It was recently demonstrated that ammonia inhibits sodium absorption in the proximal colon of rats. In order to investigate the effect of luminal ammonia in the distal colon, sodium and chloride transport were measured in Ussing chambers. Under short-circuit conditions, distal colon absorbed sodium and chloride. When luminal ammonia (30 mmol l-1) was present, sodium and chloride absorption was diminished. Inhibition of the two Na+-H+ exchanger isoforms NHE2 and NHE3, which are known to be located in the apical membrane of the distal colon epithelium, failed to influence the effect of ammonia on transepithelial sodium and chloride fluxes. The inhibitory effect of ammonia was eliminated under the following conditions: after block of carbonic anhydrases with acetazolamide, in the presence of an unspecific blocker of Na+-H+ exchangers, and under chloride-free conditions. Ammonia did not alter electrogenic sodium absorption. These results demonstrate that luminal ammonia inhibits sodium and chloride absorption in rat distal colon. We suggest that ammonia inhibits NaCl absorption by interfering with a Na+-H+ exchanger that is not NHE2 or NHE3. Experimental Physiology (2002) 87.3, 311-319.

It is commonly known that consumption of foods and beverages rich in polyphenols is associated with a lower incidence of cardiovascular disease. The purpose of this study was to assess whether the application of red wine polyphenols influences the kinetic properties of renal Na+,K+-ATPase in rats in which hypertension has been experimentally induced by the nitric oxide synthase inhibitor L-NAME. Treatment with polyphenols during the recovery from hypertension to normotension resulted in the complete revival of the functional properties of the Na+,K+-ATPase, as indicated by the total restoration of Km, KNa (concentration of Na+ necessary to achieve half-maximal reaction velocity) and Vmax for enzyme activation by ATP and/or Na+ to pre-hypertension values. Two positive effects of polyphenols during the recovery period are indicated: a restoration of the affinity of the ATP and Na+ binding sites to control values and a probable increase in the number of Na+,K+-ATPase molecules to a level comparable to that in control conditions, as suggested by the complete renewal of Vmax. Experimental Physiology (2003) 88.4, 475-482.

Secretion of fluid and proteins by salivary cells is under the control of parasympathetic and sympathetic autonomic nerves. In a recent study we have shown that, in the rat submandibular gland, autonomic nerves can also increase the secretion of IgA, a product of plasma cells secreted into saliva as SIgA (IgA bound to Secretory Component, the cleaved poly-immunoglobulin receptor). The present study aimed to determine if parotid secretion of SIgA is increased by autonomic nerves and to compare SIgA secretion with other parotid proteins stored and secreted by acinar and ductal cells. Assay of IgA in saliva evoked by parasympathetic nerve stimulation immediately following an extended rest period under anaesthesia indicated that it had been secreted into intraductal saliva in the absence of stimulation during the rest period. The mean rate of unstimulated IgA secretion (2.77 ± 0.28 µg min-1 g-1) and the 2.5-fold increase in IgA secretion evoked by parasympathetic stimulation were similar to results found previously in the rat submandibular gland. Sympathetic nerve stimulation increased SIgA secretion 2.7-fold, much less than in the submandibular gland. SDS-PAGE and Western blot analysis with anti-IgA and anti-Secretory Component antibodies confirmed that SIgA was the predominant form of IgA in saliva. Acinar-derived amylase and ductal-derived tissue kallikrein were more profoundly increased by parasympathetic and particularly sympathetic stimulation than SIgA. Overall, the results of the present study indicate that SIgA forms a prominent component of unstimulated parotid salivary protein secretion and that its secretion is similarly increased by stimulation of either autonomic nerve supply. The secretion of other parotid salivary proteins that are synthesized and stored by acinar or ductal cells is upregulated to a much greater extent by parasympathetic and particularly sympathetic stimulation. Experimental Physiology (2000) 85.5, 511-518.

