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CARDIOVASCULAR |
1 Cell and Metabolic Signalling Group, School of Medicine and Dentistry, Medical Biology Centre, 97 Lisburn Road, Queen's University, Belfast BT9 7BL, Northern Ireland, UK
2
Department of Physiology, Division of Medical Sciences, Medical School, Vincent Drive, Birmingham B15 2TT, UK
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Abstract |
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(Received 22 June 2007;
accepted after revision 9 August 2007;
first published online 16 August 2007)
Corresponding author C. D. Johnson: Cell and Metabolic Signalling Research Group, Medical Biology Centre, Queen's University of Belfast, 97 Lisburn Rd, Belfast BT9 7BL, UK. Email: cajohnson{at}qub.ac.uk
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Introduction |
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2-adrenoreceptors (Tateishi & Faber, 1995; Coney & Marshall, 2007). By contrast, the effect of systemic hypoxia upon the cutaneous circulation, which has a rich sympathetic innervation and is heavily involved in thermoregulation (Rowell, 1983), is much less clear. It was deduced from the effects of sympathetic denervation and body warming in the rabbit, that although graded systemic hypoxia evokes vasodilatation in the ear and hindlimb skin, sympathetic vasoconstrictor activity increases to arterial resistance vessels of hindlimb skin in severe hypoxia, but decreases to arteriovenous anastomes (AVAs) of the ear, with a weak underlying sympathetic vasoconstriction (Chalmers & Korner, 1966), presumably in resistance vessels. It was also reported that systemic hypoxia evokes cutaneous vasoconstriction in the hand of human subjects (Abrahamson et al. 1943). Later, it was shown that systemic hypoxia evoked a decrease in sympathetic activity to the rabbit ear unless the hypoxia was severe, when an increase in cutaneous sympathetic activity occurred (Iriki & Kozawa, 1975). Further experiments on decerebrated rabbits led to the conclusion that suprabulbar structures, and by implication central thermoregulatory regions, are required for the cutaneous inhibitory response to systemic hypoxia (Iriki & Kozawa, 1976). However, these sympathetic recordings were made from multifibre preparations and so gave no indication of whether different fibres showed directionally different responses and/or supplied different types of blood vessels. On the other hand, in the cat, systemic hypoxia or direct stimulation of carotid chemoreceptors evoked a decrease in many of the sympathetic fibres that supplied the skin of the hindlimb and paw, but no change, or an increase in activity in others (Gregor & Jänig, 1977; Blumberg et al. 1980). These fibres were ‘split’ from the whole nerve with no direct evidence of the vessels they were supplying. However, it was speculated that they were destined for AVAs (and veins) and arterial resistance vessels, respectively, in accord with the interpretation Chalmers & Korner (1966) placed on their results (Gregor & Jänig, 1977; Blumberg et al. 1980). Subsequently, it has been argued that cutaneous vasodilatation in response to systemic hypoxia is part of a centrally regulated decrease in the thermoregulatory set point (anapyrexia) that leads to heat loss, inhibition of shivering thermogenesis, and a decrease in O2 consumption and is therefore O2 sparing (e.g. Gautier & Bonora, 1992; Steiner & Branco, 2002; Madden & Morrison, 2005).
In view of all of these findings and proposals, the primary objective of the present study was to use the focal recording technique to investigate the effects of systemic hypoxia on the activity of single sympathetic nerve fibres on the surface of the caudal ventral artery (CVA) of the rat tail (Johnson & Gilbey, 1994, 1996) whilst simultaneously recording tail blood flow (TBF) from the CVA (Johnson et al. 2001), and to accomplish this at relatively low and high core temperatures. The tail circulation of the rat, like the cutaneous circulation, plays a major role in thermoregulation (Torrington, 1966).
By using the focal recording technique it has already been shown that the activity in sympathetic fibres that supply the CVA often has respiratory-related rhythmicity (Johnson & Gilbey, 1996, 1998) as is common in sympathetic fibres (Häbler et al. 1994). However the dominant rhythm was not necessarily identical with the respiratory rhythm and has been termed the T-rhythm (Johnson & Gilbey, 1996), with a frequency of 0.4–1.2 Hz under normocapnic, normothermic conditions. The T-rhythym was more likely to become entrained to the respiratory rhythm when central respiratory drive (CRD) was increased by hypercapnia (Chang et al. 1999), but it persisted when CRD was absent, and was decreased by aortic baroreceptor stimulation, which had no effect on CRD (Johnson & Gilbey, 1996, 1998). Importantly, during hyperthermia, the T-rhythm frequency decreased, as did the mean firing frequency, even though CRD increased (Johnson & Gilbey, 1996, 1998). It is now widely accepted that changes in the rhythmicity of sympathetic activity are important in producing changes in vascular tone (see McAllen & Malpas, 1997). Certainly, rhythmic sympathetic discharge produces greater vasoconstriction than the same number of impulses delivered at constant frequency in both tail and skeletal muscle of the rat in vivo (Johnson et al. 2001; Coney & Marshall, 2003), in other vascular beds and in isolated arteries (e.g. Pernow et al. 1989). This is, at least in part, because the patterning of the activity determines the relative importance and magnitude of effect of the different sympathetic cotransmitters (e.g. Kennedy et al. 1986; Sjöblom-Widfeldt & Nilsson, 1990). Thus, the second objective of the present study was to investigate the effect of systemic hypoxia upon the T-rhythm and respiratory rhythmicity of the sympathetic fibres that supply the CVA at two different core temperatures and to establish the relationship between any changes in rhythmicity and the vascular response in the CVA. We used a core temperature of 36.3°C when sympathetic vasoconstrictor activity to, and vascular tone of, the CVA was relatively high, and 39°C when sympathetic activity to the tail was ‘switched off’ and vascular tone was low (Johnson & Gilbey, 1996; Häbler et al. 2000).
