As far as other alerting stimuli are concerned, such as sudden sound, cold water or emotional stress, it is known that the cardiovascular components of the alerting responses and behavioural alerting do not necessarily habituate together. Moreover, there may be variation between individuals, so that some show habituation of one or more cardiovascular components of the alerting response on repetition of the stimulus, while others show no change, or even sensitisation of one or more components For systemic hypoxia, it is tempting to speculate that those individuals who show no habituation of the cardiovascular components of the alerting response to chemoreceptor stimulation would be most at risk of suffering the acute effects of a sudden rise in arterial pressure and tachycardia, such as aneurysm or myocardial infarction during repeated asthmatic attacks and more at risk of developing hypertension as a consequence of sleep apnoea.
This pattern seems to be superimposed upon more gradual changes that are graded with the level of hypoxia 55, In the cat, there is hyperventilation which is well maintained at least during a 3-min period of hypoxia, accompanied by a rather small tachycardia and rise in arterial pressure and no change, or slight vasodilatation in mesenteric, renal and skeletal muscle vasculature In the rat, there is also hyperventilation, but with a more pronounced tachycardia and substantial vasodilatation in mesenteric, renal, cerebral and skeletal muscle vasculature.
Moreover, the hyperventilation and tachycardia tend to return towards, or below the baseline, this becoming more obvious if the period of hypoxia is prolonged to 5 or 10 min 55,59,60; see Figure 3. The net effect of these changes is that arterial pressure falls in the rat to an extent that is graded with the level of hypoxia By performing experiments in which we have vagotomised, kept PaCO 2 constant, or paralysed and artificially ventilated the animals, we have been able to establish the roles of the secondary effects of hyperventilation in these gradual changes.
They are relatively weak in both species in agreement with their effects on the responses evoked by selective stimulation of carotid chemoreceptors see above. In the cat, the lung stretch receptors with vagal afferents apparently have no significant influence on the heart rate or vascular responses to systemic hypoxia, but if PaCO 2 is prevented from falling with the hyperventilation, then there is bradycardia rather than tachycardia, vasoconstriction in the renal and mesenteric circulation, and no change or slight dilatation in skeletal muscle This strongly suggests that in the normal situation, the fall in PaCO 2 , plays a major role in counteracting the bradycardia and vasoconstriction that would be expected as a primary response to hypoxic stimulation of carotid chemoreceptors.
Since vasoconstriction did not occur in muscle, even when PaCO 2 was controlled, it seems likely that in this tissue, the neurally mediated vasoconstriction was opposed by the local dilator influences of hypoxia. By contrast, in the rat, the fall in PaCO 2 makes only a minor contribution to the tachycardia and muscle vasodilatation in severe hypoxia On the other hand, the lung stretch receptors with vagal afferents do contribute to the tachycardia, but not to the peripheral vasodilatation Indeed, when ventilation was kept constant by artificial ventilation, then hypoxia induced bradycardia, but with substantial vasodilatation in skeletal muscle By considering these results together with the effects of various antagonists of the sympathetic nervous system, we have concluded that the primary bradycardia of hypoxic stimulation of carotid chemoreceptors is opposed both by the secondary effects of hyperventilation on lung stretch receptors and by the ability of central nervous hypoxia to increase cardiac sympathetic activity 56,60, The late bradycardia that occurs when hypoxia is prolonged can be attributed not only to the primary bradycardia of carotid chemoreceptor stimulation, but also to the local effects of hypoxia on the heart 60,63 , while the late decrease in ventilation towards or below the baseline reflects the central effect of hypoxia on respiratory neurones Clearly, this later decrease in the ventilatory response means that lung stretch receptors make less contribution to the tachycardia as the period of hypoxia progresses see The peripheral vasodilatation in mesenteric and in muscle vasculature largely reflects the local dilator effects of tissue hypoxia.
These influences are so strong that they apparently overcome the primary reflex vasoconstriction expected from carotid chemoreceptor stimulation and are largely responsible for the fall in systemic arterial pressure The rat is, therefore, far more dominated by the local effects of hypoxia on central respiratory neurones, heart and vasculature than the cat.