The present study aimed at investigating the responsiveness of different parts of the primary afferent neurones to a brief hypoxia, hypercapnia or ischaemia under in vivo conditions. Action potentials were recorded in separate groups of anaesthetized rats from (i) the peripheral end of the central stump of the cut L3, L4 or L5 dorsal root (dorsal root preparation); (ii) the central end of the peripheral stump of the cut saphenous nerve (saphenous-receptor preparation); (iii) the distal end of a segment of the saphenous nerve cut at both ends (axon preparation). In paralysed animals interruption of artificial ventilation for 20-60 s elicited or increased the frequency of action potentials in both the dorsal root and saphenous-receptor preparations. Activation of these preparations was also achieved by inspiration of gas mixtures containing 10-0 % oxygen (mixed with nitrogen) or 20-50 % carbon dioxide (mixed with oxygen) which elicited in the blood a decrease in PO2 or an increase in PCO2 with a fall in pH. Occlusion of the femoral artery for 3 min also caused spike generation in the saphenous-receptor preparations with little alteration in blood pressure. All these stimuli failed to evoke action potentials in the axon preparations. Systemic (300 mg kg-1 S.C.) or perineural (2 %) capsaicin pretreatment failed to inhibit the effect of hypoxia, hypercapnia or ischaemia, indicating a significant contribution of capsaicin-insensitive neurones to the responses. It is concluded that central and peripheral terminals but not axons of primary afferent neurones are excited by a brief hypoxia or hypercapnia and the peripheral terminals by a short local ischaemia as well. Excitation of central terminals by hypoxia or hypercapnia revealed in this way an antidromic activation of dorsal roots in response to natural chemical stimuli.

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.

This study examined the role of calcium in the generation of reactive oxygen species (ROS) in human lymphocytes activated by the chemoattractant formyl-Met-Leu-Phe (fMLP) and the T-cell mitogen phytohaemagglutinin (PHA). The concentrations of cytosolic calcium ([Ca2+]i) and ROS were monitored simultaneously with a fluorescence spectrophotometer after the cells had been incubated in fura-2 (calcium-sensitive dye) and 2',7'-dichlorofluorescein diacetate (DCF-DA, ROS-sensitive dye). The lymphocytes were stimulated with fMLP (200 nmol l-1) or PHA (10 µmol l-1) in the absence and presence of extracellular calcium. A dose-response test was also conducted for extracellular calcium. fMLP and PHA significantly increased both [Ca2+]i (P < 0.001) and ROS concentrations (P < 0.001) above the control levels in the presence of extracellular calcium. However, such increases were abolished in the absence of extracellular calcium, suggesting total dependence of the responses to both fMLP and PHA on transplasma-membrane calcium influx. There were also graded increases in ROS with increasing concentrations of extracellular calcium. The results show that transplasma-membrane calcium influx is essential for fMLP- and PHA-induced generation of reactive oxygen species in human lymphocytes.

There have been several studies on the effect of short-term creatine (Cr) supplementation on exercise performance, but none have investigated both voluntary and stimulated muscle contractions in the same experiment. Fourteen moderately active young men (19-28 years) were randomly assigned, in a double blind manner, to either a creatine (Cr) or placebo (P) group. The subjects supplemented their regular diet 4 times a day for 5 days with either 5 g Cr + 5 g maltodextrin (Cr group), or 5 g maltodextrin (P group). Isometric maximal voluntary contraction (MVC), muscle activation, as assessed using the modified twitch interpolation technique, electrically stimulated contractile properties, electromyography (EMG), endurance time and recovery from fatigue were measured in the elbow flexors. The fatigue protocol involved both voluntary and stimulated contractions. Following supplementation there was a significant weight gain in the Cr group (1.0 kg), whereas the P group did not change. For each group, pre-supplementation measures were not significantly different from post-supplementation for MVC, twitch and tetanic tensions at rest, time to peak tension, half-relaxation time and contraction duration. Prior to Cr supplementation time to fatigue was 10 ± 4 min (mean ± S.E.M.) for both groups, and following supplementation there was a non-significant increase of 1 min in each group. MVC force, muscle activation, EMG, stimulated tensions and durations were similar for the Cr and P groups over the course of the fatigue protocol and did not change after supplementation. Furthermore, recovery of MVC, stimulated tensions and contractile speeds did not differ as a result of Cr supplementation. These results indicate that short-term Cr supplementation does not influence isometric elbow flexion force, muscle activation, stimulated contractile properties, or delay time to fatigue or improve recovery.

