The effects of exercise training were investigated on the vascular responses in the isolated guinea-pig saphenous artery. Exercising animals swam 5 days week-1 for 6 weeks (60 min day-1 for weeks 1 and 2; 75 min day-1 for weeks 3 and 4; 90 min day-1 for weeks 5 and 6), while control animals were placed into shallow water for the same duration. Trained animals had significantly higher ventricular:body weight ratios, increased citrate synthase activity in the latissimus dorsi, and enhanced Na+ pump concentrations in the latissimus dorsi and gastrocnemius muscles (P < 0.05). In vitro isometric techniques were used to measure constriction and relaxation responses of saphenous artery rings from trained and control animals. There were no significant differences in the constriction responses to KCl (50 mm) and phenylephrine (0.3-100 µM) in arterial rings from control versus trained animals. Relaxation responses to acetylcholine (10 µM; ACh-relaxation), following preconstriction with phenylephrine (10 µM), were significantly enhanced in rings from trained animals (P < 0.05). Acetylcholine relaxed the vessels to 47 ± 6 % (control) and 18 ± 3 % (trained) of the preconstriction responses to phenylephrine. The nitric oxide synthase inhibitor N G-nitro-L-arginine (L-NA; 50 µM) significantly attenuated the ACh-relaxation in control and trained animals (P < 0.05). The effect of L-NA on the ACh-relaxation was significantly larger in trained (change in ACh-relaxation with L-NA = 29 ± 9 %) than control (14 ± 3 %) animals (P < 0.05). In conclusion, exercise training enhanced the ACh-relaxation of the isolated guinea-pig saphenous artery. Inhibition of nitric oxide synthase attenuated the ACh-relaxation of rings from control and trained animals, but this effect was significantly larger in the vessels from trained animals. These results are consistent with the idea that nitric oxide could contribute to the enhanced ACh-relaxation of the saphenous artery with exercise training.

There is a great need for closer integration between physiologists and molecular biologists. These two research fields might soon form a single research discipline under the umbrella of molecular physiology. One of the areas where this interaction may be particularly fruitful is with somatic gene transfer using replication-deficient viral vectors. We applied this approach to study the central control of the cardiovascular system at the level of the nucleus of the solitary tract (NTS). We assess critically this new methodology as applied to experiments in an integrative environment (such as the whole animal). The usefulness of in vivo gene transfer is illustrated by an experiment where viral gene delivery helped to circumvent the problem imposed by an absence of a specific pharmacological blocker of the enzyme, endothelial nitric oxide synthase (eNOS). The pros and cons of using adenoviral vectors as opposed to conventional pharmacological approaches are discussed. We conclude that the use of adenoviruses to manipulate genes offers a new avenue for physiologists studying neuronal mechanisms in integrative models.

This study examined the effect of pre-exercise carbohydrate (CHO) ingestion on pyruvate dehydrogenase complex (PDC) activation, acetyl group availability and substrate level phosphorylation (glycogenolysis and phosphocreatine (PCr) hydrolysis) in human skeletal muscle during the transition from rest to steady-state exercise. Seven male subjects performed two 10 min treadmill runs at 70 % maximum oxygen uptake (VO2,max), 1 week apart. Each subject ingested 8 ml (kg body mass (BM))-1 of either a placebo solution (CON trial) or a 5.5 % CHO solution (CHO trial) 10 min before each run. Muscle biopsy samples were obtained from the vastus lateralis at rest and immediately after each trial. Muscle PDC activity was higher at the end of exercise in the CHO trial compared with the CON trial (1.78 ± 0.18 and 1.27 ± 0.16 mmol min-1 (kg wet matter (WM))-1, respectively; P 0.05) and this was accompanied by lower acetylcarnitine (7.1 ± 1.2 and 9.1 ± 1.1 mmol kg-1 (dry matter (DM))-1 in CHO and CON, respectively; P 0.05) and citrate concentrations (0.73 ± 0.05 and 0.91 ± 0.10 mmol (kg DM)-1 in CHO and CON, respectively; P 0.05). No difference was observed between trials in the rates of muscle glycogen and PCr breakdown and lactate accumulation. This is the first study to demonstrate that CHO ingestion prior to exercise augments the exercise-induced activation of muscle PDC and reduces acetylcarnitine accumulation during the transition from rest to steady-state exercise. However, those changes did not affect the contribution of substrate level phosphorylation to ATP resynthesis. Experimental Physiology (2000) 85.5, 581-586.

