. The renal artery was occluded for 30 min and renal haemodynamic and excretory function followed for 90 min of reperfusion while either saline, the non-selective endothelin 1 receptor (ETA/ETB) antagonist SB209670 or the selective ETA receptor antagonist UK-350,926 was infused. In the post-ischaemic period, renal cortical and medullary perfusions were reduced by 40-50 %. When SB209670 was administered (30 µg kg-1 min-1 I.V.) for 30 min before, during and for 90 min after renal artery occlusion, cortical and medullary perfusions returned to baseline levels, responses different from those obtained during saline infusion (both P < 0.05). In the presence of UK-350,926 (30 µg kg-1 min-1 I.V.), perfusion in the medulla returned to baseline on clamp removal whereas that in the cortex remained depressed (P < 0.05). Renal ischaemia for 30 min decreased glomerular filtration rate during reperfusion and increased urine flow and sodium excretion 5- to 15-fold. UK-350,926 (30 µg kg-1 min-1 I.V.) reduced (P < 0.05) fluid excretion prior to ischaemia but during reperfusion, glomerular filtration rate returned to basal levels and there were progressive increases in fluid excretion which were smaller compared to the saline-treated group (all P < 0.05). The ischaemic challenge may cause release of endothelin, which acts on ETB receptors in the cortex and ETA receptors in the medulla to decrease perfusion. The blunted natriuresis and diuresis during blockade of ETA receptors may result from either a vascular or tubular action of endothelin. Experimental Physiology (2003) 88.4, 483-490.

Phasic changes in pressure have been reported to occur in the bladder which are not associated with micturition. Spontaneous intravesical pressure changes can be recorded from bladders in vitro or bladders in vivo isolated from the central nervous system suggesting that the bladder itself is capable of autonomous activity. Experiments using isolated cells and muscle strips indicate that the smooth muscle can generate spontaneous activity. Whether this is the origin of phasic changes in the intact organ remains unknown. The present study set out to establish the presence and characteristics of autonomous activity in the isolated guinea pig bladder. Multiple-point motion analysis and concurrent intravesical pressure recording were used to identify and quantify spontaneous and evoked activity. Highly complex autonomous activity was observed in unstimulated bladders. This activity comprised localised micro-contractions in single or multiple discrete regions, waves of activity and micro-stretches. Low-amplitude phasic 'micro-transients' were seen in the intravesical pressure trace in association with micro-contractions. Incremental increases in the intravesical volume recruited additional areas of activity. Atropine and tetrodotoxin had no effect on the micro-transients or micro-contractions. Exposure to the muscarinic agonist arecaidine (10-300 nM) initially increased the incidence of micro-contractions which subsequently became co-ordinated into phasic pressure rises and contraction waves, interspersed with periods of total quiescence. The findings describe the generation and co-ordination of autonomous activity in the bladder wall and also demonstrate complex phasic activity. This approach has shown the importance of assessing the integrative properties of the entire organ in studies of the physiology and patho-physiology of the bladder. Experimental Physiology (2003) 88.1, 19-30.

L-Arginine transport is mediated by the cationic/neutral amino acid transport system y+L and cationic amino acid transporters y+/CATs in human umbilical vein endothelial cells (HUVECs). System y+/CATs activity may be rate-limiting for nitric oxide (NO) synthesis, but no reports have demonstrated system y+L involvement in NO synthesis in endothelium. We investigated the role of system y+L in NO synthesis in HUVECs. Transport of 1.5 µM L-arginine was inhibited (P < 0.05) by L-lysine (Ki, 1.4 µM), L-leucine (Ki, 1.8 µM) and L-phenylalanine (Ki, 4.1 µM), but was unaltered (P > 0.05) by L-alanine or L-cysteine. The system y+/CATs inhibitor, N-ethylmaleimide (NEM), did not alter 1.5 µM L-arginine transport, but inhibited (92 ± 3 %) 100 µM L-arginine transport. L-Arginine transport in the presence of NEM was saturable (Vmax, 0.37 ± 0.02 pmol (µg protein)-1 min-1; Km, 1.5 ± 0.3 µM) and competitively inhibited by L-leucine in the presence of Na+ (Vmax, 0.49 ± 0.06 pmol (µg protein)-1 min-1; Km, 6.5 ± 0.9 µM). HUVECs express SLC3A2/4F2hc, SLC7A7/4F2-lc2 and SLC7A6/4F2-lc3 genes encoding for the high-affinity transport system y+L. NG-Nitro-L-arginine methyl ester and L-leucine, but not NEM, inhibited NO synthesis in medium containing 1.5 µM L-arginine. Cells exposed to 25 mM D-glucose (24 h) exhibited reduced system y+L activity (Vmax, 0.15 ± 0.008 pmol (µg protein)-1 min-1; Km, 1.4 ± 0.3 µM) and NO synthesis. However, 25 mM D-glucose increased NO synthesis and L-arginine transport via system y+. Thus, L-arginine transport through system y+L plays a role in NO synthesis, which could be a determining factor in pathological conditions where the endothelial L-arginine-NO pathway is altered, such as in diabetes mellitus. Experimental Physiology (2003) 88.6, 699-710.

