Click here for information on Cardiovascular Physiology Concepts, 3rd edition, a textbook published by Wolters Kluwer Klabunde The SA node displays intrinsic automaticity spontaneous pacemaker activity at a rate of action potentials "beats" per minute.
This intrinsic rhythm is primarily influenced by autonomic nerves , with vagal influences being dominant over sympathetic influences at rest. The SA node is predominantly innervated by efferent branches of the right vagus nerves, although some innervation from the left vagus is often observed. A similar response is noted when a drug such as atropine is administered. This drug blocks vagal influences at the SA node by antagonizing the muscarinic receptors that bind to acetylcholine, which is the neurotransmitter released by the vagus nerve.
For heart rate to increase during physical activity, the medullary centers controlling autonomic function reduce vagal efferent activity and increase sympathetic efferent activity to the SA node. High heart rates cannot be achieved in the absence of vagal inhibition. To increase heart rate, the autonomic nervous system increases sympathetic outflow to the SA node, with concurrent inhibition of vagal tone.
Inhibition of vagal tone is necessary for the sympathetic nerves to increase heart rate because vagal influences inhibit the action of sympathetic nerve activity at the SA node. Norepinephrine released by sympathetic activation of the SA node binds to beta-adrenoceptors.
This increases the rate of pacemaker firing primarily by increasing the slope of phase 4 , which decreases the time to reach threshold. 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.
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