A method of telemetric measurement of antroduodenal myoelectrical activity (EMG) in freely moving pigs has been developed. Silver bipolar electrodes were sutured on the antrum and duodenum and connected to a telemetry transmitter implanted extraperitoneally between the abdominal muscles. The EMG signals were collected by a receiver, filtered, amplified and archived by a computer. The telemetric EMG signal did not differ from that obtained with a conventional wire method. Substantial differences between day and night migrating myoelectric complex (MMC) patterns were found. The advantages of telemetric EMG recording make it a useful tool for long-term recording of antroduodenal EMG.

In the past several years, the progress in the development of molecular biology and the elucidation of gene sequences has created new approaches for studying biological functions and developing new diagnostic and therapeutic strategies. One of the most exciting advances has been the development of antisense technology, which represents a new strategy allowing modulation of protein synthesis with high specificity by preventing protein expression at the level of RNA or DNA. Many classical pharmacological approaches in neurobiological research are often based on the inhibition of biologically active proteins, such as receptors for neurotransmitters, or enzymes involved in neurotransmitter synthesis or degradation. The use of antisense oligodeoxynucleotides offers an alternative tool to manipulate selectively the expression of neurotransmitters or their receptors in neuronal tissue. This approach is especially useful when selective, high-affinity antagonists are not available. As a result, this technology has gained acceptance in the study of cell signalling mechanisms and the molecular basis of neuronal function. This paper provides a brief background to the antisense technique and explores methodological aspects, particularly in the whole animal. The use of the antisense technology in studies focused on central mechanisms regulating the cardiovascular system is then discussed.

We report the first simultaneous measurements of pHi, [Ca2+]i and tension, upon alteration of pHi, in isolated rat mesenteric arteries loaded with both carboxy SNARF and indo-1. In these vessels (pre-contracted by 30 mM KCl) alterations of pHi, by addition and subsequent washout of weak bases, produced complicated effects on tone. Although the changes in contractility did not mirror the changes in pHi they were, at all times, accompanied by parallel changes in [Ca2+]i. Experimental Physiology (2000) 85.3, 349-351.

We recently reported that a higher percentage of type I fibres in vastus lateralis and a greater peak oxygen uptake ([Vdot]O2) were associated with a greater initial rise in [Vdot]O2 (Δ[Vdot]O2 /ΔW, where W is work rate) following the onset of heavy constant power output exercise (above the lactate threshold, LT). It was unclear if these results were true only for heavy exercise, or if the association between fibre type and/or fitness and Δ[Vdot]O2 /ΔW would also be seen for moderate (< LT) exercise. The purpose of the present study was to compare the relationships between fibre type or peak [Vdot]O2 and Δ[Vdot]O2 /ΔW determined for moderate (< LT) and heavy (> LT) exercise intensities during incremental exercise. Nine healthy subjects performed an incremental ramp test on a cycle ergometer. The [Vdot]O2 /Wslope was calculated for the domain of power outputs up to the LT (S1), from the LT towards peak [Vdot]O2 (S2), and over the entire linear portion of the Δ[Vdot]O2 /ΔW response (ST), and compared to fibre type distribution determined from biopsy of the vastus lateralis, and to peak [Vdot]O2 (as ml kg-1 min-1). Significant correlations between Δ[Vdot]O2 /ΔW and the proportion of type I fibres were found for each exercise domain (r is 0.69, 0.71 and 0.84 for S1, S2 and ST, respectively, P < 0.05). S1 ranged between about 9 ml min-1 W-1 for a low proportion of type I fibres and 11 ml min-1 W-1 for a high proportion of type I fibres. Similar correlations were also found between S2 (r = 0.70) and ST (r = 0.76) and peak [Vdot]O2. These results are consistent with our previous findings during > LT constant power output exercise, and suggest that the proportion of type I fibres, and possibly fitness as indicated by peak [Vdot]O2, is associated with greater Δ[Vdot]O2 /ΔW during the initial adjustment to < LT as well as > LT exercise. These results do not appear to be explained by classical descriptions of the kinetics of adjustment of [Vdot]O2 following the onset of ramp or constant power output exercise. They might reflect enhanced motor unit recruitment in subjects with a greater percentage of type I fibres, and/or who are more aerobically fit. However, the underlying mechanism for these findings must await further study.