In this study, we investigated the ability of acute infusions of isoprenaline to alter renin and angiotensinogen gene expression in the kidney of rats anaesthetised with chloralose-urethane. Groups of rats received I.V. infusions of either saline or the β-adrenoceptor agonist isoprenaline at 400 ng kg-1 min-1 for 4 h. The isoprenaline infusion caused a sustained decrease in mean blood pressure of approximately 20 mmHg (P < 0.01), an increase in heart rate of 50 beats min-1 (P < 0.01) and reductions in urine flow and sodium excretion of 80-90 % (both P < 0.01). Renal blood flow and glomerular filtration rate were transiently reduced by 21 % (P < 0.01) and 61 % (P < 0.001), respectively, in the first hour, recovering to baseline levels after 4 h of infusion. At the end of the study, plasma renin activity was raised approximately 6-fold (P < 0.01) while renal renin and angiotensinogen mRNA levels were 1.8- and 1.5-fold higher (both P < 0.05) compared to the control group (saline infusion). The isoprenaline-induced renin secretion could have been mediated via the activation of β-adrenoceptors resulting in the exocytosis of renin-containing granules, with a smaller contribution being due to reduced renal haemodynamics. The increase in renal renin gene expression in response to isoprenaline was probably due primarily to the intracellular signalling processes acting directly on nuclear mechanisms. Similarly, the increased renal angiotensinogen gene expression most probably reflected a direct action of the isoprenaline. These findings provide evidence that catecholamines are involved in mechanisms that rapidly alter the expression of the genes of the renin-angiotensin system within the kidney.Experimental Physiology (2003) 88.2, 221-227.

The fibre types that run in a vagal branch projecting to the rat heart are described in this study. In order to obtain spontaneous discharge in this vagal branch and optimal recording conditions, we compared the decerebrate state to urethane, urethane-chloralose and pentobarbital-chloralose anaesthesia with regard to level of chronotropic cardiac vagal tone. Administration of atropine (2 mg kg-1, I.V.) significantly decreased baseline cardiac interval only in the decerebrate and urethane-anaesthetised rat (by 0.018 ± 0.001 s and 0.019 ± 0.002 s, respectively). As a result of these experiments, urethane was chosen as the anaesthetic for all subsequent studies. Using a heart rate signal-averaging method we demonstrated that rat cardiac vagal preganglionic neurones innervating the sinoatrial node should have an expiratory discharge pattern, as reported in other species. However, only 5 % of chronotropic vagal tone was found to be subject to respiratory sinus arrhythmia. A suction microelectrode method, combined with spike-triggered averaging, was employed to record activity from a total of 58 vagal afferents that had axons in this branch. Approximately 75 % of these latter sensory fibres displayed cardiac rhythm. In a separate study we also recorded 318 preganglionic neurones with axons in the right cardiac vagal branch of the rat. Respiratory-modulated preganglionic units were statistically less common than tonically firing units. Six preganglionic subtypes were categorised according to conduction velocity and respiratory discharge pattern. Myelinated B-fibre and unmyelinated C-fibre types were found to be equally prevalent and equally likely to be reflexly excited during the pulmonary chemoreflex and the peripheral arterial chemoreflexes. The electrophysiological analysis has shown how diverse the discharge patterns of the preganglionic neurones or interneurones are whose axons course in the right cardiac vagal branch of the rat. The results of these experiments demonstrate the usefulness of combining spike discrimination with multiple spike-triggered averaging to simultaneously record B and C centrifugal vagal efferents. Experimental Physiology (2003) 88.6, 711-723.