This is of particular interest because there are reports in the literature indicating that the respiratory and cardiovascular responses evoked by systemic hypoxia in neonates are very similar to those we have seen in the rat: characteristically, ventilation increases and then falls and generally arterial pressure decreases see 64, We have suggested this may arise because small mammals in general, whether the neonates of large mammalian species or the adults of small mammalian species, have a higher rate of O 2 consumption per gram body weight than larger mammals: they may therefore be more susceptible to the local metabolic effects of hypoxia when O 2 supply is reduced Unfortunately, the pattern of response that is produced by the local effects of hypoxia is potentially life-threatening as is explained below.
The fact that respiration increases initially in neonates who become hypoxic, but then falls, has been put forward as an explanation for sudden infant death syndrome SIDS or cot death We believe the concomitant cardiovascular changes are crucially important in this situation.
In experiments on rats in which we have recorded cerebral blood flow, we have demonstrated that although there is cerebral vasodilatation in response to systemic hypoxia, cerebral blood flow begins to fall when ventilation and heart rate drop below their resting values and arterial pressure drops below the autoregulatory range of about 60 mmHg We have proposed that the respiratory and cardiovascular changes may generate a positive feedback loop Figure 4.
Thus, when ventilation begins to fall, this exacerbates the fall in PaO 2 and the peripheral vasodilatation and bradycardia that are caused by the local effects of hypoxia, so potentiating the fall in arterial pressure. Once the arterial pressure is below the autoregulatory range, then cerebral blood flow falls, the O 2 supply to the brain is further reduced and the central neural hypoxia is exacerbated so that the central respiratory neurones are further depressed Figure 4 - The proposed positive feedback loop that may develop during systemic hypoxia, particularly in small adult mammals and neonates.
Our experiments on newborn piglets indicate that this positive feedback loop is particularly likely to develop in individuals in whom the stimulatory effect of hypoxia on respiration is weak Furthermore, our studies on rats that have been kept chronically hypoxic from birth in a hypoxic chamber, have shown that the bradycardia fall in arterial pressure and fall in cerebral blood flow induced by acute hypoxia is greatly exaggerated in these animals relative to those seen in controls Thus, it seems that chronic hypoxia from birth accentuates those very responses that contribute to the positive feedback loop.
This is entirely consistent with studies indicating that babies who are most at risk of SIDS are those who have been hypoxic from birth Although the section above has emphasised the importance of the local effects of hypoxia in the rat and other small mammals, it is important to recognise that the local effects do contribute to the overall response to hypoxia in larger mammals as well.
It is simply that in larger mammals the balance is tipped more strongly towards the neurally mediated, reflex effects of hypoxia.
Thus, a fall in ventilation when hypoxia is severe or prolonged that can be attributed in part to a depressive effect of hypoxia on the central nervous system 68 is a generally recognised phenomenon occurring, for example, in the cat and in human subjects 69, Similarly, it is known that heart rate and arterial pressure begin to fall when systemic hypoxia is severe or prolonged, for example, in both the cat and human subjects 56, It is also known that in human subjects systemic hypoxia induces vasodilatation in splanchnic circulation and forearm muscle 71,72 and that when the influence of the sympathetic nerve fibres on forearm muscle is blocked, systemic hypoxia still induces substantial muscle vasodilatation, as would be consistent with a local dilator influence of hypoxia The question of what produces these local effects is therefore important and may be of general relevance.
It is generally accepted that adenosine is produced in tissues when they become hypoxic. When we began our experiments adenosine concentrations had been shown to rise substantially in the brain soon after the onset of hypoxia Moreover, adenosine had not only been implicated in hypoxia-induced cerebral vasodilatation 74 , but it had been shown to depress ventilation by actions on respiratory neurones.
In fact, substances such as aminophylline and theophylline whose effects include blockade of adenosine receptors have been shown to reduce respiratory depression associated with systemic hypoxia in neonates 75 , as well as in adult cats and human subjects 69, Further, adenosine is well known to be released in the heart under hypoxic conditions and adenosine not only induces coronary vasodilatation 76 , but can induce bradycardia by direct actions on the sinoatrial node and by interfering with sympathetic and vagal transmission Adenosine had also been shown to be released by skeletal muscle during muscle contraction when there is a relative hypoxia 78 and by the use of various adenosine antagonists, adenosine had been implicated in the muscle vasodilatation that occurs during contraction e.
We therefore hypothesised that adenosine plays a major role in the cerebral and respiratory and cardiovascular changes that occur in the rat during systemic hypoxia.
