Wellcome Prize Lecture
Cell surface, ion-sensing receptors
- Daniela Riccardi
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- 25 June 2002, pp. 403-411
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Changes in extracellular calcium (CaB) concentration ([Ca2+]o) affect kidney function both under basal and hormone-stimulated conditions. The molecular identification of an extracellular Ca2+-sensing receptor (CaR) has confirmed a direct role of CaB on parathyroid and kidney function (i.e. independent of calciotropic hormones)s as a modulator of Ca2+ homeostasis. In addition, evidence accumulated over the last 10 years has shown that CaR is also expressed in regions outside the calcium homeostatic system where its role is largely undefined but seems to be linked to regulation of local ionic homeostasis. The parathyroid and kidney CaRs are 1081 and 1079 amino acids long, respectively, and belong to the type III family of G protein-coupled receptors (GPCRs), which includes other CaRs, metabotropic glutamate receptors and putative vomeronasal organ receptors. For the CaR, its low (millimolar) affinity for Ca2+, its positive cooperativity and its large ionsensing extracellular domain, indicate that the receptor is more sensitive to changes in net cationic charge rather than to a specific ligand. Mg2+, trivalent cations of the lanthanide series and polyvalent cations such as spermine and aminoglycoside antibiotics can all activate the receptor in vitro with EC50 values in the micromolar range for trivalent and polyvalent cations or in the millimolar range for Ca2+ and Mg2+. In addition to true CaR agonists, CaR sensitivity to CaBis also susceptible to allosteric modulation by ionic strength, L-amino acids and by pharmacological agents. This review will address endogenous and exogenous CaR agonists, the role of the receptor in the calcium homeostatic system and some speculation on possible role(s) of the CaR in regions not involved in mineral ion homeostasis.
The G. L. Brown Prize Lecture
Hypoxic regulation of ion channel function and expression
- Chris Peers
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- 25 June 2002, pp. 413-422
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Acute hypoxia regulates the activity of specific ion channels in a rapid and reversible manner. Such effects underlie appropriate cellular responses to hypoxia which are designed to initiate cardiorespiratory reflexes and contribute importantly to other tissue responses, all of which are designed to improve tissue O2 supply. These responses include excitation of chemoreceptors as well as pulmonary vasoconstriction and systemic vasodilatation. However, such responses may also contribute to the adverse responses to hypoxia, such as excitotoxicity in the central nervous system. Whilst numerous ion channel types are known to be modulated by acute hypoxia, the nature of the O2 sensor in most tissues remains to be identified. Prolonged (chronic) hypoxia regulates functional expression of ion channels, and so remodels excitability of various cell types. Whilst this may contribute to adaptive responses such as high-altitude acclimatization, such altered channel expression may also contribute to the onset of pathological disorders, including Alzheimer's disease. Indeed, evidence is emerging that production of pathological peptides associated with Alzheimer's disease is increased during prolonged hypoxia. Such effects may account for the known increased incidence of this disease in patients who have previously endured hypoxic episodes, such as congestive heart failure and stroke. Identification of the mechanisms coupling hypoxia to the increased production of these peptides is likely to be of therapeutic benefit.
Mini Review Article
Mortality, cardiac vagal control and physical training – what’s the link?
- Ashesh N. Buch, John H. Coote, John N. Townend
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- 25 June 2002, pp. 423-435
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Research Article
Methoxsalen stimulates electrogenic Cl− secretion in the mouse jejunum
- Kirk L. Hamilton, A. Grant Butt, Samantha Cheng, Derek J. Carter
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- 25 June 2002, pp. 437-445
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We used the short-circuit current (Isc) and patch-clamp techniques to investigate the effects of methoxsalen (MTX) on the electrogenic Cl− secretion of the mouse jejunum. MTX stimulated a sustained increase in Isc that was dose dependent. Bumetanide inhibited MTX-stimulated Isc in a dose-dependent manner consistent with activation of Cl− secretion. MTX failed to stimulate Isc following maximal activation of the cAMP pathway by forskolin, but did increase Isc after a submaximal dose of forskolin. Glibenclamide, a blocker of the cystic fibrosis transmembrane conductance regulator (CFTR), reduced the MTX-stimulated increase of Isc by 59 ± 6%. The cAMP-dependent K+ channel blocker 293B did not alter the MTX-activated Isc; however, clotrimazole, an intermediate Ca2+-activated K+ channel (IKCa) blocker, reduced the MTX-stimulated Isc. MTX did not alter Na+–glucose cotransport across the mouse jejunum.In cell-attached membrane patches, MTX increased the open probability of the basolateral IKCa channel of isolated crypts. These data suggest that the CFTR and IKCa channels participate in the MTX-activated, sustained Cl− secretory response of the mouse jejunum.