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Methods |
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Experiments were performed on spontaneously breathing male Wistar rats (270–350 g). All experiments were approved by UK legislation under the Animals (Scientific Procedures) Act 1986. Rats were initially anaesthetized with an oxygen–halothane (3.5%) mixture and then maintained by intravenous infusion of Saffan (7–12 mg kg–1 h–1; Schering-Plough Animal Health, Welwyn Garden City, UK) as previously described (Johnson et al. 2001). Both brachial arteries were cannulated to allow arterial blood pressure (ABP) to be continuously recorded and to provide samples for analysis of the partial pressures of O2 and CO2 (Pa,O2, Pa,CO2, respectively) and arterial pH (see below). The trachea was cannulated low in the neck and the animal allowed to breathe spontaneously with room air. Tracheal pressure (TP) was recorded as an index of respiratory frequency by means of a side arm leading from the tracheal cannula to a pressure transducer (NL108A, Digitimer, UK). Arterial blood samples were taken regularly throughout experiments to maintain blood gases at levels reported in Table 1. Core temperature was measured from the oesophagus and maintained at 37°C by means of a homeothermic blanket placed under the animal except when changed during the protocol (see below). A cotton wool blanket was placed over the rat when recordings were being made at a higher core temperature. This was removed when the animal was allowed to cool as part of the protocol (see below for further details). Tail skin temperature was not measured: the bath in which the tail was placed (see below) was at room temperature (21–25°C), and rose slightly (1–3°C) when the animal was heated.
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All signals were stored on computer via a lab interface (1401; Cambridge Electronic Design (CED), Cambridge, UK) compatible with software for on- and off-line monitoring and analysis (Spike2, CED). Software calculated mean arterial blood pressure from the blood pressure trace along with heart rate. Similarly, respiratory frequency (Rf) was calculated on-line from the TP signal. Tail and femoral vascular resistance (TVR, FVR, respectively) were calculated on-line as TBF or FBF divided by ABP with a calculation frequency of 5 Hz. This software also generates trigger signals from nerve action potential, ABP and TP wave-forms, which were used for time series histogram analysis of action potential patterning (interspike interval histograms (ISIHs), auto- and cross-correlograms, see Johnson & Gilbey, 1996). These were calculated over 60 s epochs, so that the 5 min period of hypoxia (see below) generated five histograms for each variable. Modal intervals for the first peak in the ISIHs were used to calculate intraburst intervals. In most units, a second peak, corresponding to interburst interval, was not clearly defined (see Results). Thus, no attempt was made to obtain group data for these intervals. Auto-correlations of nerve activity were used to show the periodicity of sympathetic discharge. TP-triggered cross-correlations of nerve discharge were used to examine periodicity of respiration: this reflected the periodicity of CRD as the animal was spontaneously breathing. Modal frequencies of the respiratory cycle and T-rhythm were calculated from the reciprocal of peak-to-peak time. These histograms allowed comparison between central respiratory and T-rhythm periodicities: we did not attempt to deduce the phase relationships between the two rhythms because TP does not give precise information on the timing of central respiratory activity. Similarly, we did not attempt detailed analysis of the modulation of sympathetic nerve activity by CRD.
Protocol
In early experiments, when the core temperature of the rat was maintained at 
37°C (36.7–37.3°C), TBF was variable (0.3–1.75 ml min–1). When TBF was in the high end of this range, it was not possible to record on-going activity, whereas this was possible when TBF was in the low end of the range. Therefore, for the first part of the protocol in experiments reported here, core temperature was kept slightly below 37°C (see Results) such that TBF was relatively low and TVR relatively high to facilitate recording of ongoing sympathetic activity from the CVA. The singular nature of the recorded, on-going action potentials was confirmed by comparison with an action potential evoked from the LSCs and constancy of shape (Fig. 1, see Johnson & Gilbey, 1996). On-going activity and other variables were monitored for a 5 min control period. The inspirate was then switched from air to 12% O2 in N2 for 5 min, and then back to air for 5 min. At the end of each 5 min period, an arterial blood sample was taken for gas analysis. After a recovery period of 10 min, and assuming that the neural recording was still intact, this part of the protocol was repeated except that the rat breathed 8% O2 rather than 12% O2.