To test this hypothesis we have used 8-phenyltheophylline 8-PT which is a selective adenosine receptor antagonist that does not inhibit phosphodiesterase activity like aminophylline and theophylline. In addition, when 8-PT was applied topically to the cerebral cortex, the hypoxia-induced cerebral vasodilatation was attenuated On the other hand, when 8-sulphophenyltheophylline, an adenosine receptor antagonist that does not cross the blood brain barrier, or adenosine deaminase, which breaks down adenosine, but does not cross the blood brain barrier, were given systemically, they did not affect the respiratory response to hypoxia, had less effect on the late fall in heart rate than 8-PT, but still caused a substantial reduction of the muscle vasodilatation These results provide strong evidence that adenosine released locally in the brain, heart and skeletal muscle is responsible respectively for the respiratory depression and cerebral vasodilatation, the bradycardia and the muscle vasodilatation.
They also reinforce our proposal that the respiratory and cardiovascular changes are interdependent in a potentially positive feedback manner 60,63; see Figure 4 : if the antagonist used had no effect on the respiratory component of the response then its effects on the cardiac and vasodilator components were less pronounced than for an antagonist that had the potential to affect all components of the response.
By using specific antagonists for the subtypes of adenosine receptor, we have recently shown that the adenosine that is released in systemic hypoxia probably acts via A 2A receptors to produce cerebral vasodilatation 81 , but via A 1 receptors to produce muscle vasodilatation 82, Our own evidence, together with that of others, indicates the respiratory depression and bradycardia are probably mediated by A 1 receptors 82, Since adenosine is generally released in hypoxic tissues and since its ability to depress respiration by a central action and to cause bradycardia and cerebral and muscle vasodilatation is common to a range of mammalian species, it seems reasonable to assume that adenosine plays a major role in the local effects of hypoxia on respiration and the cardiovascular system in all mammalian species.
Experiments already performed on hypoxia-induced respiratory depression and on hypoxia-induced bradycardia in isolated hearts in a number of species including adult man, cat, rabbit and guinea pig are consistent with that view 69,70, Interactions between reflex and local effects of hypoxia in muscle microcirculation. The experiments of the type discussed above in which pharmacological antagonists are given systemically are useful in that they can indicate whether particular nerve-mediated, hormonally mediated or local influences contribute to the gross change in vascular conductance or resistance that occurs in skeletal muscle or other tissues during systemic hypoxia.
However, they tell us little of how these factors interact at the level of tissue microcirculation to determine the O 2 supply to the capillaries and thereby to the tissue cells.
Further they suffer from the disadvantage that many pharmacological antagonists when given systemically affect arterial pressure and therefore their effect on the change in regional vascular conductance induced by systemic hypoxia may be in part related to their effect on perfusion pressure. To address these issues we have performed many experiments on the microcirculation of the spinotrapezius muscle of the rat with the muscle prepared for intravital microscopy.
Pharmacological agonists and antagonists can then be applied topically to the muscle in doses that achieve local effects, but which do not affect systemic variables, or the changes induced in them by systemic hypoxia. Experiments of this type have shown that systemic hypoxia induces both increases and decreases in the diameter, dilatation and constriction, respectively, of individual arterioles of the spinotrapezius muscle On balance, dilator responses are more common than constrictor responses and dilator responses are more common and larger in the distal, or terminal arterioles, than in the proximal arterioles Thus, the fact that gross muscle vascular conductance increases during systemic hypoxia disguises the fact that within muscle some vessels constrict while a majority dilate.
When an a adrenoceptor antagonist, phentolamine, was applied to the spinotrapezius, mean increases in arteriolar diameter produced in particular sections of the arteriolar tree by systemic hypoxia were potentiated, while mean decreases in arteriolar diameter were reduced, or reversed to dilator responses.
More detailed analysis of each section of the arteriolar tree showed that only vessels that constricted in hypoxia were affected by phentolamine, while those that dilated were not These observations are consistent with the occurrence of an increase in sympathetic nerve activity to skeletal muscle during systemic hypoxia, as would be expected from the primary response to carotid chemoreceptor stimulation see above and suggest that the sympathetic nerve activity preferentially constricts the primary and secondary arterioles.