We investigated how sympathetic nerve activity and vasoactive hormones interact in controlling renal haemodynamics in pentobarbitone-anaesthetized rabbits. Renal blood flow was progressively reduced by electrical stimulation (0.5-3 Hz) of the renal nerves, during renal arterial infusion of saline, vasoconstrictors (angiotensin II and [Phe2,Ile3,Orn8]-vasopressin), or vasodilators (acetylcholine, adrenomedullin and the nitric oxide donor methylamine hexamethylene NONOate (MAHMA NONOate). A frequency-rich stimulus was also applied to test whether the vasoactive agents affect the dynamic control of renal blood flow by sympathetic nerve activity. The vasodilators tended to increase renal blood flow, but only the effect of MAHMA NONOate was statistically significant. [Phe2,Ile3,Orn8]-vasopressin reduced medullary perfusion (by 61 ± 12 %) but not renal blood flow or cortical perfusion. Angiotensin II reduced renal blood flow (33 ± 3 %) and cortical perfusion (14 ± 5 %) but not medullary perfusion. Steady-state responses of renal blood flow and cortical perfusion during renal nerve stimulation were attenuated during infusion of acetylcholine and [Phe2,Ile3,Orn8]-vasopressin, while angiotensin II attenuated responses of medullary perfusion, and MAHMA NONOate and adrenomedullin had no significant effects. The dynamic response to sympathetic nerve activity (renal blood flow responded as a low pass filter with a pure time delay of ~664 ms) was not altered by the vasoactive agents. We conclude that some vasoactive agents can modulate steady-state renal haemodynamic responses to sympathetic nerve activity in a regionally specific manner, independent of their effects on baseline renovascular tone. However, they have little impact on the dynamic response of renal blood flow to sympathetic nerve activity. Experimental Physiology (2003) 88.2, 229-241.

The aim of this study was to determine the site within the brain at which inhibition of renal sympathetic nerve activity (RSNA) occurs following right atrial receptor stimulation. The atrial receptors were stimulated by inflating a balloon at the right vena cava-atrium junction and the reflex effect was observed before and during application of neurotransmitter agonists and antagonists into the paraventricular nucleus (PVN), or intrathecally to the spinal cord. Balloon inflation reduced RSNA by 29.1 ± 3 % without changing blood pressure in anaesthetised Wistar rats. Microinjection of the GABAA receptor antagonist bicuculline (0.025 mM, 100 nl) into the PVN increased RSNA by 42.3 ± 5 % and this was changed little by balloon inflation when PVN increased RSNA by 50.6 ± 6.3 %. Microinjection of the nitric oxide synthase (NOS) inhibitors L-NAME (0.1 mM, 100 nl) or L-NMMA (0.2 mM, 100 nl) into PVN elicited increases in RSNA of 36 ± 8 % or 54 ± 10 %, respectively. Balloon inflation during PVN stimulation plus NOS inhibition resulted in RSNA activity of 8 ± 4 % or -1 ± 1 %, respectively, compared to baseline control. Baseline RSNA was similar throughout this series of tests ranging from 9.1 ± 1.3 to 11.5 ± 1.1 spike counts s-1. To rule out the possibility that the atrial reflex inhibition was in part dependent on a dopamine-mediated PVN-spinal projection pathway inhibiting RSNA at a spinal locus, a dopamine D1 receptor antagonist SCH 23390 was intrathecally applied to the spinal cord. The effect of subsequent balloon inflation on RSNA was not significantly reduced. It was concluded that atrial receptor activation causes an inhibition of RSNA at the PVN and that this effect is mediated by GABA. Experimental Physiology (2003) 88.3, 335-342.

