In the vagally intact anaesthetised dog, we have investigated the role of nitric oxide (NO) on a normal sinus arrhythmia using an inhibitor of neuronally released NO, 1-(2-trifluoromethylphenyl) imidazole (TRIM). The mean and S.D. of the R-R interval was used to describe mean heart rate and heart rate variability, respectively. TRIM (0.8 mg I.C.) injected into the sinus node artery increased the mean heart rate slightly but reduced heart rate variability 3-fold from a control of 790 ± 124 ms (mean ± S.D.; n = 5) to 666 ± 36 ms (P < 0.01 Student's paired t test, n = 5). These results suggest that neuronally released NO may have a vagal facilitatory role in the maintenance of sinus arrhythmia in the normal heart. Experimental Physiology (2001) 86.5, 539-541.

The hypotensive and vasorelaxing peptides adrenomedullin (AM) and its gene-related peptide, proadrenomedullin N-terminal 20 peptide (PAMP), were found to be distributed on the surface of the colonic mucosa. AM and PAMP showed dose-dependent antimicrobial activity against E. coli. The results suggest that the novel vasoactive peptides AM and PAMP play an important role in mucosal defence. Experimental Physiology (2001) 86.5, 543-545.

The pathogenesis of chronic fatigue syndrome (CFS) remains unknown. Thresholds and latencies of motor evoked potentials (MEPs) in response to transcranial magnetic stimulation (TMS) are normal but intracortical inhibition has not been investigated. Eleven patients with CFS were compared with 11 control subjects. Each patient completed a questionnaire using visual analogue indices of pain, fatigue, anxiety and depression. Subjects released a button to initiate simple (SRTs) and choice reaction time (CRTs) tasks; for each task, movement times were measured between release of the initiation button and depression of a second button 15 cm away. Subjects held a 10 % maximum voluntary contraction in the thenar muscles of their dominant hand while TMS was applied to the motor cortex; the duration and extent of inhibition of surface electromyographic (EMG) activity were assessed at stimulus strengths above and below the threshold for MEPs. Patients had significantly (P < 0.05) higher mean indices of fatigue than of pain, anxiety or depression. Mean (± S.E.M.) SRTs (but not CRTs) were longer in patients (309 ± 45 ms) than in controls (218 ± 9 ms). Movement times were longer in patients for both SRTs and CRTs. TMS thresholds, expressed as a percentage of the maximum stimulator output, were not significantly (P > 0.05) different in both groups for both MEPs (patients, 34 ± 3 %; controls, 36 ± 3 %) and inhibition of voluntary contraction (patients, 29 ± 2 %; controls, 34 ± 4 %). The duration and extent of inhibition did not differ significantly between groups at any stimulus strength. The pattern of change in duration and extent of inhibition with increasing stimulus intensity was no different in the two groups. The duration and extent of corticospinal inhibition in patients with CFS did not differ from controls, adding further evidence to the notion that the feeling of fatigue and the slowness of movement seen in CFS is not manifest in corticospinal output pathways. Experimental Physiology (2001) 86.5, 547-550.

Muscle cells in the nematode Ascaris suum undergo bouts of oscillation in the behaving worm, these being correlated with progressing waves of contraction along the body of the worm. The bouts have three time scales: a rough period of 7-20 s, 10-20 short bursts of spikes within a bout, and three to eight spikes per burst. This paper has two aims: showing that there is consistency between measurements of individual currents and measurements on whole muscle cells, and creating a building block to eventually explain the locomotion in this 'simple' system. A realistic model for a single Ascaris suum muscle cell is developed using existing data from experiments which have established the types of ionic currents in the muscle cell and many of their kinetic properties. Numerical simulations are carried out. The model cell reproduces the two shorter time scales present. It has some robustness with regard to parameter changes, but also allows for the different numbers of spikes per burst seen in recordings from muscle cells. The third time scale, the length of a bout, may originate from some system effect, a combination of neural and stretch effects and possibly a secondary effect of the calcium-activated chloride channel. Experimental Physiology (2001) 86.5, 551-559.