The animal was then slowly warmed until ongoing-sympathetic activity switched off as part of the thermoregulatory response to an increase in core temperature (see Results). The position of the electrode on the original nerve recording site was confirmed by establishing that an action potential could be evoked from the LSCs. This was particularly important because it was common for the recording to be lost, presumably due to movement associated with respiratory changes, or vasomotion of the blood vessel beneath the electrode tip during temperature changes or hypoxia. The animal was then given 12% and then 8% O2 to breathe for 5 min each as described above. If unit activity did not resume during either period of hypoxia, further attempts were made to record an action potential evoked by stimulating the LSCs to confirm that the original recording site was intact. Experiments in which no action potential could be evoked are not included in the analysis of this part of the protocol.
Statistical analyses
Results are expressed as means ± S.E.M. At the lower and at the higher core temperature (modest hypothermia and hyperthermia, respectively), the values recorded under control conditions over the minute prior to each period of hypoxia, in each of the 5 min during hypoxia were compared by one-way analysis of variance (ANOVA) followed by Bonferroni's post hoc test when appropriate (P < 0.05). Comparisons were also made between baseline values recorded at the lower and higher core temperatures by using one-way ANOVA.
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Results |
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Respiratory modulation was clear in all CVA units recorded in both levels of hypoxia, and thus the frequency of the respiratory-related rhythmicity increased with Rf (see Fig. 3Bd for example). However, during 12% O2, there was no significant change in the mean frequency of CVA unit activity (group mean: 1.38 ± 0.21 versus 1.41 ± 0.26 Hz, n = 13; see Fig. 2D), although 6/13 units showed a slight increase in discharge frequency (from 1.54 ± 0.29 to 1.87 ± 0.30 Hz) and 7/13 a slight decrease (from 1.15 ± 0.31 to 0.81 ± 0.32 Hz). There was no obvious relationship between control discharge rate and response to hypoxia (see Fig. 4). During 12% O2, there was also no significant change in T-rhythm frequency (Fig. 2G): in three units the T-rhythm (1.00 ± 0.12 Hz) disappeared during hypoxia and had not returned after 5 min of recovery, in two units the T-rhythm frequency moderately increased (from 0.66 ± 0.26 to 0.76 ± 0.28 Hz), in two units it decreased (from 1.11 ± 0.14 to 0.83 ± 0.15 Hz) and in six it was unchanged (0.96 ± 0.43 Hz). There was no obvious relationship between change in rate and T-rhythm frequency, these two variables changing in the same direction in only one unit. Of the eight units with T-rhythms that were locked to that of respiration during normoxia, synchrony was lost in six units during 12% O2 remained in a ratio of 1 : 1 in one and changed from 1 : 1 to 1 : 2 in the other.
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There was no apparent relationship between the CVA unit response to 12 and 8% O2: there were changes of rate in the same direction in only 2/8 units, Similarly, there was no apparent relationship between change in T-rhythm frequency in 12% O2 and 8% O2. The ISIHs showed that there were no differences in modal intraburst frequencies between control periods and either level of hypoxia: control, 22.6 ± 3.3 Hz (n = 11); 12% O2, 21.7 ± 2.9 Hz (n = 11); 8% O2, 22.6 ± 4.5 Hz (n = 6). In two units in which there was an obvious second ISIH peak in normoxia, reflecting the T-rhythm, the interburst interval decreased during hypoxia, and a third smaller peak with a shorter interspike interval possibly corresponding to the respiratory frequency, was also apparent (see Fig. 3Ba). In the remaining units, a second peak was no more obvious in hypoxia than in normoxia (see above).
Responses evoked during hyperthermia
When core temperature was raised to 39.2 ± 0.4°C (n = 11) there was no change in ABP, but there were marked decreases in baseline TVR and FVR and increases in TBF and FBF (Fig. 5E, F, H and I). Concomitantly both baseline HR and Rf increased (Table 1 and Fig. 5A and C). Accompanying the fall in TVR, there was a switch-off of unit activity recorded from the CVA (Figs 1B and 5D).
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Concomitantly, during 12% O2, none of the 13 units from which recordings were made switched back on: in each case, attachment of the electrode to the nerve was confirmed by evoking a response from the LSCs during hypoxia (see Fig. 1Bd and 5F). However, during 8% O2, in 4 of the 8 units in which the recording site remained viable, the increase in TVR was accompanied by recommencement of unit firing (Figs 1C and 5I). The frequency of this discharge was considerably lower than that recorded during normoxia or hypoxia at the lower core temperature (cf. Fig. 2Af and 2Bf). Of these four units, two had responded with a slight increase in discharge rate during 8% O2 in moderate hypothermia, one had responded with a decrease and in one unit there had been no change in rate. No T-rhythm was observable, although strong respiratory-related modulation was apparent in the TP-triggered cross-correlograms (see Fig. 6A and C).