However, they also indicate that many arterioles from all sections of the arteriolar tree do not respond to sympathetic activation in hypoxia, even though we know they are innervated by sympathetic fibres. On the other hand, when the adenosine receptor antagonist, 8-PT, was topically applied to the spinotrapezius muscle it reduced mean increases in diameter induced in particular sections of the arteriolar tree by systemic hypoxia, or converted them to mean decreases in diameter, the responses of the terminal arterioles being particularly affected These observations are, of course, fully consistent with the evidence discussed above that adenosine plays a major role in the hypoxia-induced muscle vasodilation and indicate that the terminal arterioles, the vessels that are traditionally thought to be most responsive to locally released vasodilator metabolites, are particularly affected by locally released adenosine.
Nevertheless, only those arterioles that were dilated by systemic hypoxia were affected by 8-PT, even though we were able to show that all arterioles were responsive to exogenous adenosine These observations were in turn consistent with evidence that vasopressin is released in response to selective stimulation of carotid chemoreceptor and that vasopressin receptor blockade reduces the increase in gross muscle vascular conductance induced by systemic hypoxia 89 and with evidence that adrenaline is released into the blood stream by hypoxic stimulation of carotid chemoreceptors and makes a contribution, albeit small, to the hypoxia-induced increase in gross muscle vascular conductance However, we have to conclude from the microcirculatory studies that some arterioles "escape" the constrictor influence of vasopressin or" escape" the dilator influence of adrenaline during systemic hypoxia, even though one would expect the concentrations of the two hormones reached in individual arterioles to be very similar and even though we could show they were all capable of responding appropriately to exogenous vasopressin or adrenaline The most obvious explanation for the heterogeneity of the responses seen amongst the arterioles during systemic hypoxia is that the major determinant of the response in any given arteriole is in fact the local level of hypoxia see 91 and Figure 5.
It is known that there is considerable variation in the level of tissue PO 2 found in different regions of skeletal muscle during normoxia This reflects several factors including i regional differences in the oxygen consumption of the nearby muscle fibres, ii distance along the arteriolar tree from the major supplying artery given that O 2 diffuses out of arterioles along their length, and iii proximity of arterioles and venules with opposite directions of blood flow, given that O 2 may diffuse from an arteriole to a venule, thus short-circuiting O 2 supply to tissue downstream of the arteriole.
It would be expected that adenosine would reach higher concentrations during systemic hypoxia in regions of the muscle where the local level of hypoxia is relatively severe, either because of a high level of O 2 consumption or a poor "anatomical" distribution of O 2. On the other hand, the concentration of adenosine would be low in regions of the muscle where the local level of hypoxia is relatively mild. The arterioles in such regions may then be particularly vulnerable to constrictor influences such as those of sympathetic nerve activity and circulating vasopressin Figure 5 - Schematic diagram showing how the balance of the nerve and hormonally mediated constrictor influences and the locally and hormonally mediated dilator influences of systemic hypoxia on blood vessels within skeletal muscle may be different depending on the local level of hypoxia.
In regions where the level of hypoxia is more severe the balance may be more readily tipped towards vasodilatation. For further discussion see text. This heterogeneity in the responses of the muscle arterioles during systemic hypoxia may be functionally important in allowing a more homogenous distribution of O 2 in the various parts of the muscle at a time when the gross O 2 supply is reduced. In other words, the behaviour we have seen in individual arterioles of muscle during systemic hypoxia may explain the finding that the variation in the levels of tissue PO 2 within muscle is considerably reduced during systemic hypoxia concomitant with the fall in average tissue PO 2 It may also demonstrate how the O 2 consumption of resting muscle can be maintained constant during systemic hypoxia, for a more homogeneous distribution of blood flow and therefore O 2 supply through the capillary network would help muscle fibres to maintain their O 2 consumption by increasing their O 2 extraction On the basis of the literature, it is theoretically possible that during systemic hypoxia adenosine is released from skeletal muscle fibres, vascular smooth muscle, or endothelium.
Also ATP released from these sites or from sympathetic nerve varicosities or red blood cells may be hydrolysed extracellularly to adenosine by the action of 5'ectonucleotidase. Further, it is theoretically possible that adenosine induces vasodilatation by acting on the vascular smooth muscle or endothelium, or more indirectly, by acting on the skeletal muscle fibres, or at prejunctional sites on the sympathetic nerve varicosities So far, we have only investigated a few of these possibilities.