The mechanisms which underlie the inotropic actions of phorbol dibutyrate (PDBu), a synthetic compound which can directly activate protein kinase C (PKC), were investigated in guinea-pig isolated ventricular myocytes. Exposure of cells to PDBu (10-7 M) reduced myocyte contraction amplitude to 46 ± 3 % of control (n = 8; P < 0.05) with an associated shortening in action potential duration (action potential duration at 90 % repolarisation (APD90) was reduced to 83 ± 1 % of control; P < 0.05). The negative inotropic actions of PDBu and the shortening in action potential duration were abolished in the presence of a selective PKC inhibitor, Ro31-8220. Calcium transients (constructed from calcium-activated tail currents following interruption of action potentials by voltage clamp to -70 mV) were reduced following exposure to 10-7 M PDBu by 38 ± 2 % (n = 9, P < 0.05). L-type calcium currents were not significantly altered following exposure to 10-7 M PDBu (98 ± 2 % of control; P > 0.05). In contrast, delayed rectifier potassium currents (IK) were enhanced to 154 ± 8 % of control (n = 7; P < 0.05) by 10-7 M PDBu. This enhancement of IK may contribute to the observed shortening in action potential duration observed following exposure to PDBu under the conditions of our experiments. When the action potential configuration was maintained throughout the experiment by applying a voltage-clamp waveform, 10-7 M PDBu still reduced contraction amplitude to 57 ± 3 % of control (P < 0.05). Exposure to 10-7 M PDBu also suppressed spontaneous activity (both spontaneous potential fluctuations induced by the β-adrenergic agonist isoprenaline (40 nM), and transient inward currents induced by the cardiac glycoside ouabain (1 µM) under voltage clamp). It therefore appears that the reduction in myocyte contraction amplitude induced by exposure to PDBu may result in part through mechanisms independent of action potential shortening, which may include direct actions of protein kinase C on the function of the sarcoplasmic reticulum (SR) calcium store and/or on contractile proteins (though action potential shortening would be expected to cause a further decrease as a consequence of reduced calcium loading of the SR). The reduction of spontaneous activity caused by PDBu may also result from changes in the function of the SR store mediated by protein kinase C. Experimental Physiology (2001) 86.5, 561-570.

We investigated the transport systems that can sustain Na+ and Cl- movements across bovine gall bladder epithelium, focusing on the Na+-H+ exchanger (NHE) family and chloride conductive pathways. Experiments conducted using the fluorescent probe acridine orange (AO) with brush-border membrane vesicles (BBMV) or vesicles obtained from the total epithelium (EMV) demonstrated the presence of a Na+-H+ exchange in both preparations. The use of specific inhibitors indicated the presence of an apical NHE3 exchanger and a NHE1 isoform which should reside in the basolateral membrane. Using reverse transcriptase (RT) PCR, we identified cDNA fragments corresponding to the NHE1, NHE3, Cl--HCO3- (AE2a) transporters and to the CFTR channel. Using the patch-clamp technique, we investigated Cl- conductances on cultured epithelial cells. We found a 5 pS Cl- channel with a voltage-independent open probability, insensitive to stilbenes (SITS), Zn2+ and cAMP. The results suggest that absorption and secretion coexist in calf gall bladder epithelium. A Na+-H+-Cl--HCO3- double exchange may, at least partially, sustain the absorptive function, and a Cl- apical conductive pathway may be involved in secretion. The conductance we observed does not seem to be cAMP-regulated, unlike other mammalian gall bladders. Experimental Physiology (2001) 86.5, 571-583.