Although square-wave sustained and R wave-triggered pulsatile stimuli have been used to assess carotid baroreflex (CBR) function in humans, it remains unclear whether these different stimulus protocols elicit comparable responses and whether CBR responses adapt during prolonged stimulation. Thus, we measured muscle sympathetic nerve activity (MSNA), heart rate (HR) and mean arterial pressure (MAP) in response to +30 Torr neck pressure (NP) and -30 Torr neck suction (NS) delivered for 20 s either as a sustained or pulsatile stimulus. CBR-mediated changes in MSNA, HR and MAP were similar with sustained and pulsatile stimuli. The time course of MSNA and HR responses identified that significant changes occurred during the initial 5 s and were better maintained over 20 s with NP than with NS. Changes in MAP exhibited a slower onset with the peak increase during NP occurring at 10 s (sustained, 7 ± 1 mmHg; pulsatile, 7 ± 1 mmHg; P > 0.05) and the nadir during NS occurring at 20 s (sustained, -7 ± 1 mmHg; pulsatile, -9 ± 2 mmHg; P > 0.05). These data demonstrate that sustained and pulsatile NP and NS produce comparable CBR-mediated responses. Furthermore, despite MSNA and HR returning towards baseline during NS, CBR-mediated changes in MAP are well maintained over 20 s of NS and NP. Experimental Physiology (2003) 88.5, 595-601.

Biogenesis of mitochondria is happening constantly due to the physiological and developmental situation of a cell. As mitochondrial biogenesis is a complex process producing about 20 % of cellular protein, the expression of the 1000 genes involved is expected to be coordinated and regulated tightly. The variety of physiological stimuli and differentiation states lead to the idea of a complex network connecting many different regulatory pathways. By analysing nuclear encoded mitochondrial genes some of the factors involved in the regulation and coordination of mitochondrial gene expression were identified. These factors include general transcription factors such as Sp1 or YY1, as well as transcription factors specific for mitochondrial genes like the nuclear respiratory factors NRF1 and 2. An important control function linked to the physiological situation of a cell is triggered by hormones such as steroid and thyroid hormones. Even cell type-specific regulatory proteins like the myogenin transcription factor family have a strong influence on some mitochondrial genes in the specific cellular background. The regulatory function of most of these proteins can be modulated and enhanced by the coactivators PGC-1α and β and PRC. Although regulatory pathways have been characterized in more detail in recent years, no regulation mechanism has been shown to work on all analysed mitochondrial genes, and the general concept of mitochondrial regulation still remains unclear. Experimental Physiology (2003) 88.1, 33-40.

The exogenous application of GABA into the cisterna magna of the freely moving rat decreases hindquarters vascular tone as well as arterial pressure. GABA could influence GABA receptor subtypes A, B or C. However, the hindquarters vascular response to the stimulation of each receptor subtype has not yet been investigated. The present study therefore characterized the response to the GABAB receptor agonist baclofen injected into the cisterna magna of the conscious rat. Intracisternally injected baclofen induced long-lasting increases in hindquarters vascular resistance and arterial pressure in a dose-dependent manner. Both actions induced by baclofen were completely blocked by a prior intracisternal injection with the GABAB receptor antagonist CGP 35348 (p-[3-aminopropyl]-p-diethoxymethylphosphinic acid), and systemically by ganglionic blockade. These actions of baclofen were also abolished centrally by sodium pentobarbital anaesthesia. The results suggest that GABAB receptor stimulation via the cisterna magna induced hindquarters vasoconstriction, probably due to central disinhibition of sympathetic activity. Experimental Physiology (2003) 88.4, 491-496.

Spontaneous localised propagating waves of contraction and localised stretches have been reported to occur in the isolated whole bladder of the guinea pig. The physiological role and the cellular processes underlying these events are unknown. In order to gain insight into the mechanisms generating this complex activity, experiments were performed to examine and compare the responses of the whole bladder preparation to (i) the muscarinic agonists carbachol and arecaidine, (ii) the nicotinic ligand lobeline and (iii) nerve stimulation. High concentrations of the muscarinic agonists (>3 µM) induced a slow rise in intra-vesical pressure upon which were superimposed pressure transients, while low concentrations (< 300 nM) induced only phasic rises in pressure. One interpretation of these data is that there are two separate mechanisms activated by muscarinic agonists: one generating contracture and the other phasic activity. Immunocytochemical staining revealed M3 muscarinic receptors on smooth muscle cells within trabeculae and a second population of positive cells in the sub-urothelial layer. This observation raises the possibility that the actions of muscarinic agonists are a consequence of activating different cell types. Lobeline (1-60 µM) activated phasic contractions but did not cause a rise in basal pressure. Atropine did not inhibit the lobeline-induced responses but abolished the muscarinic responses. Also, hexamethonium or tetrodotoxin did not affect the lobeline-induced responses. These observations suggest that the mechanism generating phasic activity is activated by a nicotinic stimulus that does not involve ganglia, nerves or the neuromuscular junction. Stimulation of the bladder nerve at frequencies between 20 and 30 Hz for 5 s resulted in a rapid rise in intra-vesical pressure. Prolonged nerve stimulation (10-200 s) at frequencies between 1 and 10 Hz activated phasic rises in pressure. Low frequency nerve stimulation increased the frequency of agonist-induced phasic activity. Thus, nerve stimulation can also produce two forms of activity and low frequency stimulation can augment the processes generating phasic activity. These observations suggest that there are two distinct types of bladder activity: global contractions involving most of the bladder wall and phasic contractions comprising propagating waves of contraction. The mechanisms generating these contractile events appear to be different and they may involve cells located in different regions of the bladder. The nature of these mechanisms and their possible physiological significance is discussed. Experimental Physiology (2003) 88.3, 343-357.