This indicates that most of the adenosine that is vasoactive is released as such from the intracellular sites It was also known that K ATP channels are present on skeletal muscle fibres Figure 6 - Schematic diagram showing some of the factors that influence the arterioles of skeletal muscle during systemic hypoxia and the cellular mechanisms by which they may act.
Noradrenaline released from sympathetic nerve fibres and circulating in the blood stream exerts a constrictor influence via a receptors. Adenosine may also act directly on the vascular smooth muscle.
Current evidence indicates that the adenosine receptors on the endothelium that are stimulated in hypoxia are of the A 1 subtype while those on the vascular smooth muscle and skeletal muscle fibres are of the A 2A subtype. Thus, it seemed reasonable to conclude that there are adenosine receptors on skeletal muscle fibres that are coupled to K ATP channels: this has since been confirmed by electrophysiological recordings Indeed, the fact that glibenclamide affected the early and not the late part of the muscle vasodilatation of hypoxia suggests that the opening of K ATP channels is particularly important in initiating the vasodilatation rather than maintaining it and raises the possibility that the K ATP channels that are of major importance in the vasodilatation are on the vascular smooth muscle, or endothelium, rather than on the skeletal muscle fibres.
On the other hand, the very fact that 8-PT had a much larger effect than glibenclamide on hypoxia-induced dilatation strongly suggests that adenosine also acts in a manner that is independent of K ATP channels. For L-NAME greatly reduced both the muscle vasodilatation induced by systemic hypoxia and that induced by infusion of adenosine. Thus, it seems that the great majority of the component of the hypoxia-induced dilatation that is mediated by adenosine is also dependent on NO synthesis by the endothelium It could be that the K ATP channels that initiate the muscle vasodilatation are on the endothelium and coupled to adenosine receptors so that their activation triggers synthesis of NO by hyperpolarising the endothelial cells.
In agreement with this proposal, our recent studies, which have shown that the hypoxia-induced muscle dilatation is mediated by A 1 adenosine receptors, have also indicated that muscle vasodilatation mediated by A 1 receptors is dependent both on the opening of K ATP channels and on NO synthesis ,; Figure 6.
Thus, we can summarise our results to date by stating that the adenosine that makes the major contribution to the muscle vasodilatation that occurs in the rat during acute systemic hypoxia probably acts by stimulating adenosine A 1 receptors on the endothelium and increasing the synthesis of NO which then induces relaxation of the vascular smooth muscle.
Since the endothelium is a very effective metabolic barrier to the transport of adenosine 84 , and since adenosine deaminase, which does not cross the vascular endothelium, was just as effective in reducing hypoxia-induced vasodilatation as 8-PT, an adenosine receptor antagonist 63 , it seems most likely that the majority of the adenosine is released from the endothelium and acts on the endothelium in an autocrine fashion.
Acute systemic hypoxia is of interest in its own right because it can occur in a number of clinical conditions, on immediate exposure to high altitude and on accidental or experimental exposure to hypoxic gas mixtures.
However, chronic systemic hypoxia, and the adaptations that occur in this condition, is arguably more important because chronic hypoxia is so common in many respiratory and cardiovascular disorders and because it occurs in individuals who acclimatise to living at high altitude. The number of laboratory studies that have been performed on respiratory and cardiovascular adaptations to chronic systemic hypoxia is still rather small. The results of studies performed on chronically hypoxic patients are complicated by the pathological condition that underlies their hypoxic state, while those performed on healthy individuals who climb to high altitude are complicated by many factors including the effects of exercise and exposure to low temperature.
This suggests that cardiovascular adaptations must have occurred: the muscle vasodilatation and reduction in arterial pressure that might be expected from the response to acute systemic hypoxia are apparently absent, as are the sympathetically mediated tachycardia that might be expected as a secondary consequence of hyperventilation and as a result of hypoxia of the central nervous system see above.
However, since the adenosine receptor antagonist, 8-PT, increased the control level of ventilation in the CH rats it seems there must still be sufficient hypoxia of the central nervous system to cause a tonic release of adenosine and depression of central respiratory neurones On the other hand, since 8-PT had no influence on the control levels of arterial pressure, heart rate or muscle vascular conductance in the CH rats, this indicates there are no tonic influences of adenosine upon the systemic circulation.