The regulation of vascular tone includes modulation of contractile element calcium sensitivity. We tested the involvement of the Rho-associated protein kinase p160ROCK in tone and calcium sensitivity of cannulated rat mesenteric small arteries. These vessels developed basal tone and showed myogenic responses upon pressure steps, resulting from an increase in calcium in combination with a high contractile element calcium sensitivity. Y-27632, believed to be a specific p160ROCK inhibitor, caused concentration-dependent inhibition of basal tone, with near full inhibition at 3 µM. At this concentration, myogenic responses were absent and stepwise pressure elevation resulted in severe vascular distension. Y-27632 did not affect pressure-induced changes in intracellular calcium but rather reduced pressure-induced as well as phenylephrine-induced calcium sensitisation. Thus in the presence of the blocker, for a given calcium concentration, tone was greatly reduced, and the divergence in sensitivity between pressure and phenylephrine as stimuli on the one hand and potassium on the other disappeared. K+ (125 mM) and ionomycin still caused contraction in the presence of the p160ROCK blocker. These data show that in pressurised small arteries the Rho-p160ROCK pathway is active in the absence of vasoconstrictors, keeping the vessels in a state of high calcium sensitivity and basal tone. Experimental Physiology (2001) 86.5, 585-592.

Interstitial adenosine concentrations in red soleus (SL) or white extensor digitorum longus (EDL) muscles of anaesthetised rats were determined using microdialysis and HPLC. Systemic hypoxia was induced by ventilating the animals with 10 % oxygen in nitrogen for 15 min: arterial PO2 decreased from 111.8 ± 10.9 to 42.2 ± 4.3 mmHg (n = 4; P < 0.01) and mean systemic arterial blood pressure from 97.6 ± 4.9 to 59.0 ± 3.6 mmHg (n = 22; P < 0.001). The interstitial adenosine concentration was not significantly changed from its control values of 294 ± 44 nM (n = 20) in EDL and 302 ± 36 nM (n = 20) in SL during hypoxia or the recovery period. The interstitial lactate concentration did not change in the early part of the hypoxia but increased from 1.0 ± 0.2 to 1.4 ± 0.3 mM (n = 6; P < 0.05) in SL and from 2.0 ± 0.4 to 2.4 ± 0.4 mM (n = 6; P < 0.05) in EDL during the later part of the hypoxia, and remained elevated in the recovery period. Muscle contractions (2 Hz for 15 min) produced a transient increase in the interstitial adenosine concentration of SL from 150 ± 35 to 244 ± 75 nM (n = 10; P < 0.05) during the first 5 min of stimulation. In EDL the interstitial adenosine concentration increased from 145 ± 50 to 435 ± 144 nM (n = 10; P < 0.05) in the later part of the contraction and remained elevated in the early part of the recovery period. These data suggest that: (i) in systemic hypoxia adenosine does not appear in the interstitial space, which rules out its release from skeletal muscle, although it may be formed by the vascular tissues in this condition; (ii) adenosine is formed in the interstitial space of skeletal muscle during muscle contractions; (iii) there is slow clearance of adenosine from the interstitial space of white muscle, perhaps due to the low vascularity of the tissue. Experimental Physiology (2001) 86.5, 593-598.

This study investigated if prior eccentric contractions, and thus mechanical strain and muscle damage, exert an effect on the muscle membrane phospholipid fatty acid composition in rats, and whether a possible effect could be attenuated by dietary supplements. Twenty-three rats were randomised to three groups who received chow with added fish oil (n = 8), vitamin C (n = 8) or no supplement (n = 7). After 3 weeks of feeding, calf muscles on one side were stimulated electrically during anaesthesia causing eccentric contractions. Two days later the white gastrocnemius, a part of the stimulated calf muscle, was excised from both legs. In the muscles stimulated to contract eccentrically, compared to the control muscles, the proportion of arachidonic acid, C20:4,n-6 (17.7 ± 0.6; 16.4 ± 0.4 % of total fatty acids, respectively) and docosapentanoeic acid, C22:5,n-3 (2.9 ± 0.1 and 2.7 ± 0.1 % of total fatty acids, respectively) was uniformly higher across groups (P < 0.02) with no differences between diet groups. The proportion of long chain polyunsaturates was also significantly higher in the eccentrically contracted (39.9 ± 0.6 % of total fatty acids) compared to the control leg (38.2 ± 0.6 % of total fatty acids; P < 0.01). In contrast no differences were observed in the fatty acid composition of the triacylglycerols stored within the muscle. Thus one severe bout of eccentric contractions modulates the fatty acid composition of the muscle membrane phospholipids when compared to a control leg, and supplemental intake of fish oil or vitamin C did not attenuate this effect. Experimental Physiology (2001) 86.5, 599-604.