Altering [K+]o might have different effects on action potential duration (APD) in myocytes from different regions. Therefore, the effects of [K+]o on regional differences in action potential characteristics were investigated in sub-endocardial, mid-myocardial and sub-epicardial myocytes isolated from the base of guinea-pig left ventricular free wall using three different [K+]o (2.7, 5.4 and 8.1 mM KCl). Action potentials were recorded using the switch-clamp technique at 0.5 Hz. Increasing [K+]o from 2.7 to 8.1 mM shortened the action potential duration to 90 % repolarization (APD90; mean APD90 values in sub-endocardial, mid-myocardial and sub-epicardial myocytes were, respectively, 295 +- 9, 286 +- 9 and 266 +- 8 ms in 2.7 mM [K+]o, 270 +- 7, 255 +- 7 and 215 +- 7 ms in 5.4 mM [K+]o, 234 +- 7, 212 +- 10 and 155 +- 8 ms in 8.1 mM [K+]o), depolarized the resting potential, and reduced the amplitude of the action potential. The effect of increasing [K+]o on action potential characteristics was more pronounced in sub-epicardial myocytes than in sub-endocardial and mid-myocardial myocytes. The regional differences in APD90 in 5.4 mM [K+]o were increased in 8.1 mM [K+]o and abolished in 2.7 mM [K+]o. In conclusion, changing [K+]o produces more pronounced effects on action potentials in sub-epicardial myocytes than in sub-endocardial myocytes, modifying the normal heterogeneity of action potentials. The differences in the response of sub-epicardium and sub-endocardium to [K+]o may contribute to the flattening or inversion of the T wave commonly seen in patients presenting with hypokalaemia and the upright and tall T waves observed in electrocardiograms recorded during hyperkalaemia, although the underlying ionic currents remain to be determined.

The effect of different pedalling rates (40, 60, 80, 100 and 120 rev min-1) on power generating capability, oxygen uptake ([Vdot]O2) and blood lactate concentration [La]b during incremental tests was studied in seven subjects. No significant differences in [Vdot]O2,max were found (mean ± S.D., 5.31 ± 0.13 l min-1). The final external power output delivered to the ergometer during incremental tests (PI,max) was not significantly different when cycling at 60, 80 or 100 rev min-1 (366 ± 5 W). A significant decrease in PI,max of ∼60 W was observed at 40 and 120 rev min-1 compared with 60 and 100 rev min-1, respectively (P < 0.01). At 120 rev min-1 there was also a pronounced upward shift of the [Vdot]O2-power output ([Vdot]O2-P) relationship. At 50 W δ[Vdot]O2 between 80 and 100 rev min-1 amounted to +0.43 l min-1 but to +0.87 l min-1 between 100 and 120 rev min-1. The power output corresponding to 2 and 4 mmol l-1 blood lactate concentration (P[La]2 and P[La]4 ) was also significantly lower (> 50 W) at 120 rev min-1 (P < 0.01) while pedalling at 40, 60, 80 and 100 rev min-1 showed no significant difference. The maximal peak power output (PM,max) during 10 s sprints increased with pedalling rate up to 100 rev min-1. Our study indicates that with increasing pedalling rate the reserves in power generating capability increase, as illustrated by the PI,max/PM,max ratio (54.8, 44.8, 38.1, 34.6, 29.2 %), the P[La]4/PM,max ratio (50.4, 38.9, 31.0, 27.7, 22.9 %) and the P[La]2/PM,max ratio (42.8, 33.5, 25.6, 23.1, 15.6 %) increases. Taking into consideration the [Vdot]O2,max, the PI,max and the reserve in power generating capability we concluded that choosing a high pedalling rate when performing high intensity cycling exercise may be beneficial since it provides greater reserve in power generating capability and this may be advantageous to the muscle in terms of resisting fatigue. However, beyond 100 rev min-1 there is a decrease in external power that can be delivered for an given [Vdot]O2 with an associated earlier onset of metabolic acidosis and clearly this will be disadvantageous for sustained high intensity exercise.