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Discussion |
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For the first part of our protocol, core temperature was maintained at 36.3°C so as to ensure ongoing activity in sympathetic units on the CVA and achieve stable levels of TBF and TVR. Although most experiments on anaesthetized rats are performed with core temperature maintained at 37°C, core temperature in the conscious rat is 38°C (e.g. Kregel et al. 1990). Thus 36.3°C represents modest hypothermia. Under this condition, CVA unit activity in spontaneously breathing rats anaesthetized with Saffan was comparable to that in spontaneously breathing, or artificially ventilated rats under pentobarbitone/chloralose anaesthesia and maintained at 37°C, with or without vagi and/or aortic and sinus nerves cut (see Johnson & Gilbey, 1994, 1996; Chang et al. 1999, 2000). Thus, activity in all units was rhythmic and the dominant rhythm had a frequency of 0.4–1.2 Hz (0.96 Hz), termed the T-rhythm (Johnson & Gilbey, 1996): it was sometimes the same as and sometimes different from the central respiratory rhythm. By contrast, Häbler et al. (1999), who recorded from the ventral collector nerve (VCN) to the tail in artificially ventilated rats maintained at 37°C under pentobarbitone anaesthesia with vagi, aortic and sinus nerves cut, reported that central respiratory rhythm was dominant and there was no independent T-rhythm. Reasons for the disparity are not clear given the variety of conditions under which the T-rhythm has been recorded. However, our results are compatible with the proposal that sympathetic neurones that supply the CVA are driven by multiple T-rhythm oscillators (Chang et al. 1999, 2000).
Responses evoked during modest hypothermia
Although neither level of systemic hypoxia evoked a statistically significant change in mean discharge frequency of CVA units, some showed an increase and others a decrease. These findings might seem consistent with those of Jänig and colleagues (Gregor & Jänig, 1977; Blumberg et al. 1980) who reported opposing patterns of behaviour in single sympathetic fibres supplying the paw and skin of the cat during systemic hypoxia, and deduced these represented fibres destined for arteries or AVAs, respectively. However, in the present study, there was no consistency in the responses of individual units to the two levels of hypoxia. Further, we recorded from fibres in the adventitia of the proximal CVA and there is no reason to suppose they supplied any vessel other than the CVA. Branches arise from paravascular bundles and innervate short lengths of the CVA: AVAs have their own nerve supply and are mainly in the distal tail (Sittiracha et al. 1987; Anderson & McLachlan, 1991). Thus, it is unlikely that we recorded from functionally different populations of neurones. Rather, the very small changes in mean frequency, < 1Hz in either direction, probably reflected variable changes in rhythmicity in individual CVA neurones (see below).
The T-rhythm frequency did not change significantly during either level of hypoxia, some individual units showing no change, some an increase, others a decrease and a few losing their T-rhythm. When CVA unit activity is continuously recorded under stable experimental conditions, the rhythmicity shows periods of instability with changes in pattern of discharge and T-rhythm frequency (Johnson & Gilbey, 1996; Chang et al. 1999). Thus, the present variability may reflect this inherent instability. Certainly, the present results suggest that the combination of an increase in CRD caused by peripheral chemoreceptor stimulation and of baroreceptor unloading caused by the hypoxia-induced fall in ABP, has no consistent effect on T-rhythm frequency. This apparently contrasts with the findings that blood volume expansion, or continuous stimulation aortic baroreceptor afferents in artificially ventilated rats, did not affect CRD frequency, but decreased T-rhythm frequency in CVA units (Johnson & Gilbey, 1998). Vascular and cardiac components of baroreceptor reflex are fully effective in Saffan-anaesthetized rats (e.g. Hebert & Marshall, 1988). Thus, the present results indicate that at least in modest hypothermia, either baroreceptor unloading is not as effective as baroreceptor stimulation in altering T-rhythm frequency, or that baroreceptor inputs are less effective when CRD frequency is concurrently increased by peripheral chemoreceptor stimulation.
Most CVA units also had a respiratory-related rhythm, as reported by Johnson & Gilbey (1996) in spontaneously breathing rats. During mild and severe hypoxia, the frequency of this respiratory rhythm increased, i.e. CVA unit rhythmicity followed the increase in CRD frequency evoked by peripheral chemoreceptor stimulation. Due to the variability of the T-rhythm frequency during hypoxia (see above), the synchronization between T-rhythm and respiratory rhythm that existed in 50% of units in normoxia, was generally lost during hypoxia. By contrast, under the highly controlled conditions of pneumothorax and constant artificial ventilation with vagi cut, the increase in CRD evoked by hypercapnia led to greater synchronization of the T-rhythm and CRD in individual and pairs of CVA units (Chang et al. 1999). Thus, the present results suggest that in modest hypothermia, synchronization of the influences of CRD and T-rhythm oscillators on CVA unit activity occurs less readily under more natural conditions when increased CRD is associated with an increase in CRD frequency. This suggestion is consistent with the finding that in artificially ventilated rats, synchronization of the T-rhythm and CRD was less likely when the frequency of the lung inflation cycle was moved further away from the T-rhythm frequency (Chang et al. 2000).