Normal rats or rats parasympathetically denervated on one side by cutting the auriculo-temporal nerve were maintained on a liquid diet for 1 week. After fasting overnight, experimental rats were then offered hard, pelleted food over a period of 2 h, while unfed animals served as controls. The reflex-induced increase in the [3H]leucine incorporation into trichloroacetic acid-insoluble material of the parotid glands following intake of the food in the presence of the muscarinic blocker atropine and α- and β-adrenoceptor antagonists was greater (104 %) than in the absence of the blockers (75 %) in normal rats. The picture was the same when the innervated glands of rats subjected to unilateral parasympathetic denervation were examined. In this case, the protein synthesis increased by 108 % in the presence of the blockers and by 63 % in their absence. Analysis of the parasympathetically denervated and contralateral innervated glands revealed no support for a cholinergic or adrenergic contribution to this response. The increase in protein synthesis in the innervated glands was 86 % in the rats treated with atropine, whilst it was 76 % in those treated with α- and β-adrenoceptor antagonists. The protein synthesis in the denervated glands increased by 57 % in the absence of receptor blockade. Neither atropine (51 %), nor a- and b-adrenoceptor antagonists (52 %), nor a combination of the three blockers (55 %) affected the response of the denervated glands. A large part of the response in the presence of the traditional autonomic receptor blockers was thus dependent on the parasympathetic auriculo-temporal nerve. Under natural feeding conditions, the parasympathetic non-adrenergic, non-cholinergic (NANC) mechanisms are likely to contribute to the synthesis of secretory proteins. Experimental Physiology (2001) 86.5, 605-610.

We showed recently that post-frusemide (furosemide) natriuresis was associated with a major depression of medullary circulation. In the present study, prior to administration of frusemide the tubular transport of NaCl was modified by loading the animals with 5 % saline to elucidate a possible interrelation between the tubular and vascular effects of the drug. Moreover, a possible involvement of the renin-angiotensin system was examined by pharmacological blockade using captopril, an inhibitor of angiotensin converting enzyme (1 mg kg-1, I.V.), or losartan, a selective inhibitor of angiotensin AT1 receptor (10 mg kg-1, I.V.). The effects of frusemide (0.25 mg kg-1 I.V., then the same dose given over 1 h) on renal medullary and cortical circulation (using laser-Doppler flowmetry) and renal excretion of sodium (UNaV), water and total solutes were measured in anaesthetised rats. With no pre-treatment, frusemide decreased the medullary flow (36.6 ± 6.0 %) significantly more than the cortical flow (10.1 ± 1.0 %; P < 0.001). The difference between the medulla and cortex was not significant in rats which showed high UNaV after hypertonic saline loading (2.0 ± 0.4 vs. 0.4 ± 0.1 µmol min-1 in non-loaded rats): 21.1 ± 3.9 % and 15.8 ± 1.5 %, respectively. At very high UNaV (9.5 ± 1.1 µmol min-1) the post-frusemide decrease in blood flow tended to be smaller in the medulla (7.6 ± 7.7 %) than in the cortex (16.2 ± 2.6 %). The fall in medullary blood flow was attenuated by pre-treatment with captopril (22.0 ± 3.3 %) and abolished by pre-treatment with losartan (2.8 ± 11.8 %). The decrease in cortical blood flow was not changed by hypertonic saline or angiotensin II blockers. The abolition of the post-frusemide depression of medullary blood flow by previous salt loading confirms the proposed link between tubular transport status and vasoconstriction. A similar modification of the response by blockade of the renin-angiotensin system suggests that the system is involved in the mechanism of medullary vasoconstriction. Experimental Physiology (2001) 86.5, 611-616.