Influence of castration on isoprenaline-induced amylase release in parotid gland from male rats
- Lucila Busch, Enri Borda
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- 25 June 2002, pp. 447-452
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The purpose of this study was to determine the influence of testosterone, the male sex hormone, on β-adrenergic agonist-induced amylase secretion from rat parotid glands. Isoprenaline (isoproterenol)-induced amylase secretion was measured in vitro from the parotid glands of control and castrated rats with and without testosterone replacement. The isoprenaline-induced amylase release was reduced in parotid glands from castrated rats compared to controls. The reduction of amylase release by isoprenaline in parotid glands of castrated rats, could be reversed by administration of testosterone. Furthermore, β-adrenergic receptor density and the level of isoprenaline-evoked cAMP in parotid glands from castrated rats was lower compared to intact rats. Using SQ-22536 (an adenylyl cyclase inhibitor), dibutyryl cAMP (a cAMP analogue) and verapamil (a calcium channel blocker), we conclude that the impairment of amylase release from parotid glands after castration was not related to either adenylyl cyclase activity or cAMP accumulation. Amylase release from the parotid glands of castrated rats appears to be mediated by an increase in calcium ion influx.
Effect of intermittent hypoxia on cardiovascular function, adrenoceptors and muscarinic receptors in Wistar rats
- R. Germack, F. Leon-Velarde, R. Valdes De La Barra, J. Farias, G. Soto, J. P. Richalet
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- 25 June 2002, pp. 453-460
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The usual model of intermittent hypoxia (sleep apnoea) corresponds to repeated episodes of hypoxia from a few seconds to a few hours interspersed with episodes of normoxia. The aim of this study was to evaluate in rats the effect of two periods of intermittent exposure for 2 months to hypoxia (IHX1, 24 h in hypoxia (428 Torr), 24 h in normoxia; IHX2, 48 h in hypoxia (428 Torr), 24 h in normoxia) as a new model of hypoxia simulating intermittent exposure to high altitude experienced by Andean miners. We assessed the haematological parameters, time course of resting heart rate and systolic blood pressure. We also evaluated the expression of adrenergic and muscarinic receptors. IHX1 and IHX2 produced an increase in haematocrit, haemoglobin concentration and mean corpuscular volume as previously seen in most hypoxic models. IHX1 and IHX2 induced a similar sustained elevation of systolic blood pressure (132 ± 2 and 135 ± 3 mmHg, respectively, vs. the control level of 121 ± 16 mmHg) after 10 days of exposure without change in heart rate. Right ventricular (RV) hypertrophy (225 ± 13 and 268 ± 15 mg g−1, vs. 178 ± 7 mg g−1) and downregulation of α1-adrenoceptor (RV: 127 ± 21 and 94 ± 16 fmol mg−1vs. 157 ± 8 fmol mg−1; left ventricle (LV): 141 ± 5 and 126 ± 9 fmol mg−1vs. 152 ± 5 fmol mg−1) have been found in both groups, with right ventricular hypertrophy being greater and α1-adrenoceptor density being lower in IHX2 than in HX1 groups. These data indicate that both parameters are related to the time of exposure to hypoxia. IHX1 and IHX2 produced the same magnitude of upregulation of muscarinic receptors (LV, 60%; RV, 40%), and no change in β-adrenoceptors. In conclusion, exposure to intermittent hypoxia led to polycythaemia and RV hypertrophy as observed in other types of hypoxia. A specific cardiovascular response was seen, that is an increase in blood pressure without change in heart rate, which was different from the one observed in episodic and chronic hypoxia. Furthermore, this model involved specific modifications of α1-adrenergic and muscarinic expression.