Thus, the present findings indicate that during modest hypothermia, mild or severe systemic hypoxia has relatively little effect on the pattern of sympathetic discharge to the CVA. There was no consistent change in T-rhythm frequency, whereas the frequency of the respiratory rhythm increased, but resulted in minor changes in mean discharge frequency. Further, the ISIHs revealed that neither level of hypoxia had any effect on intraburst frequency, which remained at 22 Hz. Moreover, interburst intervals were inconsistent in both normoxia and hypoxia, reflecting the presence of a T-rhythm and/or a respiratory rhythm. It is therefore very unlikely that changes in the patterning of the sympathetic discharge to the CVA contributed to the substantial decrease in TVR. Rather, this vasodilatation may reflect blunting of the 2 component of the sympathetic vasoconstrictor influence on the CVA (Bao et al. 1993), which is especially vulnerable to hypoxia (Tateishi & Faber, 1995; Coney & Marshall, 2007). It may also reflect myogenic dilatation induced by the hypoxia-induced fall in ABP and/or dilatation induced by adenosine and NO that are released by the endothelium, as occurs in hindlimb muscle (Edmunds et al. 2003; Ray et al. 2002).
These proposals are consistent with the report that in normothermia, local dilator influences were totally responsible for vasodilatation evoked by systemic hypoxia (Pa,O2 37–31 mmHg) in the hindlimb skin of rabbits and partly responsible for vasodilatation in the ear (Chalmers & Korner, 1966). We cannot discount the possibility that vasodilatation induced by inhibition of sympathetic activity to AVAs supplied by the CVA contributed to the fall in TVR, as reported for the rabbit ear (Chalmers & Korner, 1966; Iriki & Kozawa, 1975, 1976). However, TBF remained constant at both levels of hypoxia and so heat delivery through the CVA was not changed. Thus, there is no reason to suppose that during modest hypothermia, the effect of mild or severe systemic hypoxia on sympathetic activity to the CVA or its vasculature, was part of an anapyrexic response that reduces core temperature (e.g. Steiner & Branco, 2002). We already know that muscle vasodilatation and increased O2 extraction allows muscle O2 consumption 
to remain constant during the levels of hypoxia used in the present study (Edmunds & Marshall, 2001). Indeed, given muscle 
is largely responsible for whole body 
, it is unlikely that even the 5 min period of severe hypoxia used in the present study evoked the O2-sparing components of anapyresis. For comparison, conscious normothermic rats breathing 13 or 11% O2 for 20 min showed no fall in body temperature or 
(Gautier & Bonora, 1992).
Effects of systemic hypoxia during hyperthermia
When core temperature was raised to 39.2°C, Rf increased, sympathetic discharge in CVA units ceased and there was a gradual decrease in TVR indicating vasodilatation attributable to sympathetic withdrawal. This pattern is fully consistent with previous findings (Johnson & Gilbey, 1996; Häbler et al. 2000; Owens et al. 2002). The fall in TVR presumably reflected vasodilatation in the arterial resistance vessels and AVAs of the tail (Torrington, 1966). Concomitantly, baseline FVR fell by 50%. Given vascular resistance and blood flow in limb muscles are not changed by hyperthermia (Detry et al. 1972), while MSNA is increased (Niimi et al. 1997; Keller et al. 2006), the decrease in FVR can be attributed to vasodilatation caused by inhibition of sympathetic vasoconstrictor drive to hindlimb skin. Certainly, gross forearm vascular resistance falls during hyperthermia due to cutaneous vasodilatation (Detry et al. 1972; Rowell et al. 1989). As ABP was well maintained in hyperthermia, there must have been a substantial increase in splanchnic and renal vascular resistance and effective baroreceptor regulation of ABP, as in conscious rats (Kregel et al. 1990).