The glucagon response to insulin-induced hypoglycaemia was tested in rats that had been pinealectomised (Px), pinealectomised and fitted with melatonin implants (Px + MLT), or sham-operated (SO). The glucagon response to hypoglycaemia observed in SO rats (216 ± 27 pg ml-1 at baseline versus 397 ± 35 pg ml-1 at the hypoglycaemic peak, mean ± S.D.) was stronger than that in Px rats (180 ± 37 pg ml-1 and 229 ± 21 pg ml-1, respectively) and weaker than that in Px + MLT rats (256 ± 19 pg ml-1 and 516 ± 11 pg ml-1, respectively). Our data indicate that the capacity to release glucagon during insulin-induced hypoglycaemia is altered in pinealectomised rats. Experimental Physiology (2001) 86.5, 617-620.

The involvement of angiotensin AT1 receptors in sodium appetite was studied in hypothyroid rats treated with the angiotensin II antagonist losartan. Losartan was administered chronically by the oral route or acutely by the subcutaneous route after water and sodium depletion or water, sodium and food deprivation. Three days after addition of losartan to the food at the dose of 1.0 mg g-1, the rats significantly reduced (P < 0.02) their spontaneous intake of 1.8 % NaCl. Increasing the dose of losartan to 2.0 and 4.0 mg g-1 did not reduce NaCl intake; in contrast, the intensity of the sodium appetite gradually returned to previous levels. The simultaneous administration of captopril, an angiotensin converting enzyme inhibitor, and losartan significantly increased (P < 0.05) NaCl intake and after captopril removal NaCl intake returned to the levels observed with losartan treatment alone. The administration of losartan 4 days after the beginning of captopril treatment significantly reduced (P < 0.0001) NaCl intake. Following acute administration of losartan, water- and sodium-depleted rats significantly reduced their NaCl and water intake (P < 0.001). The administration of losartan also induced a significant reduction in NaCl and water intake in water, NaCl and food-deprived rats (P < 0.0001 and P < 0.001, respectively). The present results show that chronic treatment with oral losartan inhibited spontaneous sodium appetite in hypothyroid rats. Continuation of treatment rendered rats resistant to the blockade of AT1 receptors. Water and sodium depletion and water, NaCl and food deprivation induced sodium appetite, which in the short term depends on cerebral angiotensinergic activity mediated by the activation of AT1 receptors. Experimental Physiology (2001) 86.5, 621-628.

Changes in the composition of fibre types and the capillary supply of skeletal muscle (tibialis anterior) were quantified in rats and hamsters subjected to 8-10 weeks of cold exposure and reduced photoperiod (10 °C, 1 h light-23 h dark). Muscle mass decreased in both species (by 12 % and 17 %, respectively). Following acclimation to cold there were no specific changes in fibre cross-sectional area (FCSA) in rats, whereas in hamsters there was a substantial atrophy of Type II, but not Type I fibres. In rat muscle there was little difference between the two groups in average capillary to fibre ratio (C:F) (1.76 ± 0.15, normothermia, N; 1.69 ± 0.05, hypothermia, H) and average capillary density (CD) (188 ± 14 mm-2, N; 201 ± 12 mm-2, H). Similarly, the average C:F was unaltered in hamsters (2.75 ± 0.11, N; 2.72 ± 0.15, H), although the 30 % smaller fibre size observed with hypothermia resulted in a corresponding increase in average CD, to 1539 ± 80 mm-2 (P < 0.01). However, there was a coordinated regional adaptation to cold exposure in hamsters resulting in capillary rarefaction in the glycolytic cortex and angiogenesis in the oxidative core. Following acclimation of rats to cold there was a reduction in the supply area of individual vessels (capillary domain), particularly in the cortex (9310, N; 8938 µm2, H; P < 0.05). In contrast, hypothermic hamsters showed only a small decrease in mean domain area in the cortex (948 µm2, N; 846 µm2, H; n.s.) but a marked reduction in the core (871 µm2, N; 604 µm2, H; P < 0.01). Rats showed little or no change in local capillary supply (LCFR) to fast fibres on acclimation to cold, while in hamsters the LCFR of Type IIb fibres showed a decrease in the cortex (2.7, N; 2.3, H) and an increase in the core (3.0, N; 3.3, H) during acclimation to cold. These data suggest that during a simulated onset of winter rats maintain FCSA and capillary supply as part of an avoidance strategy, whereas hamsters increase muscle capillarity in part as a consequence of disuse atrophy. Experimental Physiology (2001) 86.5, 629-639.