This suggests the heart and peripheral tissues are no longer hypoxic There was an increase in ventilation and heart rate, a fall in arterial pressure and an increase in muscle vascular conductance with a later fall in ventilation and heart rate towards control levels. Our experiments on the microcirculation of the spinotrapezius muscle were consistent with both of these possibilities.
Further, the effects of adenosine receptor blockade on these responses were fully comparable in the CH and N rats: in each section of the arteriolar tree, mean increases in diameter were reduced or reversed to mean decreases in diameter and quantitatively the sizes of these effects were similar in CH and N rats The maximal dilatation produced by topical application of adenosine in each section of the arteriolar tree was also similar in the CH and N rats, so there was no reason to suppose that the arterioles of the CH rats were capable of greater maximal dilatation in response to adenosine or any other dilator influence than those of N rats We have made very similar observations in the microcirculation of the intestinal mesentery in CH and N rats There are a number of possible explanations for these results.
Another explanation, which is not mutually exclusive, is that the arterioles of CH rats are less affected by the reflex vasoconstrictor influences of acute hypoxia see above than those of N rats and so they are more readily overcome by the dilator influences. The last possibility seemed to be a particularly interesting one to us. Firstly, it was reported that chronically hypoxic patients with respiratory disease showed a reduced ability to maintain their arterial pressure when they were subjected to lower body negative pressure : this might be explained if they show impaired vasoconstrictor responses to the sympathetic neurotransmitter noradrenaline.
Secondly, it had also been reported that the dorsal aorta of CH rats shows a reduced ability to constrict to phenylephrine, vasopressin and angiotensin as compared with N rats We therefore performed experiments on the spinotrapezius muscle and mesentery of CH and N rats, to obtain dose-response curves for the effects of noradrenaline on the arterioles. For both the mesentery and muscle, the most obvious difference between the CH and N rats was that the maximum vasoconstrictor responses evoked in the arterioles by noradrenaline were greatly reduced in the CH rats and the size of this effect was similar in the mesentery and muscle Since arterioles of the intestinal mesentery have little or no tissue parenchyma around them, there was no reason to argue that the responses to noradrenaline were suppressed by some factor released by tissue cells.
Rather, it seems the constrictor responses to noradrenaline must be reduced by some factor that is intrinsic to the blood vessel wall. As a way of investigating this phenomenon, we chose first to study the iliac artery of the rat in vitro , this being an artery that supplies the skeletal muscles of the hind limb.
This indicates that there was no difference in the number of noradrenaline receptor sites, nor in the binding of noradrenaline to the receptors. However, the disparity between the iliac arteries of CH and N rats only existed when the endothelium was present: when the endothelium was removed, the maximum response to noradrenaline was similar in the arteries from the CH and N rats , An obvious possibility was that NO might be involved.
Furthermore, whereas L-NAME produced only a small increase in the maximum response to noradrenaline in the iliac arteries from the N rats, it substantially increased the maximum response of the arteries from the CH rats so that their maximum response became comparable to that of the N rats.
By contrast, L-NAME had no significant effect on the noradrenaline-dose response curves of endothelium denuded iliac arteries from either CH or N rats. This provided strong evidence that the basal synthesis of NO by the endothelium is increased in the iliac arteries of CH rats and suggested that NO was responsible for the impaired vasoconstrictor responses to noradrenaline Having obtained this evidence in vitro it was then important to establish whether a similar effect could be produced in vivo.
In fact, in experiments on mesenteric arterioles of CH rats, the maximum constrictor response evoked by noradrenaline was greatly enhanced by topical application of L-NAME to the mesentery, so that it equalled the maximum vasoconstrictor response recorded in N rats Marshall JM, unpublished observations. Thus, our current hypothesis is that chronic hypoxia causes an up-regulation of NO synthesis in the endothelium of the systemic circulation.
This may be attributed at least in part to the effect of an increase in shear stress on the endothelium, caused by the hypoxia-induced increase in haematocrit for shear stress is known to stimulate NO synthesis As a consequence of increased NO synthesis, we propose that the dilator influence of any substance that achieves its dilator effects in an NO-dependent manner, such as adenosine, may be enhanced in chronic hypoxia.