Synchrony analysis between blood pressure and sympathetic nerve signal inhibited by atrial receptor stimulation in Wistar rats
- Zhuo Yang, Tao Zhang, John H. Coote
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- 25 June 2002, pp. 461-468
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Recently attempts have been made to analyse blood pressure (BP) and renal sympathetic nerve activity (RSNA) to determine how patterns contained within them might reflect control by the autonomic nervous system. To date, these studies have primarily used coherence analysis of BP and RSNA in the frequency domain. However, this analysis is unable to assess the non-linear properties of the underlying cardiovascular control system. In this study we employed not only coherence analysis but also cross-entropy analysis using balloon inflation (‘balloon-on’) to assess the influence of right atrial receptors on the relationship between BP and RSNA under two conditions in anaesthetised Wistar rats. Balloon-on stimulation alone inhibited RSNA by 28 ± 4% in eight rats without changing BP. This effect on integrated nerve activity was not present when atrial stimulation was applied during stimulation of a site in the paraventricular nucleus (PVN) of the hypothalamus which increased RSNA by 158.7 ± 58% and increased BP by 17.1 ± 2.3 mmHg. However, the cross-entropy measurement was significantly decreased (P < 0.05) during balloon-on stimulation in both the conditions revealing that there is greater synchrony between the oscillating signals contained within the BP and RSNA time series. Thus during the enhanced RSNA elicited by stimulation of the PVN, the inhibitory influence of atrial receptors, although apparently blocked, was still effective in that it resulted in the energy of the RSNA spectrum becoming more evenly distributed over a range of frequencies. The data show that cross-entropy calculations are able to characterize the non-linearities of underlying cardiovascular control.
Effect of maternal feed restriction on blood pressure in the adult guinea pig
- Karen L. Kind, Giuseppe Simonetta, Peter M. Clifton, Jeffrey S. Robinson, Julie A. Owens
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- 25 June 2002, pp. 469-477
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Small size at birth has been associated with increased blood pressure in adult men and women. In rats, isocaloric protein restriction reduces fetal growth and increases systolic blood pressure in adult offspring. Balanced maternal undernutrition in the rat also increases adult blood pressure, but not consistently. The aim of this study was to determine the effect of moderate balanced maternal undernutrition (85% of ad libitum intake from 4 weeks before, and throughout pregnancy) on blood pressure of adult offspring in the guinea pig, a species that is relatively mature at birth. Blood pressure was measured in chronically catheterised offspring of ad libitum fed or feed-restricted mothers, at 3 months of age (young adult). Maternal feed restriction reduced birth weight (−17%) and increased systolic blood pressure (+9%, P < 0.03) in young adult male offspring. In offspring of ad libitum fed and feed-restricted mothers, combined data showed that systolic blood pressure and mean arterial pressure correlated negatively with head width at birth (P = 0.02 and P = 0.04, respectively, n = 28). Systolic blood pressure also correlated negatively with birth weight and the ratio birth weight/birth length, but only in offspring of ad libitum fed mothers (P = 0.04 and P = 0.03, respectively, n = 22). The effect of maternal feed restriction on systolic blood pressure in male offspring was not significant when adjusted for these measures of size at birth. Thus, moderate balanced undernutrition in the guinea pig increases systolic blood pressure in young adult male offspring; however, these effects may be mediated, at least in part, through effects on fetal growth.