This study compared the effects of high frequency oscillatory ventilation (HFOV) and intermittent mandatory ventilation (IMV) on the homeostasis of nitric oxide (NO) in the lower respiratory tract of healthy rabbits. The mechanisms underlying a putative stretch response of NO formation in the airways were further elucidated. Male New Zealand White rabbits were anaesthetized, tracheotomized and ventilated with IMV or HFOV in random order. Total NO excretion increased from 9σ6 ± 0σ8 nl min-1 (mean ± S.E.M.) during IMV to 22σ6 ± 2σ7 nl min-1 during HFOV (P < 0σ001). This increase was not explained by changes of functional residual capacity ([Delta]>FRC). A similar increase in NO excretion during HFOV was seen in isolated buffer-perfused lungs under constant circulatory conditions (P < 0σ05, n = 4). Intratracheal mean CO2 and NO concentrations, measured at 2σ5, 5, 7σ5 and 10 cm below tracheostomy, increased significantly with increasing distance into the lung during both IMV and HFOV (P < 0σ001 for each comparison). At every intratracheal location of the sampling catheter, particularly low in the airways, both CO2 and NO concentrations were significantly higher during HFOV than during IMV (P < 0σ01 for each comparison). We conclude that HFOV increases pulmonary NO production in healthy rabbits. Increased stretch activation of the respiratory system during HFOV is suggested as a possible underlying mechanism. The increase in mean airway NO concentrations may have biological effects in the respiratory tract. Whether it can account for some of the benefits of HFOV treatment needs to be considered.

In the pathogenesis of autoimmune diseases, tolerance against self-determinants is lost and autoreactive lymphocytes are activated leading to pathological damage of single or multiple organs. Viral and other microbial infections have been implicated in these processes. Viruses may induce immunopathological damage by maintaining a chronic immune response against the locally persisting infectious agent. Alternatively, viruses may help to initiate anti-self immunoreactivity, e.g. by induction of an inflammatory milieu needed to overcome tolerance against self-antigens. Presentation of viral antigens and/or previously immunologically ignored self-antigens in secondary lymphoid organs is most probably the key event in the initiation of autoimmune diseases. Translocation of antigens to secondary lymphoid organs and primary induction of T cell responses is primarily mediated by dendritic cells (DCs). We discuss here two transgenic models of autoimmune diseases where DC-mediated antigen transport initiated autoimmune responses against microbial neoself antigens. In the first model, dose and timing of antigen delivery by DCs and turnover of antigenic peptides presented by DCs are the main parameters regulating the outcome of autoimmune diabetes. In the second model, chronic stimulation of organ-specific immune responses via DCs leads to severe cardiovascular immunopathology with arteritis, myocarditis and eventually dilated cardiomyopathy. Taken together, transgenic mouse models are valuable tools for delineating basic pathogenic mechanisms and evaluating therapeutic strategies to interfere with early detrimental processes that lead to manifest autoimmune diseases.

This study examined the effect of the phenylalkylamine calcium channel blocker verapamil, on resting left ventricular (LV) function and O2 uptake rate (VO2) during exercise at maximal and submaximal work rates. Nine older hypertensive (71 years; OH), 10 older sedentary normotensive (69 years; OS), 10 older active (71 years; OA) and 10 young (24 years; Y) individuals volunteered. Studies were completed in the control condition and 4-6 h following 240 mg verapamil SR per os. Resting LV systolic (fractional shortening; FS) and diastolic (early : late (E/A) flow velocity ratio and isovolumic relaxation time (IVRT)) were measured by Doppler echocardiography. Maximal oxygen uptake (VO2,max) and, on subsequent test days, four transitions to and from a 6 min square wave exercise perturbation at a sub-anaerobic threshold intensity of 40 W (OH, OS, OA) or 100 W (Y) for determination of VO2 kinetics were performed on a cycle ergometer. Breath-by-breath VO2 transients were fitted with a monoexponential equation, starting at phase 2 of the response, while heart rate (HR) was fitted from phase 1, for the determination of the time constant of VO2 ([tau]VO2) and HR ([tau]HR). Baseline left ventricular FS was significantly greater in the OS (32 %), OA (34 %) and Y (34 %) than in the OH (23 %) groups, while E/A was significantly greater in the OA (1Σ16) and Y (2Σ34) than in the OH (0Σ9) and OS (0Σ82) groups (P < 0Σ05). Baseline VO2,max was higher and [tau]VO2 faster in the young (41Σ4 ml kg-1 min-1; 25Σ2 s) than in the older groups and in the OA (28Σ8 ml kg-1 min-1; 44Σ3 s) than in both OH (20Σ8 ml kg-1 min-1; 71Σ3 s) and OS (22Σ0 ml kg-1 min-1; 59Σ5 s) groups (P < 0Σ05). Heart rate kinetics showed similar differences to VO2 kinetics among the groups. After verapamil, no significant changes in FS, E/A or IVRT were observed in the OA and Y groups. In the OH group, FS (32 %) and E/A (1Σ15) increased while IVRT decreased significantly (from 0Σ103 to 0Σ07; P < 0Σ05). In the OS group, only E/A increased significantly (0Σ82 to 1Σ0; P < 0Σ05). None of the exercise variables (VO2,max, [tau]VO2 or [tau]HR) were altered for the OA or Y groups. VO2,max increased (from 20Σ8 to 22Σ8 ml kg-1 min-1) in the OH and (from 22Σ0 to 24Σ1 ml kg-1 min-1) in the OS (P < 0Σ05). [tau]VO2 was accelerated from 71Σ3 to 49Σ2 s in the OH group and from 59Σ5 to 48Σ2 s in the OS group (P < 0Σ05). These results suggest that VO2 responses at maximal and submaximal work rates may be dependent upon the initial cardiac pump function of the study population.