This study was performed to compare glucose metabolism in anaesthetised spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) in an attempt to clarify whether this animal model of hypertension approximates the insulin-resistant state seen in human hypertension. With this aim the minimal model of glucose kinetics was applied to glucose and insulin data derived from a 12-sample, 120 min intravenous glucose tolerance test (IVGTT) performed in ten SHR and nine WKY rats under pentobarbital anaesthesia. This method provided two metabolic indices: the glucose effectiveness, SG, which quantifies the ability of glucose per se to enhance its rate of disappearance and to inhibit hepatic glucose production, and the insulin sensitivity, SI, which measures the ability of insulin to enhance plasma glucose disappearance and to inhibit hepatic glucose production. Systolic and diastolic arterial pressures in the SHR group were significantly higher (P < 0.0005) than in the WKY group. Mean SG and SI estimates from the SHR group (SG = 16.2 (± 2.0) × 10-2 dl min-1 kg-1 and SI = 12.5 (± 1.9) × 10-4 dl min-1 kg-1 (µU ml-1)-1) were not significantly different (P > 0.05) from mean estimates that characterised the WKY group (SG = 13.1 (± 1.5) × 10-2 dl min-1 kg-1 and SI = 15.8 (± 4.3) × 10-4 dl min-1 kg-1 (µU ml-1)-1). This result is in contrast with reported findings from humans in which insulin sensitivity is significantly reduced in the presence of hypertension.

In addition to its known effect on renal tubular transport, frusemide (furosemide) has been shown to affect renal circulation. This study in the anaesthetised rat examined the influence of frusemide (bolus 0.25 or 0.5 mg kg-1 I.V., then infusion delivering the same dose over 1 h) on renal cortical and medullary circulation measured as laser-Doppler blood (cell) flux. The responses were compared with simultaneously measured changes in renal excretion and in the tissue admittance, an index of medullary ionic hypertonicity of the interstitium. Renal vascular responses to frusemide were significant but not dose dependent. During low-dose frusemide infusion cortical flux decreased 11.5 ± 0.9 % and medullary flux decreased 32.3 ± 3.5 % (difference significant at P < 0.001). During high-dose infusion the decreases were by 13.5 ± 1.4 and 29.3 ± 3.8 %, respectively (difference significant at P < 0.001). Sodium excretion increased 15-fold (by 3.7 ± 0.4 µmol min-1) and 30-fold (by 5.9 ± 1.1 µmol min-1) during low- and high-rate infusion of frusemide, respectively. By contrast, medullary tissue admittance decreased similarly with the two doses: maximally by 13.4 ± 1.4 and 10.9 ± 0.9 %, respectively. The observations that an exaggerated post-frusemide decrease in blood flow within the medulla coincided with decreasing tissue admittance in this zone and that neither medullary blood flow nor admittance changes were related to the dose suggest a causal relationship between interstitial ionic hypertonicity and vascular resistance. We propose that the post-frusemide decrease in medullary tissue NaCl depressed medullary circulation by inhibiting local generation of vasodilator prostaglandins.

The effects of nitric oxide synthase (NOS) inhibition (effected using L-NAME, 14 mg (kg body mass (BM))-1, administered intravenously) on systemic and renal circulation and renal excretory function has been investigated in anaesthetized Wistar rats subjected to one of two different degrees of isotonic extracellular (EC) volume expansion (40 and 60 ml kg-1 (240 min)-1). The administration of L-NAME resulted in an increase in mean arterial blood pressure and total peripheral vascular resistance (TPR), and a significant reduction in cardiac output (CO) and the kidney fraction of CO in both experimental groups. The total renal blood flow (RBF) dropped from 557 ± 43.4 to 149 ± 13.1 ml min-1 (100 g BM)-1 and from 592 ± 45.9 to 191 ± 16.3 ml min-1 (100 g BM)-1 in the 40 and 60 ml kg-1 (240 min)-1 experimental volume expansion groups, respectively. A redistribution of the intrarenal circulation from the medulla of the kidney toward the cortex may have occurred. The NOS inhibition induced a significant decrease in the glomerular filtration rate (GFR; from 1.18 ± 0.10 to 0.53 ± 0.08 ml min-1 (100 g BM)-1 and from 1.26 ± 0.07 to 0.73 ± 0.08 ml min-1 (100 g BM)-1 in the 40 and 60 ml kg-1 (240 min)-1 experimental volume expansion groups, respectively), and the filtration fraction increased. The urine excretion dropped in parallel with the GFR, while the reduction in sodium and potassium excretion was more marked than that of the GFR, raising the possibility of a direct effect on the kidney tubules. The difference in EC volume expansion (the calculated increases in the EC volume in the last 90 min were 1.30 and 5.44 % in the two time control groups and 3.66 and 7.45 % in the two L-NAME-treated groups) did not induce any significant modification of the L-NAME effect.