The effects of carbonic anhydrase inhibition on the responsiveness to CO2 of pressure-sensitive laryngeal receptors were examined in anaesthetised, paralysed cats. Laryngeal CO2-sensitive receptors from the superior laryngeal nerve were selected by their responsiveness to intralaryngeal pressure and to perfusion of solution equilibrated with 9 % CO2. The carbonic anhydrase inhibitor, methazolamide, when given intralaryngeally at 10-4 M, diminished or abolished the responses to the CO2-equilibrated solution in four of six pressure-sensitive receptors. Histochemical staining for carbonic anhydrase activity showed that the larynges perfused with methazolamide had diminished carbonic anhydrase activity, especially on the superficial layers of surface epithelium. Compared to untreated controls, when given intravenously (50 mg kg-1) methazolamide diminished or abolished the responses to CO2 of five of the six fibres studied. Histochemical staining of these larynges showed no carbonic anhydrase reactivity at the sites of laryngeal receptors. These results suggest that the responses to CO2 of laryngeal pressure-sensitive receptors are dependent on the presence of carbonic anhydrase. Inhibition of laryngeal receptor carbonic anhydrase activity by methazolamide is more reliably achieved by systemic rather than by luminal administration. Experimental Physiology (2001) 86.5, 641-649.

Abnormal loading and distension of the right ventricle may induce arrhythmia through the process of mechanoelectrical feedback. Nonetheless, the electrophysiological effects of right ventricular distension are ill-defined and the mechanisms which underpin mechanoelectrical feedback in the right ventricle are unknown. We examined the effects of changes in right ventricular load (complete occlusion of both caval veins or the main pulmonary artery) in 14 anaesthetised lambs, instrumented with right ventricular surface electrodes and strain gauges for recording monophasic action potential and segment length, and an integrated conductance and micromanometer-tipped catheter for measurement of right ventricular pressure and volume. Caval occlusion did not alter right ventricular segment length and monophasic action potential duration. By contrast, pulmonary arterial occlusion increased the segment length and decreased the monophasic action potential duration at 25, 50 and 70 % repolarisation by 29 ± 6, 22 ± 4 and 17 ± 3 ms, respectively (all P < 0.01). Of the 42 pulmonary arterial occlusions, 38 were associated with early afterdepolarisations (EADs) which increased progressively in magnitude as the occlusion was maintained until, in 32, overt arrhythmia was observed. By contrast, none of the four occlusions in which EADs were not observed resulted in arrhythmia. As a result, the proportion of occlusions which resulted in arrhythmia were greater in those associated with EADs than in those which were not (P = 0.002). Right ventricular distension alters the pattern of repolarisation, precipitates early afterdepolarisations and results in a variety of ventricular arrhythmia, including ventricular tachycardia. Experimental Physiology (2001) 86.5, 651-657.

We hypothesised that the observed acceleration in the kinetics of exercise on-transient oxygen uptake (V˙O2) of five older humans (77 ± 7 years (mean ± S.D.) following 9 weeks of single-leg endurance exercise training was due to adaptations at the level of the muscle cell. Prior to, and following training, subjects performed constant-load single-limb knee extension exercise. Following training V˙O2 kinetics (phase 2, τ) were accelerated in the trained leg (week 0, 92 ± 44 s; week 9, 48 ± 22 s) and unchanged in the untrained leg (week 0, 104 ± 43 s; week 9, 126 ± 35 s). The kinetics of mean blood velocity in the femoral artery were faster than the kinetics of V˙O2, but were unchanged in both the trained (week 0, 19 ± 10 s; week 9, 26 ± 11 s) and untrained leg (week 0, 20 ± 18 s; week 9, 18 ± 10 s). Maximal citrate synthase activity, measured from biopsies of the vastus lateralis muscle, increased (P < 0.05) in the trained leg (week 0, 6.7 ± 2.0 µmol (g wet wt)-1 min-1; week 9, 11.4 ± 3.6 µmol (g wet wt)-1 min-1) but was unchanged in the untrained leg (week 0, 5.9 ± 0.5 µmol (g wet wt)-1 min-1; week 9, 7.9 ± 1.9 µmol (g wet wt)-1 min-1). These data suggest that the acceleration of V˙O2 kinetics was due to an improved rate of O2 utilisation by the muscle, but was not a result of increased O2 delivery. Experimental Physiology (2001) 86.5, 659-665.