This would be expected to lead to an increase in the vasodilator effect of acute hypoxia, just as our results have demonstrated. On the other hand, up-regulation of NO synthesis would also be expected to reduce the effects of the reflex vasoconstrictor influences of acute hypoxia, again, just as our results imply. From a sound foundation of knowledge about the responses that can be evoked by selective stimulation of carotid chemoreceptors, we have been able to show that activation of the defence areas by the carotid chemoreceptors and that elicitation of the characteristic pattern of the alerting defence response is an integral part of the full response to acute systemic hypoxia.
But we have also shown how this response, as well as the classical primary cardiovascular reflex responses to carotid chemoreceptor stimulation of bradycardia and generalised vasoconstriction and the cardiovascular changes that are secondary to chemoreceptor-induced hyperventilation can be modified, or even overcome, by the local effects of hypoxia on the central nervous system, heart and peripheral tissues. It seems that these local effects of respiratory depression mediated by the influence of hypoxia on central respiratory neurones, bradycardia and peripheral vasodilatation generally become manifest in severe, or longer periods of acute hypoxia, but are more likely to predominate in small adult mammals and neonates: they have the potential to form a positive feedback loop that leads to death.
Our results suggest that adenosine plays a major role in producing these local effects of tissue hypoxia and have shown some of the cellular mechanisms by which adenosine achieves these effects. In particular, our observations on the microcirculation of skeletal muscle have demonstrated how adenosine, acting in part in a NO-dependent manner, can overcome the vasoconstrictor influences of chemoreceptor-induced activation of sympathetic noradrenergic fibres and of circulating hormones on individual arterioles and so can increase the homogeneity of the O 2 supply through the capillary network.
The sum total of experimental studies performed on chronic systemic hypoxia leaves many questions unanswered. To date, the results suggest that within weeks of chronic hypoxia, adaptations have taken place such that ventilation is tonically raised, but arterial pressure and heart rate are normal.
This alone suggests that the normal ability of hyperventilation to induce tachycardia is impaired. In addition, when a further acute hypoxic challenge is superimposed upon the chronically hypoxic state, the normal ability of chemoreceptor-induced stimulation to cause tachycardia secondary to hyperventilation and reflex vasoconstriction seems impaired A question that is of particular interest is whether the impairments in the functional responses to peripheral chemoreceptor stimulation that occur in chronic hypoxia are accompanied by increases or decreases in the cardiac vagal and sympathetic nerve activity that produces them.
Bernthal T Chemo-reflex control of vascular reactions through the carotid body. American Journal of Physiology , Sinus carotidien et reflexes respiratoires. Influences respiratoires reflexes de l'acidose, de l'alcolose, de l'anhydride carbonique, de l'ion hydrogene et de l'anoxemic.
During prolonged dives, bradycardia becomes more pronounced because of activation of the peripheral chemoreceptors by a reduction in the arterial partial pressure of oxygen O2 , responsible for slowing of heart rate. The vasoconstriction is associated with a redistribution of the blood flow, which saves O2 for the O2-sensitive organs, such as the heart and brain.
The results of several investigations carried out both in animals and in humans show that the diving response has an O2-conserving effect, both during exercise and at rest, thus lengthening the time to the onset of serious hypoxic damage. Without adequate oxygen, ATP dependent ion pumps in the cell membrane cannot operate. Because a hyperpolarized state at the end of phase 3 is necessary for pacemaker channels to become reactivated, pacemaker channels remain inactivated in depolarized cells.
This suppresses pacemaker currents and decreases the slope of phase 4. This is one reason why cellular hypoxia, which depolarizes the cell and alters phase 3 hyperpolarization, leads to a reduction in pacemaker rate i. Severe hypoxia completely stops pacemaker activity. Various drugs used as antiarrhythmics also affect SA nodal rhythm. Drugs affecting autonomic control or autonomic receptors e. Digitalis causes bradycardia by increasing parasympathetic vagal activity on the SA node; however, at toxic concentrations, digitalis increases automaticity and therefore can cause tachyarrhythmias.
Pacemaker activity is influenced dramatically by age. Many different formulas have been developed to estimate the effects of age on maximal HR HR max ; however, the following simple formula is commonly used and serves to illustrate how age generally affects HR max :. HR max cannot be modified appreciably by exercise training; therefore, even highly conditioned older athletes will have a reduced HR max.
Please note that for any given individual, their HR max will be strongly influenced by genetic factors as well as by other factors previously mentioned. Cardiovascular Physiology Concepts Richard E.
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