For synaptic and cellular analyses of the mammalian respiratory network, intracellular recording and good pharmacological access to respiratory neurones is required. Using an existing arterially perfused in situ preparation of neonatal rat, we report on a method allowing stable intracellular recordings of ventrolateral medullary respiratory neurones. The in situ preparation generates a recognizable eupnoeic respiratory motor pattern similar to that reported in vivo. Using this preparation, we have developed a methodology for the use of patch pipettes to record from neurones within the ventral respiratory group. This technique in the arterially perfused neonatal rat is novel and has the advantage that neurones can be recorded from an intact and well-oxygenated brainstem in which the pontine regions are known to be viable. We describe the methods, present the first whole cell recordings of numerous types of respiratory neurones from neonatal rats in such a preparation, and demonstrate the applicability of the model for neuropharmacological experiments. Experimental Physiology (2003) 88.6, 725-732.

It has been reported that long-term selective inhibition of neuronal nitric oxide synthase (nNOS) produces elevated blood pressure (BP) in normal rats. The present study was designed to analyse the possible influences of the sodium-retaining hormone deoxycorticosterone acetate (DOCA) and of an increased sodium intake on BP effects induced by the chronic blockade of nNOS with 7-nitroindazole (7NI). Two experiments were performed using 7NI at a dose of either 10 mg kg-1 day-1 (experiment 1) or 30 mg kg-1 day-1 (experiment 2). The following groups were used in both experiments: control rats, and rats that received either 1 % saline drinking water (Salt), deoxycorticosterone acetate (DOCA), 7NI, 7NI plus 1 % saline (7NI + Salt) or 7NI plus DOCA (7NI + DOCA). The tail systolic BP (SBP) was measured in all rats once a week. At the end of the experimental period, the mean arterial pressure (MAP) and metabolic, morphological and renal variables were measured. There were no significant differences in the tail SBP, final MAP or glomerular filtration rate between the experimental groups and the control group. In both experiments, the plasma renin activity (PRA) was significantly inhibited in the Salt groups and suppressed in the DOCA groups. The PRA significantly increased in the 7NI groups, whereas the 7NI + Salt and 7NI + DOCA groups showed a significant inhibition in PRA, especially compared to the 7NI groups in the two experiments. We conclude that chronic nNOS blockade is unable to increase BP in normal, saline-drinking or DOCA-treated rats. Furthermore, the nNOS blockade does not interfere with the counterbalance between renin and an increased sodium intake or retention. Experimental Physiology (2003) 88.2, 243-250.

The aims of this study were: (1) to determine the within-subject, between-day variability in end-tidal PCO2 (PET,CO2); (2) to determine whether the within-subject, between-day variability in PET,CO2 was caused by variations in metabolic acid-base status; and (3) to determine whether between-subject variations in blood gas variables arose predominantly through variations in respiratory or renal pH control mechanisms. Fourteen healthy males were studied, of whom 12 provided adequate data for further analysis. Each subject was studied on at least six different occasions, with each visit separated by at least 1 week. On each occasion, PET,CO2 was determined over a 4-10 min period using a fine nasal catheter taped just inside the nose, and an arterialised capillary blood sample was obtained from each ear and analysed for blood gases. The following results were obtained. (1) PET,CO2 showed a standard deviation (S.D.) for the within-subject, between-day variation of 1.06 mmHg. (2) Less than 5 % (P = NS) of the variability in PET,CO2 could be explained by underlying variations in metabolic acid-base status. (3) The variation in blood gas values between individuals did not fit a pattern associated with either a predominantly respiratory or a predominantly renal origin. Furthermore, the pattern of variation in the blood gas data suggested that variations in the renal controller for pH and the respiratory controller for pH were not independent. The precise origins of variability in blood gas regulation remain obscure. Experimental Physiology (2003) 88.5, 603-610.