The importance of angiotensin type-1 (AT1) receptor stimulation during renal development has recently been established in both pharmacological and knockout models. We have previously reported irreversible and progressive papillary atrophy and a reduced baseline renal interstitial hydrostatic pressure (RIHP) after neonatal angiotensin-converting enzyme (ACE) inhibition. The aim of the present study was to investigate the consequences of these abnormalities on urinary sodium excretion during acute extracellular sodium loading. Rats were treated neonatally with enalapril (10 mg kg-1 day-1) or saline control from days 3 to 23 after birth. Urinary sodium excretion was assessed in relation to mean arterial pressure (MAP) and RIHP responses in adult anaesthetised rats during moderate (1·5 and 3 % body weight) and severe (9 % body weight) saline-induced volume expansion. Control rats responded to the moderate volume expansion by increasing MAP by 16 ± 6 % and RIHP by 40 ± 23 %, respectively. In neonatally enalapril-treated rats, however, MAP and RIHP remained unchanged and were associated with a smaller increase in sodium excretion (44 ± 11 % of the total amount infused versus 71 ± 16 % for controls, P < 0·05). In contrast, severe volume expansion resulted in marked pressure rises in both the enalapril-treated group (36 ± 12 and 112 ± 48 % of baseline for MAP and RIHP, respectively) and the control group (34 ± 21 and 130 ± 34 % of baseline for MAP and RIHP, respectively). Moreover, the increases in MAP and RIHP were associated with complete excretion of the severe sodium challenge within 60 min in both treatment groups. We conclude that a RIHP response appears to be a prerequisite for adequate urinary sodium excretion in this model of papillary atrophy. Hence, an intact renal medulla is not mandatory in the renal handling of sodium during extracellular loading.

Experiments were carried out to determine if endogenous pyrogen-induced fever impairs protective responses of newborn rats to hypoxia. Twenty-seven 5- to 6-day-old conscious rat pups received a subcutaneous injection of 0.20 µg of recombinant rat interleukin-1β (rrIL-1β) per kilogram of body weight to induce fever, or an equal volume of vehicle. They were then either exposed to a single period of hypoxia produced by breathing an anoxic gas mixture (97 % N2-3 % CO2) and their time to last gasp was determined, or they were exposed repeatedly to hypoxia and their ability to autoresuscitate from primary apnoea was determined. Core temperature increased significantly following administration of rrIL-1β but did not change following administration of vehicle (i.e. vehicle, 0.0 ± 0.1 °C; rrIL-1β, 0.7 ± 0.3 °C; P < 0.001) before exposure to hypoxia. IL-1β-induced fever did not alter the time to last gasp when the pups were exposed to a single period of hypoxia or the number of successful autoresuscitations upon repeated exposure to hypoxia. Thus, our data do not support the hypothesis that endogenous pyrogen-induced fever impairs the protective responses in newborns that may prevent death during hypoxia as may occur during single or repeated episodes of prolonged sleep apnoea. Experimental Physiology (2002) 87.1, 17-24.