It is generally accepted that pheromones act by stimulating of the dendritic receptors of the olfactory neurones massed in the olfactory epithelium. This study was designed to ascertain whether it is possible for the boar pheromone androstenol (5alpha-androst-16-en-3-ol) to be transported from the nasal cavity of anaesthetized gilts to the brain and hypophysis via local transfer from the blood in the perihypophyseal vascular complex. The experiment was performed on days 18-21 of the porcine oestrous cycle (crossbred gilts, n = 6). Tritiated androstenol (3H-A; total amount 108 d.p.m. (758 ng)) was applied for 1 min onto the respiratory part of the nasal mucosa, 4-6 cm from the opening of the nares. Arterial blood samples from the aorta and from the carotid rete were collected every 2 min during the 60 min period following administration of the steroid. Total radioactive venous effluent from the head was removed and an adequate volume of homologous blood was transfused into the heart through the carotid external vein. At the end of the experiment gilts were killed and tissue samples of the hypophysis and some brain structures were collected to measure radioactivity. In addition, corresponding control tissues were collected from three untreated gilts and from three heads of gilts 60 min after 3H-A was applied post mortem into the nasal cavity. The concentration of 3H-A was significantly higher (P < 0.0001) in the arterial blood of the carotid rete than that of aorta. The mean rate of 3H-A counter current transfer from venous to arterial blood in the perihypophyseal vascular complex, expressed as the ratio of the 3H-A concentration in arterial blood of the carotid rete to the 3H-A concentration in blood sampled simultaneously from the aorta, was 1.96 ± 0.1. The concentration of 3H-A in plasma from the venous effluent from the head ranged from 1.3 to 1.8 pg ml-1. During the 60 min period of the experiment, 0.68 % of the total applied dose of 3H-A was resorbed from the nasal cavity into the venous blood. Moreover, we found that 3H-A was present in the olfactory bulb (P < 0.01), amygdala, septum, hypothalamus, adenohypophysis, neurohypophysis (P > 0.05) and perihypophyseal vascular complex (P < 0.01). These results demonstrate that, in anaesthetized gilts, the boar pheromone androstenol may be resorbed from the nasal mucosa, transferred in the perihypophyseal vascular complex into arterial blood supplying the brain and hypophysis, and then arrested in the hypophysis and certain brain structures. We suggest that in addition to the standard neural pathway for signalling pheromones, another pathway exists whereby androstenol, as a priming pheromone, may be resorbed from the nasal cavity into the bloodstream and then pass locally from the perihypophyseal vascular complex into the arterial blood supplying the brain and hypophysis, thus avoiding the first passage metabolism in the liver.

The present study was designed to test the hypothesis that the high renal vascular resistance characteristic of the newborn results from age-dependent changes in the responsiveness of the renal vasculature to kinins. Two studies were carried out in conscious, chronically instrumented lambs aged 1 and 6 weeks. Firstly, we measured the renal blood flow response to intra-arterial injection of the B2 receptor agonist bradykinin over the range of doses 0-800 ng kg-1. The ED50 renal blood flow response to bradykinin was 50 ng kg-1 in both age groups of lambs. Secondly, we measured the effects of intravenous administration of 12.5 µg kg-1 of the specific B2 receptor antagonist HOE 140; this dose attenuated the renal blood flow response to 50 ng kg-1 of bradykinin in both age groups. HOE 140 administration was associated with an age-dependent increase in mean arterial pressure, with little effect on heart rate or renal vascular resistance. This study provides new information regarding the effects of kinins in modulating renal haemodynamics during postnatal maturation. We reject our hypothesis and conclude that the high renal vascular resistance of the newborn does not appear to result from age-dependent changes in the responsiveness of the renal vasculature to endogenous kinins.

One or more episodes of sublethal ischaemia and reperfusion delay infarct development during subsequent, sustained ischaemia in the heart and skeletal muscle. The present study tested whether or not such ischaemic preconditioning (IP) also protects the kidney. Enflurane-anaesthetized pigs underwent 60 min of right renal vessel occlusion (RVO), followed by 8 h of reperfusion without (placebo group, n = 8) or with three preceding cycles of 10 min RVO and 10 min reperfusion (IP group, n = 8). After 8 h of reperfusion, kidneys were oliguric in both groups (placebo group: 23 ± 21 ml h-1, IP group: 24 ± 27 ml h-1). A transient polyuric phase occurred in the IP group at 2 h reperfusion. The reperfused kidneys did not excrete inulin, creatinine or urea in both groups, although renal blood flow during reperfusion was similar to baseline. Morphological damage ranged in both groups from single cell necrosis to disseminated patchy necrosis; the number of pyknotic cells tended to be higher in the IP group than in the placebo group (27.0 ± 7.1 vs. 15.6 ± 5.6 %, n.s.). In anaesthetized pigs, IP did not therefore attenuate renal dysfunction and morphological damage resulting from 60 min of renal normothermic ischaemia followed by 8 h of reperfusion.