Comparisons were made between responses evoked by noradrenaline (NA) in iliac artery rings from normoxic (N) rats and chronically hypoxic (CH) rats kept in 12 % O2 for 3-4 weeks. At PO2 of 100 mmHg, cumulative concentration-response curves (CCRC) to NA were greatly depressed in endothelium-intact (E+) rings, but not endothelium-denuded (E-) rings, of CH rats relative to N rats. However, CCRCs evoked by NA in E+ and E- rings during nitric oxide (NO) synthase inhibition were similar in N and CH rats. Reducing PO2 to 55 mmHg depressed CCRCs to NA in E+ and E- rings of CH and N rats in the absence and presence of NO synthase inhibition. At PO2 of 100 mmHg, CCRCs evoked by phenylephrine were comparable in E+ and E- rings of N and CH rats as were CCRCs for the relaxation evoked by isoprenaline, which were similarly rightward shifted by NO synthase inhibition. However, CCRCs evoked by the NO donor sodium nitroprusside were leftward shifted in E- rings of CH rats relative to N rats. Further, in the presence of the α2 adrenoceptor inhibitor rauwolscine, CCRCs to NA were comparable in E+ rings of CH and N rats. Thus, the depressive effects of chronic hypoxia on NA-evoked contractions of iliac artery are additional to those of acute hypoxia. We propose that they reflect a facilitation of the contribution of NO to α2 adrenoceptor-evoked relaxation that includes an increased sensitivity of the vascular smooth muscle of arteries from CH rats to NO. Experimental Physiology (2003) 88.4, 497-507.

Mitochondria are subcellular organelles, devoted mainly to energy production in the form of ATP, that contain their own genetic system. Mitochondrial DNA codifies a small, but essential number of polypeptides of the oxidative phosphorylation system. The mammalian mitochondrial genome is an example of extreme economy showing a compact gene organization. The coding sequences for two ribosomal RNAs (rRNAs), 22 transfer RNAs (tRNAs) and 13 polypeptides are contiguous and without introns. The tRNAs are regularly interspersed between the rRNA and protein-coding genes, playing a crucial role in RNA maturation from the polycistronic transcripts. A single major non-coding region, called the D-loop region, contains the main regulatory sequences for transcription and replication initiation. This genetic organization has its precise correspondence in the mode of expression and distinctive structural features of the RNAs. The basic mechanisms of mitochondrial DNA transcription and replication and the main cis-acting elements playing a role in both processes have been determined. Many trans-acting factors involved in mitochondrial gene expression, including the RNA and DNA polymerases, have been cloned or identified. However, the regulatory mechanisms participating in mitochondrial gene expression are still poorly understood. The interest to complete this knowledge is increased by the involvement of mitochondria in human diseases, in basic processes such as heat production, Ca2+ homeostasis and apoptosis, and by their potential role in ageing and carcinogenesis. Experimental Physiology (2003) 88.1, 41-56.

The activation of cardiovascular reflexes for postural adaptation questions whether, in healthy humans, the central blood volume is optimised to support the upright position. A functional definition of an 'optimal circulating volume' that provides the heart with enough central blood volume to establish a maximal cardiac output (CO) and mixed venous oxygen saturation (Sv,O2) at rest was evaluated in nine healthy subjects. Preload to the heart was varied by passively changing the body position from 70 deg head-up to 20 deg head-down tilt. The Sv,O2 was compared with simultaneously measured estimates of CO by computer-controlled thermodilution. The CO was in the range 8.7-3.8 l min-1 and Sv,O2 was in the range 79-58 %. Neither CO (median 6.0 (range 5.3-8.7) l min-1) nor Sv,O2 (mean ± S.D. 73.6 ± 2.6 %) changed from the supine to the 20 deg head-down position. During sustained 70 deg head-up tilt, Sv,O2 decreased to 64 ± 4 % together with a decline in CO to 4.7 (3.9-5.6) l min-1 (P < 0.05). Under conditions of varying tilt angles, a change in CO is paralleled by concordant changes in Sv,O2. Maximal values for CO and Sv,O2 during supine rest suggest that the horizontal position provides for an 'optimal' central blood volume. Experimental Physiology (2003) 88.5, 611-616.