During hyperthermia, mild systemic hypoxia failed to initiate activity in the 13 sympathetic CVA units from which activity had been recorded in normoxia, but severe hypoxia ‘switched on’ 4 out of 8 units so that they discharged at a low mean frequency of < 0.25 Hz. This discharge had no T-rhythm, but did have respiratory rhythmicity, attributable to a further increase in CRD: although Rf was similar at these two levels of hypoxia, previous studies showed that tidal volume was greater in severe hypoxia indicating greater CRD (Marshall & Metcalfe, 1988). Since TVR increased significantly in both mild and severe hypoxia, it seems reasonable to propose that some CVA units began to fire in mild hypoxia, but that more were recruited in severe hypoxia. If the population of CVA units from which we recorded were representative, then < 8% (< 1/13) discharged in mild hypoxia and 50% in severe hypoxia. That low discharge in single CVA units was associated with an increase in TVR is consistent with evidence that even single impulses delivered to perivascular nerves of the CVA in vitro evoked substantial contraction (Bao et al. 1993) and that single impulses in CVA units in vivo were accompanied by transient increases in TVR (Johnson et al. 2001). When the rabbit ear was dilated by body heating, severe hypoxia similarly evoked vasoconstriction in the ear (Chalmers & Korner, 1966). Indeed, if this observation is considered together with the present findings, it seems that when the AVAs are dilated by hyperthermia, this facilitates the ability of systemic hypoxia to evoke sympathetically evoked vasoconstriction in the arterial resistance vessels of the cutaneous circulation, by stimulating peripheral chemoreceptors (see Marshall, 1994). It should be noted that during hyperthermia, in the rat tail as well as the rabbit ear, the vasoconstrictor response to systemic hypoxia led to a substantial decrease in cutaneous blood flow and presumably restricted heat loss (cf. anapyresis).
The present study also showed that during hyperthermia, both levels of systemic hypoxia caused a significant decrease in FVR. This can most easily be explained by persistence of the hypoxia-induced vasodilatation in skeletal muscle (see above). The magnitude of the falls in FVR may have been smaller than those evoked by hypoxia during modest hypothermia, because the effect of muscle vasodilatation on FVR was offset by vasoconstriction in the arterial resistance vessels of hindlimb skin, as occurred in the tail (see above). In other words, these results are consistent with the idea that changes in core temperature differentially affect vascular responses evoked by systemic hypoxia in skeletal muscle and in skin.
Integration of influences on CVA unit activity
The very fact that the discharge evoked in CVA units by severe hypoxia in hyperthermia had respiratory rhythmicity, but no T-rhythm, accords with the idea that the oscillators that drive the T-rhythm and respiratory rhythm can be independent of one another (Johnson & Gilbey, 1996; Chang et al. 1999, 2000). They also accord with evidence that sympathetic activity to rat tail is controlled by two discrete regions of the medulla, the medullary raphé and the rostral ventrolateral medulla (RVLM). The RVLM provides the drive that maintains preganglionic neurone excitability, while the medullary raphé is the more powerful and carries the thermoregulatory drive (Smith et al. 1998; Oostuka & McAllen, 2005 and references therein). The RVLM is known to play an important role in mediating several non-thermoregulatory reflexes, including peripheral chemoreceptor and baroreceptor reflexes (see Guyenet, 2000). Thus, on the basis of the present results, we can propose that although sympathetic activity in neurones that supply CVA is switched off during hyperthermia by the raphé circuitry, they are switched on again during systemic hypoxia, in numbers and to extents that are proportional to the peripheral chemoreceptor input to the RVLM, by a drive that has respiratory rhythmicity (see Guyenet, 2000) and which induces vasoconstriction. On the other hand, during modest hypothermia, although the influence of peripheral chemoreceptor stimulation on the respiratory rhythmicity of CVA units can be demonstrated during systemic hypoxia, the dominant influence is that of the thermoregulatory input from medullary raphé on T-rhythm oscillators that drive CVA units (see Chang et al. 1999, 2000). The T-rhythm oscillators may be influenced by other inputs such as baroreceptors, but during modest hypothermia, they apparently have little net effect on pattern of discharge in the CVA units (see above). Thus, vasoconstrictor tone in the cutaneous circulation supplied by the CVA remains constant.
In summary, the present study has shown that in spontaneously breathing rats during modest hypothermia, when there is strong discharge with a T-rhythm and respiratory rhythmicity in sympathetic fibres that supply the CVA, mild or severe systemic hypoxia has no consistent effect on the T-rhythm, but increases the frequency of the respiratory rhymicity, without significantly changing mean discharge frequency, or intraburst frequency. Meanwhile, the relatively high TVR shows a modest decrease during hypoxia mediated by local dilator factors, which keep TBF constant, and maintains O2 delivery to the cutaneous circulation of the tail without disturbing its role in thermoregulation. By contrast, during hyperthermia, when sympathetic discharge to the CVA is switched off, systemic hypoxia initiates low frequency discharge with respiratory rhythmicity, but no T-rhythm. This increases the relatively low TVR and decreases the high level of TBF, so limiting delivery of O2 and heat to the tail, but allowing the cutaneous circulation to contribute to maintenance of total peripheral resistance and thereby O2 delivery to other tissues including skeletal muscle and brain.
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References |
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Anderson CR & McLachlan EM (1991). The time course of the development of the sympathetic innervation of the vasculature of the rat tail. J Auton Nerv Syst 35, 117–132.[CrossRef][Medline]
Bao JX, Gonon F & Stjarne L (1993). Frequency and train length-dependent variation in the roles of post-junctional 1 and 2 adrenoceptors for the field stimulation induced neurogenic contraction of the rat tail artery. Naunym-Schmid Arch Pharmacol 347, 601–616.[CrossRef]
Blitzer ML, Lee SD & Creager MA (1996). Endothelium-derived nitric oxide mediates hypoxic vasodilation of resistance vessels in humans. Am J Physiol Heart Circ Physiol 271, H1182–H1185.