Muscle ischaemia in rats may be relieved by overload-induced angiogenesis
- D. Deveci, S. Egginton
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- 25 June 2002, pp. 479-488
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Alleviation of muscle ischaemia by improving capillary supply has proved difficult, possibly reflecting the inability to substantially increase blood flow. We reasoned that muscle overload, which induces angiogenesis in the absence of altered blood flow, may be an alternative to drug therapy. Male Wistar rats underwent unilateral ligation of the common iliac artery, with or without ipsilateral extirpation of the tibialis anterior muscle. Six weeks later ischaemic (I) extensor digitorum longus (EDL) had a 10% (P< 0.05) decrease in relative muscle mass, while overloaded muscles (O) had undergone hypertrophy of 39% and 52% relative to contralateral (CL) and control (C) muscle masses, respectively (P<0.01). Muscle atrophy was prevented by the combination of overload and ischaemia (O/I), with hypertrophy of 24% (vs. CL) and 35% (vs. C), respectively (P<0.01). Changes in muscle fibre cross-sectional area paralleled the changes in muscle mass, with means of 1898 ± 59, 1531 ± 90, 2253 ± 155 and 2292 ± 80 mm2 for C, I, O and O/I, respectively (P<0.01 vs. C and I). Capillary to fibre ratio (C:F) was significantly increased in overloaded (2.58 ± 0.09) compared to contralateral (1.78 ± 0.04), control (1.61 ± 0.05) and ischaemic (1.73 ± 0.06) muscles (P<0.001). A similar increase in C:F was seen in overloaded plus ischaemic muscle (2.59 ± 0.07) compared to contralateral (1.40 ± 0.01) and control or ischaemic values (P<0.01). In both O and O/I muscle groups, C:F and capillary density (CD) increased most in the region of EDL where fibre size was largest, while hypertrophy of fibres was least in the same region for both groups. These data suggest that the microvascular deficit evident in chronic muscle ischaemia may be alleviated by angiogenesis that is induced by mechanical stimuli via chronic muscle overloaded.
Bicarbonate-induced alkalosis augments cellular acetyl group availability and isometric force during the rest-to-work transition in canine skeletal muscle
- Paul A. Roberts, Susan J. G. Loxham, Simon M. Poucher, Dumitru Constantin-Teodosiu, Paul L. Greenhaff
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- 25 June 2002, pp. 489-498
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Increasing blood bicarbonate content has long been cited as a potential mechanism to improve contractile function. We investigated whether sodium bicarbonate-induced metabolic alkalosis could positively affect force development during the rest-to-work transition in ischaemic skeletal muscle. Secondly, assuming it could, we investigated whether bicarbonate could augment acetyl group availability through the same equilibrium reaction as sodium acetate pre-treatment and whether this underpins, at least in part, its ergogenic effect. Multiple biopsy samples were obtained from the canine gracilis muscle during 5 min of electrically evoked ischaemic contraction, which enabled the determination of the time course of acetyl group accumulation, substrate utilisation, pyruvate dehydrogenase complex activation and tension development in animals treated with saline (control; n = 6) or sodium bicarbonate (n = 5). Treatment with bicarbonate elevated acetylcarnitine content above the control level at rest (P<0.05), but at no time point during subsequent contraction. The pyruvate dehydrogenase complex was activated following 40 s of contraction in both groups, with no differences existing between treatments at any time point. The requirement for ATP resynthesis from non-oxygen-dependent routes was no different between groups at any time point during contraction. No difference in peak twitch force production existed between groups. However, at 3 min of stimulation, tension development was better maintained in the bicarbonate group (P<0.05), being ∼20% greater than control following 5 min of contraction (P<0.05). The results demonstrate, for the first time, that bicarbonate can augment acetyl group availability prior to contraction, independent of pyruvate dehydrogenase complex activation, but cannot influence the requirement for non-oxidative ATP re-synthesis during subsequent contraction. It would appear, therefore, that the bicarbonate-induced improvement in muscle tension development was probably mediated through the metabolic alkalosis and not via the increased availability of acetyl groups within the cell.