The kinetics and the isozyme composition of lactate dehydrogenase (LDH) were measured in rat plantaris muscle during a 26 week endurance-training program. Alterations in the LDH isozyme pattern were detectable after 6 weeks as the percentage of the M4 isozyme was reduced from 89 to 76 % and the total percentage of M subunits compared with H subunits declined by 8 %. At 16 weeks, M4 accounted for only 62 % of the total. The replacement of M with H subunits continued when training was prolonged as M4 represented only 52 % of the total isozymes at 26 weeks. Conversely, training for 6 and 16 weeks produced no changes in either Vmax or Km. At 26 weeks, these values declined for both the forward (pyruvate to lactate) and backward reactions. The rate constants for both reactions were also reduced. These data suggest that changes in LDH isozyme pattern do not contribute significantly to the enhancement of lactate oxidation that may occur after training. They also suggest that the functional significance of alterations in LDH structure and/or function are best determined from analysis of the overall reaction kinetics as opposed to individual characteristics such as the isozyme pattern, Km or Vmax.

The ability to see the world around us is an immediate and striking example of the abilities of the nervous system, and perhaps for this reason, vision is one of the most intensively studied aspects of brain function (Hubel, 1995). This paper examines some of the earliest steps in vision occurring in the retina (Dowling, 1987; Rodieck, 1998).

We tested the hypotheses that: (1) Ca2+ handling and force production would be irreversibly altered in skeletal muscle during steady-state contractions when subjected to severe, prolonged hypoxia and subsequent reoxygenation; and (2) application of the cardio-protective drug trimetazidine would attenuate these alterations. Single, living skeletal muscle fibres from Xenopus laevis were injected with the Ca2+ indicator fura 2, and incubated for 1 h prior to stimulation in 100 µM TMZ-Ringer solution (TMZ; n = 6) or standard Ringer solution (CON; n = 6). Force and relative free cytosolic Ca2+ concentration ([Ca2+]c) were measured during continuous tetanic contractions produced every 5 s as fibres were sequentially perfused in the following manner: 3 min high extracellular PO2 (159 mmHg), 15 min hypoxic perfusion (3-5 mmHg) then 3 min high PO2. Hypoxia caused a decrease in force and peak [Ca2+]c in both the TMZ and CON fibres, with no significant (P < 0.05) difference between groups. However, basal [Ca2+]c was significantly lower during hypoxia in the TMZ group vs. the CON group. While reoxygenation generated only modest recovery of relative force and peak [Ca2+]c in both groups, basal [Ca2+]c remained significantly less in the TMZ group. These results demonstrated that in contracting, single skeletal muscle fibres, TMZ prevented increases in basal [Ca2+]c generated during a severe hypoxic insult and subsequent reoxygenation, yet failed to protect the cell from the deleterious effects of prolonged hypoxia followed by reoxygenation. Experimental Physiology (2003) 88.3, 415-421.

The nature of the immune response following ocular immunization with a protein and a polysaccharide and the effects such immunization have on the activities of cholinergic enzymes in the lacrimal glands of BALB/c mice were examined. Lacrimal glands are highly innervated by sympathetic and parasympathetic nerve fibres and are involved in mucosal immunity and therefore are excellent sites to study neuro-immune interactions. In this report, a T-lymphocyte-dependent protein antigen, keyhole limpet haemocyanin (KLH) and a T-lymphocyte-independent polysaccharide antigen, dextran (DEX) were administered topically to the eyes or intraperitoneally injected. Both routes of immunization produced a strong serum antibody response when KLH was the antigen. DEX, however, evoked a serum antibody response only after intraperitoneal administration. Eosin-haematoxylin staining indicated no histological abnormality or inflammatory changes in any immunized lacrimal glands, but immuno-staining revealed that only in the KLH-treated tissues were IgG-producing plasma cells discernible. Furthermore, KLH-specific antibody was also detectable using an immuno-blot assay in lacrimal glands. Polymerase chain reaction analysis with cytokine-specific primers revealed induction of interleukin-4 (lL-4) in KLH-treated lacrimal glands, but not in DEX or unimmunized tissues. Thus, the nature of the antigen seems important in the induction of the immune response in lacrimal glands. To delineate the effects that immunogenic differences might have on the activities of the cholinergic enzymes, choline acetyl-transferase (ChAT) and acetylcholinesterase (AChE) were assayed using radiolabelled substrates and measuring labelled products. Both ChAT and AChE activities were influenced following KLH immunization, while DEX had only transient effects on ChAT. This is possibly due to the fact that KLH, a protein antigen, is the effective inducer of the specific immune response in the lacrimal gland, while DEX is not. Experimental Physiology (2001) 86.2, 169-176.