We compared estimates for the phase 2 time constant (τ) of oxygen uptake (V˙O2) during moderate- and heavy-intensity exercise, and the slow component of V˙O2 during heavy-intensity exercise using previously published exponential models. Estimates for τ and the slow component were different (P < 0.05) among models. For moderate-intensity exercise, a two-component exponential model, or a mono-exponential model fitted from 20 s to 3 min were best. For heavy-intensity exercise, a three-component model fitted throughout the entire 6 min bout of exercise, or a two-component model fitted from 20 s were best. When the time delays for the two- and three-component models were equal the best statistical fit was obtained; however, this model produced an inappropriately low ΔV˙O2/ΔWR (WR, work rate) for the projected phase 2 steady state, and the estimate of phase 2 τ was shortened compared with other models. The slow component was quantified as the difference between V˙O2 at end-exercise (6 min) and at 3 min (ΔV˙O2 (6-3 min); 259 ml min-1), and also using the phase 3 amplitude terms (truncated to end-exercise) from exponential fits (409-833 ml min-1). Onset of the slow component was identified by the phase 3 time delay parameter as being of delayed onset ~2 min (vs. arbitrary 3 min). Using this delay ΔV˙O2 (6-2 min) was ~400 ml min-1. Use of valid consistent methods to estimate τ and the slow component in exercise are needed to advance physiological understanding. Experimental Physiology (2001) 86.5, 667-676.

Orthostatic stress, including standing, head-up tilting and lower body suction, results in increases in peripheral vascular resistance but little or no change in mean arterial pressure. This study was undertaken to determine whether the sensitivity of the carotid baroreceptor reflex was enhanced during conditions of decreased venous return. We studied eight healthy subjects and determined responses of pulse interval (ECG) and forearm vascular resistance (mean finger blood pressure divided by Doppler estimate of brachial artery blood velocity) to graded increases and decreases in carotid transmural pressure, effected by a neck suction/pressure device. Responses were determined with and without the application of lower body negative pressure (LBNP) at -40 mmHg. Stimulus-response curves were determined as the responses to graded neck pressure changes and the differential of this provided estimates of reflex sensitivity. Changes in carotid transmural pressure caused graded changes in R-R interval and vascular resistance. The cardiac responses were unaffected by LBNP. Vascular resistance responses, however, were significantly enhanced during LBNP and the peak gain of the reflex was increased from 1.2 ± 0.3 (mean ± S.E.M.) to 2.2 ± 0.3 units (P < 0.05). The increased baroreflex gain may contribute to maintenance of blood pressure during orthostatic stress and limit the pressure decreases during prolonged periods of such stress. Experimental Physiology (2001) 86.5, 677-681.

The aim of this study was to test the hypothesis that Huntington's disease is associated with impaired phospholipid-related signal transduction using the niacin skin flush test. This is the first reported use of this test in this patient group. The response to topical aqueous methyl nicotinate solution was recorded at 5 min intervals over 20 min in six in-patients with advanced (stage III) Huntington's disease and in 14 age- and sex-matched normal individuals with no history of this or any other major neurological disorder. The volumetric niacin response (VNR) (mean ± S.E.M.) in the patients with Huntington's disease, 16.3 ± 2.6 mol s l-1, was significantly lower than the mean VNR of 28.3 ± 2.1 mol s l-1 in the control group (P = 0.004). These results are consistent with the conclusion that Huntington's disease may be associated with an abnormality of neuronal membrane fatty acid metabolism, possibly as a consequence of an as yet unidentified action of huntingtin. Experimental Physiology (2001) 86.5, 683-685.