In order to describe the factors which, during hyperoxic exercise, can counteract the chemoreceptor-mediated inhibition of ventilation by O2, minute ventilation (VE) and the pulmonary gas exchange were studied breath-by-breath in four dogs running on a treadmill (5 km h-1) for 10 min during and following exposure to O2 of different durations. We found that a brief inhalation of O2 applied during the steady state of the VE response provoked a reduction in VE by 6.5 ± 0.9 l min-1 whereas hyperoxia applied 2 min before the onset of exercise and maintained for 2.5 min during the running tests had a significantly weaker effect on VE (-1.8 ± 0.2 l min-1, P < 0.05). The rise in pulmonary CO2 output (VCO2) during the prolonged O2 exposure was less than in normoxic exercise leading to a deficit of CO2 eliminated by the lungs of 181 ml. The return to air breathing provoked a rise in VE, which reached within 73 s a much higher level than the control tests (22.9 ± 3.6 vs. 19.5 ± 2.2 l min-1, P < 0.05); VE then subsided to control levels with a long exponential decline. The CO2 deficit during O2 breathing, was fully compensated after recovery in air within 6 min. No stimulatory effect on ventilation was observed at rest at the cessation of a similar exposure to O2 despite a higher end-tidal PCO2 (+4 ± 1 mmHg) than in exercise. In conclusion, the stimulatory effect of O2 during exercise can be clearly revealed after recovery in air and seems to operate through a more complex mechanism than that thought to be involved at rest. We propose that the changes in CO2 stores in the exercising muscles could contribute to O2-induced stimulation during exercise, possibly through stimulation of muscle afferents responding to local circulatory changes. Finally, the observation that during continuous dopamine (DA) infusion (5 µg kg-1 min-1) the VE response to recovery in air was only a slow decrease, suggests that the arterial chemoreceptors potentiate O2-induced hyperventilation, or that the vascular actions of DA counteract part of the effects provoked by CO2 accumulation in the exercising muscles.

We have investigated the mediators and mechanisms underlying the vasodilator effects of the potent vasoactive peptide, endothelin-1 (ET-1) and its isomers ET-2 and ET-3 in human skin, in vivo, using cutaneous microdialysis to quantify the release of mediators within the dermal response and scanning laser Doppler imaging to measure changes in blood flux. The effects of local anaesthesia, inhibition of nitric oxide synthase (NOS) by L-NAME and ET receptor blockade on the ET-induced vascular response were also investigated. ET-1, -2 and -3 all caused a dose-dependent area of pallor surrounded by a long-lasting flare which was accompanied by a short-lived burning pruritus. The concentration of nitric oxide (NO) in dialysate collected within the pallor response to 5 µM ET-1 (1.43 ± 0.64 µM, n = 5) was not significantly different from baseline levels collected prior to injection (0.86 ± 0.38 µM) whilst that in the flare increased to reach a peak value of 2.28 ± 0.61 µM at between 4 and 10 min after intradermal injection (P < 0.004). Pretreatment with local anaesthetic slowed the development of the flare and significantly reduced its size by up to 52 % at 20 min after injection (P < 0.05) but had no significant effect on the central pallor. L-NAME, delivered by dialysis also caused a significant reduction in the ET-1-induced flare (P < 0.005). Bosentan, the non-selective ETA/ETB antagonist, when given by dialysis at the site of injection, reduced the area of both the ET-1-induced pallor and surrounding flare by 41 and 26 %, respectively. No significant increase in tissue histamine was measured within either the pallor or flare response to ET-1, -2 or -3. Together these data confirm that the vasodilator response to endothelin-1 in human skin is neurogenic in origin and that it is in part mediated by the local release of nitric oxide. There appears to be little evidence for the involvement of mast cell-derived histamine in the initiation or modulation of ET-induced vasodilatation, in vivo.