The aim of this study was to determine the effect of acute plasma volume expansion on arterial blood-gas status during 6.5 min strenuous cycling exercise comparing six athletes with and six athletes without exercise-induced arterial hypoxaemia (EIAH). We hypothesized that plasma volume expansion could improve arterial oxygen pressure in a homogeneous sample of athletes - those with EIAH. In this paper we have extended the analysis and results of our recently published surprising findings that lengthening cardiopulmonary transit time did not improve arterial blood-gas status in a heterogeneous sample of endurance cyclists. One 500 ml bag of 10 % Pentastarch (infusion condition) or 60 ml 0.9 % saline (placebo) was infused prior to exercise in a randomized, double-blind fashion on two different days. Power output, cardiac output, oxygen consumption and arterial blood gases were measured during strenuous exercise. Cardiac output and oxygen consumption were not affected by acute hypervolaemia. There were group × condition interaction effects for arterial oxygen pressure and alveolar-arterial oxygen pressure difference, suggesting that those with hypoxaemia experienced improved arterial oxygen pressure (+4 mmHg) and lower alveolar-arterial oxygen pressure difference (-2 mmHg) with infusion. In conclusion, acute hypervolaemia improves blood-gas status in athletes with EIAH. The impairment of gas exchange occurs within the first minute of exercise, and is not impaired further throughout the remaining duration of exercise. This suggests that arterial oxygen pressure is only minimally mediated by cardiac output. Experimental Physiology (2003) 88.4, 555-564.

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.

We reported recently that hypoxia inhibits baroreflex vagal bradycardia (BVB) in rats and that this inhibition persists following chemoreceptor denervation. However, since it is possible that hypoxia also affects the central processing of chemoreceptive input, the existence of chemoreceptor-mediated inhibition of BVB cannot be ruled out. Therefore, we have studied whether selective chemoreceptor activation affects BVB in normoxic conditions. In pentobarbital-urethane-anaesthetized, succinylcholine-immobilized, artificially ventilated rats, BVB was provoked by electrical stimulation of the aortic depressor nerve. Arterial chemoreceptors were selectively activated by intracarotid injection of a minute amount of sodium cyanide. Cyanide injection consistently increased blood pressure while changing heart rate variably. BVB was inhibited in a dose-dependent manner. This inhibition, as well as changes in blood pressure and heart rate, was abolished following transection of the carotid sinus nerve (CSN) ipsilateral to the injection. Spinal cord transection at the C2 level did not affect the inhibition. On the other hand, intracarotid cyanide had no effect on bradycardia elicited by electrical stimulation of a peripheral cut end of the cervical vagus nerve. We conclude that chemoreceptor activation definitely inhibits BVB and that this inhibition is mediated by the CSN, and predominantly occurs in the central nervous system. The possibility is suggested that severe hypoxia suppresses not only BVB but also the chemoreceptor-mediated inhibition of BVB, both via the direct, central action.

The acinar cells of the ferret parotid gland are supplied with parasympathetic nerve fibres containing vasoactive intestinal peptide (VIP) and substance P. In this study intracarotid infusions of the two peptides (0·5-1·0 µg kg-1 min-1 of each for 40 min) in the pentobarbitone-anaesthetized ferret, treated with atropine and adrenoceptor antagonists, induced a loss of acinar secretory granules from this gland, by 32 % in response to VIP and by 46 % in response to substance P. Stimulation of the parasympathetic auriculo-temporal nerve (40 Hz, in the presence of adrenoceptor antagonists) caused a larger loss of acinar granules from the gland than stimulation of the sympathetic superior cervical ganglion (intermittently, 50 Hz for 1 s every 10th second, in the presence of atropine) over 40 min (52 % versus 10 %). A 27 % granular loss in response to parasympathetic stimulation followed upon atropinization. The parasympathetic response was not further diminished by the tachykinin antagonist Spantide ((D-Arg1, D-Pro2, D-Trp7,9, Leu)-substance P). Thus, despite the large exocytotic response to the infusion of substance P, the parasympathetic non-adrenergic, non-cholinergic secretion of storage granules seemed, under the present experimental conditions, to occur independently of the action of substance P.