The aim of the present work was to investigate the role of the serotoninergic system in the control of sodium appetite of hypothyroid rats (HTR) by administering drugs that affect the serotoninergic activity, and to compare the same homeostatic behaviour in euthyroid rats (ETR) also given these drugs. Fenfluramine (FEN; 5.0 mg kg-1, I.P.), which releases serotonin in the brain, significantly reduced the intake of 1.8 % NaCl in HTR subjected to water and sodium depletion (depleted) or water, sodium and food deprivation (deprived) by 31 and 45 %, respectively, 120 min after FEN injection, compared to HTR that received vehicle alone. Similarly, administration of FEN to ETR reduced 1.8 % NaCl intake in depleted and deprived rats by 64 and 46 %, respectively. The presynaptic serotonin reuptake inhibitor fluoxetine (20.0 mg kg-1, I.P.) led to the inhibition of sodium appetite in HTR during the initial 30 min in depleted rats and for up to 60 min post-injection in deprived rats, while sodium appetite inhibition persisted for longer periods in ETR. The 5HT2C receptor agonist mCPP (5.0 mg kg-1, I.P.) caused a drastic reduction in sodium appetite in HTR and ETR in depleted and deprived rats, respectively, after 120 min. Prior administration of the 5HT2C receptor antagonist LY53857 (5.0 mg kg-1, I.P.) completely blocked the inhibitory action of mCPP on sodium appetite in both HTR and ETR. In summary, our results suggest that the recruitment of serotoninergic neurons involved in the modulation of sodium appetite seems to be decreased in hypothyroidism due to a probable deficiency in the cerebral signalling pathway. Experimental Physiology (2003) 88.2, 251-260.

Gastric distension in anaesthetized pigs reflexly elicits peripheral vasoconstriction and an increase in plasma renin activity (PRA), with vagal afferent and sympathetic efferent limbs. The aim of the present study was to quantify the contribution of the renin-angiotensin system to the peripheral vasoconstriction. In pigs anaesthetized with α-chloralose, changes in anterior descending coronary, superior mesenteric and left external iliac blood flow caused by stomach distension before and after blockade of angiotensin II receptors with losartan were assessed using electromagnetic flowmeters. Gastric distension for periods of 30 min was performed by injecting 0.8 l warm Ringer solution into balloons positioned within the viscus. Changes in heart rate and renal blood flow were prevented by atrial pacing and injection of phentolamine into the renal arteries, and changes in regional perfusion pressure and in baroreceptor activity were minimized by aortic constriction and denervation of the carotid sinuses. PRA was assessed by radioimmunoassay of angiotensin I. Before blockade of angiotensin II receptors by administration of losartan, stomach distension decreased coronary blood flow by 14.2 % in six pigs and mesenteric and iliac blood flow by 11 % and 17.3 %, respectively, in another six pigs. After administration of losartan, these decreases were significantly reduced to 7.4 %, 6.8 % and 8.7 %, respectively. The above responses were abolished by bilateral section of the subdiaphragmatic vagal nerves. These results show that the peripheral vasoconstriction reflexly caused by stomach distension was significantly contributed to by the concomitant activation of the renin-angiotensin system. Experimental Physiology (2003) 88.3, 359-367.

We evaluated the hypothesis that a 'central oxygen detector' in the brainstem is necessary for depressions of ventilatory activity to be manifested in the newborn. Decerebrate piglets, ventilated with 100 % O2, were studied following neuromuscular blockade. The vagi and carotid sinus nerves were sectioned bilaterally in order to remove the influence of the peripheral chemoreceptors. Activity of the phrenic nerve was recorded as the index of the central respiratory rhythm. This activity declined and, in some preparations, ceased upon ventilation with air or a hypoxic gas, at either normocapnia or hypercapnia. The degree of depression in hypercapnic hypoxia was greatest in the youngest piglets. Following a medial section of the brainstem, extending to the caudal pons, the depression was reduced. In some preparations, a similar reduction followed the placement of radiofrequency lesions in the caudal ventromedial pons. We conclude that a region of the caudal mesencephalon or pons is necessary for the manifestation of depressions of ventilatory activity in the newborn pig. Experimental Physiology (2003) 88.4, 509-515.