The effect of treadmill incline on maximal oxygen uptake, gas exchange and the metabolic response to exercise in the horse
- Paul McDonough, Casey A. Kindig, Casey Ramsel, David C. Poole, Howard H. Erickson
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- 25 June 2002, pp. 499-506
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In healthy man, conditions that change muscle O2 delivery affect the achievable maximum rate of O2 uptake (,max) as well as the metabolic (e.g. lactate threshold, LT) and gas exchange (e.g. gas exchange threshold, The) responses to incremental exercise. Inclined (I) compared to level (L) running increases locomotory muscle EMG at a given speed in the horse, indicative of elevated metabolic demand. To our knowledge, the effect of treadmill incline on ,max, LT and The has not been addressed in the exercising quadruped. We used blood sampling and breath-by-breath expired gas analysis to test the hypothesis that I (10% gradient) would increase ,max and the rate of O2 uptake () at LT and Tge in six Thoroughbred horses during incremental running to volitional fatigue. ,max was significantly higher for I (I, 77.8 ± 4.1; L, 65.5 ± 5.3 l min−1; P<0.05), but peak plasma lactate concentration was not (I, 28.0 ± 3.7; L, 25.9 ± 3.0 mM). Arterial PCO2 increased to 62.1 ± 3.3 and 57.9 ± 2.7 Torr (I vs. L; P<0.05), yet despite this relative hypoventilation, a distinct The was present. This The occurred at a significantly different absolute (I, 49.6 ± 3.2; L, 42.4 ± 3.2 l min−1; P<0.05), but nearly identical relative (I, 63.6 ± 1.2; L, 63.9 ± 1.6% ,max) in I and L. Similarly, LT occurred at a significantly greater absolute (I, 37.3 ± 2.8; L, 26.9 ± 2.1 l min−1), but a relative that was not different (I, 47.9 ± 2.1; L, 43.9 ± 4.5% ,max). In addition, Tge occurred at a significantly higher (P ≤ 0.05) absolute and relative than LT for both I and L tests. In conclusion, ,max is higher during inclined than level running and both LT and Tge in the horse occur at a similar percentage of ,max irrespective of the absolute level of ,max. In contrast to humans, LT is a poor analogue of The in the horse.
The effects of isometric exercise training on resting blood pressure and orthostatic tolerance in humans
- Reuben Howden, J. Timothy Lightfoot, Stephen J. Brown, Ian L. Swaine
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- 25 June 2002, pp. 507-515
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Isometric exercise training has been shown to reduce resting blood pressure, but the effect that this might have on orthostatic tolerance is poorly understood. Changes in orthostatic tolerance may also be dependent on whether the upper or lower limbs of the body are trained using isometric exercise. Twenty-seven subjects were allocated to either a training or control group. A training group first undertook 5 weeks of isometric exercise training of the legs, and after an 8 week intervening period, a second training group containing six subjects from the initial training group, undertook 5 weeks of isometric arm-training. The control group were asked to continue their normal daily activities throughout the 18 weeks of the study. In all subjects orthostatic tolerance, assessed using lower body negative pressure (LBNP), and resting blood pressure were measured before and after each of the 5 week training or control periods. Estimated lean leg volume was determined before and after leg-training. During all LBNP tests, heart rate and blood pressure were recorded each minute, and the time taken to reach the highest heart rate was derived (time to peak HR). Resting systolic blood pressure (mean ± S.D.), when measured during the last week of training, was significantly reduced after both leg (−10 ± 8.7 mmHg) and arm (−12.4 ± 9.3 mmHg; P<0.05) isometric exercise training, compared to controls. This reduction disappeared when blood pressure was measured immediately before the LBNP tests, which followed training. Orthostatic tolerance only increased after leg-training (20.8 ± 16.4 LTI; P<0.05) and was accompanied by an increased time to peak HR (119.8 ± 106.3 beats min−1; P<0.05) in this group. Blood pressure responses to LBNP did not change after arm-training, leg-training or in controls (P>0.05). There was a small but significant increase in estimated lean leg volume after leg-training (0.1 ± 0.1 l; P<0.05). These results suggest that lower resting blood pressure is probably not responsible for the increased orthostatic tolerance after isometric exercise training of the legs. Rather, it is possible that the training altered some other aspect of cardiovascular control during orthostatic stress that was apparent in the changes in heart rate. Legtraining was accompanied by increases in estimated lean leg volume. The effects of isometric training on orthostatic tolerance appear to be specific to limbs that are directly involved in LBNP testing.
Book Review
Potassium Channels in Cardiovascular Biology. Edited by Stephen L. Archer and Nancy J. Rusch. Pp. 932. Kluwer Academic/Plenum Publishers, 2001. £86.25 ($125.00) hardback. ISBN 0 306 46402 0.
- Stanley Nattel
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- 25 June 2002, p. 517
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