Blumberg H, Jänig W, Rieckmann C & Szulczyk P (1980). Baroreceptor and chemoreceptor reflexes in postganglionic neurones supplying skeletal muscle and hairy skin. J Auton Nerv Syst 2, 223–240.[CrossRef][Medline]
Chalmers JP & Korner PI (1966). Effects of arterial hypoxia on cutaneous circulation of the rabbit. J Physiol 184, 685–697.
Chang H-S, Staras K & Gilbey MP (2000). Multiple oscillators provide metastability in rhythm generation. J Neuroscience 20, 5135–5143.
Chang H-S, Staras K, Smith JE & Gilbey MP (1999). Sympathetic neuronal oscillators are capable of dynamic synchronization. J Neuroscience 19, 3183–3197.
Coney AM & Marshall JM (2003). Contribution of adenosine to the depression of sympathetically evoked vasoconstriction induced by systemic hypoxia in the rat. J Physiol 549, 613–623.
Coney AM & Marshall JM (2007). Contribution of 2-adrenoceptors and Y1 neuropeptide Y receptors to the blunting of sympathetic vasoconstriction induced by systemic hypoxia in the rat. J Physiol 582, 1349–1359.
Detry J-MR, Brengelmann GL, Rowell LB & Wyss C (1972). Skin and muscle components of forearm blood flow in directly heated resting man. J Appl Physiol 32, 506–511.
Edmunds NJ & Marshall JM (2001). Oxygen delivery and oxygen consumption during systemic hypoxia: role of adenosine. J Physiol 536, 927–935.
Edmunds NJ, Moncada S & Marshall JM (2003). Does nitric oxide allow endothelial cells to sense hypoxia and mediate hypoxic vasodilatation? In vivo and in vitro studies. J Physiol 546, 521–527.
Fukuda Y, Sato A, Suzuki A & Trebski A (1989). Autonomic nerve and cardiovascular responses to changing blood oxygen and carbon dioxide levels in the rat. J Auton Nerv Syst 28, 61–74.[CrossRef][Medline]
Gautier H & Bonora M (1992). Ventilatory and metabolic responses to cold and hypoxia in intact and carotid body-denervated rats. J Appl Physiol 73, 847–857.
Gregor M & Jänig W (1977). The effects of systemic hypoxia and hypercapnia on cutaneous and muscle vasoconstrictor neurones in the cat's hind limb. Pflugers Arch 368, 71–81.[CrossRef][Medline]
Guyenet PG (2000). Neural structures that modulate sympathoexcitation during hypoxia. Resp Physiol 121, 147–161.[CrossRef][Medline]
Häbler H-J, Bartsch T & Jänig W (1999). Rhythmicity in single fiber postganglionic activity supplying the rat tail. J Neurophysiol 81, 2026–2036.
Häbler H-J, Bartsch T & Jänig W (2000). Respiratory rhythmicity in the activity of postganglionic neurones supplying the rat tail during hyperthermia. Auton Neurosci 83, 75–80.[CrossRef][Medline]
Häbler H-J, Jänig W, Krummel M & Peters OA (1994). Reflex patterns in postganglionic neurons supplying skin and skeletal muscle of the rat hind limb. J Neurophysiol 72, 2222–2236.
Hebert MT & Marshall JM (1988). Direct observations of the effects of baroreceptor stimulation on mesenteric circulation of the rat. J Physiol 400, 29–44.
Hudson S, Johnson CD, Coney AM & Marshall JM (2002). Changes in sympathetic nerve activity recorded from skeletal muscle arteries of the anaesthetized rat during graded levels of systemic hypoxia. J Physiol 544.P, 28P.
Iriki M & Kozawa E (1975). Factors controlling the regional differentiation of sympathetic outflow – influence of the chemoreceptor reflex. Brain Res 11, 281–291.[CrossRef]
Iriki M & Kozawa E (1976). Patterns of differentiation in various sympathetic efferents induced by hypoxic and by central thermal stimulation in decerebrated rabbits. Pfluegers Arch 362, 101–108.[CrossRef][Medline]
Johnson CD, Coney AM & Marshall JM (2001). Roles of norepinephrine and ATP in sympathetically evoked vasoconstriction in rat tail and hindlimb in vivo. Am J Physiol Heart Circ Physiol 281, H2432–H2440.
Johnson CD & Gilbey MP (1994). Sympathetic activity recorded from the caudal ventral artery in vivo. J Physiol 476, 437–442.