The effect of carbonic anhydrase (CA) inhibition with acetazolamide (ACZ, 10 mg kg-1 I.V.) on the peripheral and central chemosensitivity and breathing pattern was investigated in four women and three men aged 25 ± 3 years using a modified version of Read's rebreathing technique. Subjects were exposed to dynamic increases in CO2> in hypoxic and hyperoxic backgrounds during control conditions and following acute CA inhibition. All manoeuvres were repeated twice and averaged for data analysis. The central chemoreflex sensitivities, estimated from the slopes of the ventilatory response to CO2 during hyperoxic rebreathing, increased following acute CA inhibition (control vs. ACZ treatment: 1.87 ± 0.66 vs. 4.07 ± 1.03 l min-1 (mmHg CO2)-1, P < 0.05). The increased slope was reflected by an increase in the rate of rise of tidal volume and breathing frequency. Furthermore with ACZ, there was a left-ward shift of the ventilation vs. end-tidal PCO2 curve during hyperoxic hypercapnia but not hypoxic hypercapnia. The peripheral chemoreflex sensitivity was isolated by subtracting the hyperoxic slope (central only) from the hypoxic slope (central and peripheral). Following ACZ administration, the peripheral chemosensitivity was blunted (control vs. ACZ treatment: 3.66 ± 0.92 vs. 1.33 ± 0.46 l min-1 (mmHg CO2)-1, P < 0.05). In conclusion, acute CA inhibition enhanced the central chemosensitivity to CO2 but diminished the peripheral chemosensitivity.

Oscillations in the cardiovascular system have been observed in patients with periodic breathing. It is not clear whether these are driven by primary oscillations in the respiratory system or whether an intrinsic cardiovascular instability is required, as previous studies with subjects performing voluntary periodic breathing have failed to produce the cardiovascular oscillations. We investigated whether cardiovascular oscillations occurred in healthy controls performing voluntary periodic breathing. Six healthy subjects performed voluntary periodic breathing with guidance from a real-time computer display. We measured ventilation, end-tidal partial pressures of O2 (PO2) and CO2 (PCO2), heart rate, blood pressure (BP), arterial oxygen saturation and stroke volume and cardiac output by transthoracic impedance cardiography. Fourier analysis was used to quantify the size and phase of the periodic breathing-induced oscillations in these parameters. Periodic breathing (amplitude 30 % of mean ventilation) induced oscillations in end-tidal PO2 (amplitude 0.8 kPa), end-tidal PCO2 (amplitude 0.3 kPa), R-R interval (amplitude 32.6 ms), systolic BP (amplitude 3 mmHg), diastolic BP (amplitude 3 mmHg), stroke volume (amplitude 8.0 ml, mean 79.5 ml) and cardiac output (amplitude 0.6 1, mean 5.9 l min-1). The oscillations in stroke volume and cardiac output were nearly in phase with ventilation, with their peaks occurring 5.6 and 6.1 s, respectively, after the peak in ventilation. An oscillatory ventilatory pattern entrains the cardiovascular system in healthy controls into fluctuations, not only in heart rate and BP, but also in stroke volume and cardiac output

This study was designed to find out if the lymph flow, indicated as albumin clearance, from active skeletal muscle is maintained constant during a prolonged steady-state exercise. 99mTc-labelled albumin was injected bilaterally into the vastus lateralis muscles of eight endurance-trained men. The radioactivity at the injection site was monitored by a gamma-camera before, frequently during, and after a 2 h run at a controlled steady intensity of 69 ± 4 % of the maximal heart rate. The fractional clearance rate of albumin was calculated for each monitoring interval, and was expressed as percentage clearance per minute (% min-1). During the first 15 min of exercise the clearance rate was five times higher than at rest before the exercise (0.29 ± 0.12 vs. 0.06 ± 0.05 % min-1, P = 0.001). During the next 25 min of running the clearance rate fell to 0.19 ± 0.08 % min-1 (P = 0.02), from which level it was further attenuated, being 0.12 ± 0.04 % min-1 at the end of the exercise. After the exercise the clearance rate fell rapidly to the level of 0.04 ± 0.03 % min-1. The results showed that the albumin clearance from working muscles is not constant during steady-state exercise, suggesting that lymph flow from exercising skeletal muscle may not be constant despite lymphatic pumping being assumed to be unchanged during the course of exercise (i.e. constant exercise intensity and running speed).