Johnson CD & Gilbey MP (1996). On the dominant rhythm in the discharges of single sympathetic postganglionic neurons innervating the rat tail artery. J Physiol 497, 241–259.[Medline]
Johnson CD & Gilbey MP (1998). Effects of aortic nerve stimulation on discharges of sympathetic neurons innervating rat tail artery and vein. Am J Physiol Regul Integr Comp Physiol 275, R942–R949.
Keller DM, Cui J, Davis SL, Low DA & Crandall CG (2006). Heat stress enhances arterial baroreflex control of muscle sympathetic nerve activity via increased sensitivity of burst gating, not burst area, in humans. J Physiol 573, 445–451.
Kennedy C, Saville VL & Burnstock G (1986). The contributions of noradrenaline and ATP to the responses of the rabbit ear artery to sympathetic nerve stimulation depend on the parameters of stimulation. Eur J Pharmacol 122, 291–300.[CrossRef][Medline]
Kregel KC, Johnson DG, Tipton CM & Seals DR (1990). Arterial baroreceptor reflex modulation of sympathetic-cardiovascular adjustments to heat stress. Hypertension 15, 497–504.
Leuenberger UA, Gray K & Herr MD (1999). Adenosine contributes to hypoxia-induced vasodilatation in humans. J Appl Physiol 87, 2218–2224.
Madden CJ & Morrison SF (2005). Hypoxic activation of arterial chemoreceptors inhibits sympathetic outflow to brown adipose tissue in rats. J Physiol 566, 559–573.
Marshall JM (1994). Chemoreceptors and cardiovascular regulation. Physiol Rev 74, 543–594.
Marshall JM & Metcalfe JD (1988). Cardiovascular response evoked by graded levels of systemic hypoxia in the rat. J Physiol 410, 381–384.
McAllen RM & Malpas SC (1997). Sympathetic burst activity: characteristics and significance. Clin Expt Pharmacol Physiol 24, 791–799.[CrossRef]
Niimi Y, Matsukawa T, Sugiyama Y, Shamsuzzaman AS, Ito H, Sobue G & Mano T (1997). Effect of heat stress on muscle sympathetic nerve activity in humans. J Auton Nerv Syst 63, 61–67.[CrossRef][Medline]
Oostuka Y & McAllen RM (2005). Interactive drives from two brainstem premotor nuclei are essential to support rat tail sympathetic activity. Am J Physiol Regul Integr Comp Physiol 289, R1107–R1115.
Owens NC, Oostuka Y, Kanosue K & McAllen RM (2002). Thermoregulatory control of sympathetic fibres supplying the rat's tail. J Physiol 543, 849–858.
Pernow J, Schwieler J, Kahan T, Hjemdhal P, Oberle J, Wallin BG & Lundberg JM (1989). Influence of sympathetic nerve discharge pattern on norepinephrine and neuropeptide Y-release. Am J Physiol Heart Circ Physiol 257, H866–H872.
Ray CJ, Abbas MR, Coney AM & Marshall JM (2002). Interactions of adenosine, prostaglandins and nitric oxide in hypoxia-induced vasodilatation: in vivo and in vitro studies. J Physiol 544, 195–209.
Rowell LB (1983). Cardiovascular adjustments to thermal stress. Handbook of Physiology, section 2, The Cardiovascular System, vol. III, Peripheral Circulation and Organ Blood Flow, ed. Shepherd JT & Abboud FM, Ch 27, pp. 967–1023. American Physiological Society, Bethesda, MD, USA.
Rowell LB, Brengelmann GL, Savage MV & Freund PR (1989). Does acute hypoxemia blunt sympathetic activity in hyperthermia? J Appl Physiol 66, 28–33.
Sittiracha T, McLachlan EM & Bell C (1987). The innervation of the caudal artery of the rat. Neuroscience 21, 647–659.[CrossRef][Medline]
Sjöblom-Widfeldt N & Nilsson H (1990). Sympathetic transmission in small mesenteric arteries: influence of impulse pattern. Acta Physiol Scand 138, 523–528.[Medline]
Smith JE, Jansen ASP, Gilbey MP & Loewy AD (1998). CNS cell groups projecting to sympathetic outflow of tail artery: neural circuits involved in heat loss in the rat. Brain Res 786, 153–164.[CrossRef][Medline]
Somers VK, Mark AL, Zavala DC & Abboud FM (1989). Influence of ventilation and hypocapnia on sympathetic nerve responses to hypoxia in normal humans. J Appl Physiol 67, 2095–2100.
Steiner AA & Branco LGS (2002). Hypoxia-induced anapyresis: implications and putative mediators. Annu Rev Physiol 64, 263–288.[CrossRef][Medline]
Tateishi J & Faber JE (1995). Inhibition of arteriole 2-adrenoceptor but not 1-adrenoceptor constriction by acidosis and hypoxia in vitro. Am J Physiol Heart Circ Physiol 268, H2068–H2076.
Torrington RW (1966). The biology of rodent tails. A study of form and function. AAL-TR-65-8, Arctic Aeromedical Laboratory, Fort Wainright, AK, USA.
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