Oxygen has consistently been implicated in regulation of arteriolar tone, and although involvement of changes in Po2 in regulation of skeletal muscle function is intuitively compelling, no obvious "oxygen sensof' has been identified despite decades of searching. Thus it has seemed unlikely that oxygen has a direct effect on the arteriolar wall. However, recent work has revisited this issue, and although the signaling mechanisms are still not clarified, it is clear that at least in some arterioles, including those in skeletal muscle, oxygen can directly affect the cells of the arteriolar wall via a cytochrome P450-dependent pathway, and also possibly by mitigation of adrenergic vasoconstrictor tone at a step in the SMC signaling cascade that is distal to an increase in Ca2+. There is compelling evidence that KATP channels are implicated in local metabolic responses, but this does not appear to be via a direct effect of oxygen on the function of these channels in SMCs.
Most investigators have concluded that oxygen modulates local arteriolar responses indirectly—that is, as muscle metabolism changes, local PO2 will also change, as will the balance of metabolites released from the contracting muscle. It is thus easy to conceptualize a control system in which some or all such products feed back on the arteriole to produce changes in force development by the SMCs. Using this logic, a variety of possible mediators have been identified. The challenge is to demonstrate directly what role any such agents play on the cellular mechanisms regulating tone in the blood vessel wall.
By reason of its release from contracting muscle fibers during decreased Po2, adenosine (ADO) has long been implicated in metabolic control. There is evidence from direct observations of small arterioles that ADO is indeed involved in the local metabolic response. However, it accounts for only a fraction of the dilation in response to near-maximal muscle contraction and appears to have a greater effect in smaller arterioles. This might explain why studies of whole organs or in intact animals have not invariably implicated this purine in metabolic dilation. It is widely assumed that ADO acts on smooth muscle, and it is established that SMCs in skeletal muscle arterioles display both P1 and P2 purinergic receptors; however, purinergic receptors are also found on ECs, and recent work suggests that local metabolic responses in small arterioles may be coupled through Pj receptors on ECs. Purines are known to increase EC Ca2+, and this increase in EC Ca2+ has also been implicated in mediation of metabolic vasodilation in small arterioles. In some circulations (e.g., coronary) ADO acts via KATP channels, but in skeletal muscle arterioles this does not appear to be the case.
C. Ions, Particularly K+
Many ions have vasoactive properties and have been identified as possible mediators of metabolic vasodilation. These include potassium, hydrogen, and overall osmolarity, as well as charged moieties such as lactate, all of which have been detected in venous blood during changes in muscle metabolism. Of these, raised extracellular [K+] has received the most attention, and it is established that small increases in [K+] of the order of 5 to 10mM can lead to vasodilation in a variety of arterioles, including those from skeletal muscle. The mechanism(s) by which this dilation is brought about are still unclear: Evidence supporting a role for KIR channels and for Na+/K+ ATPase activation has been published, but more definitive work in this area is needed.
D. Other Molecules Contributing to Functional Hyperemia
There is considerable evidence implicating nitric oxide (NO) as a signaling intermediate—local arteriolar dilation to muscle contraction can be significantly attenuated in the presence of blockers such as L-NAME. Several different actions of NO have been identified. It appears to support vascular dilation directly, possibly via a KATP channel-dependent signaling pathway. Studies in NOS-deficient mouse models suggest that at least part of the NO is derived from nNOS located in skeletal muscle fibers; contributions from eNOS have also been identified, but there is a lot still to be learned about the mechanisms underlying this response. In many systems, NO release from ECs has been implicated in flow-dependent responses, and it is possible that this stimulus also contributes to NO release during blood flow changes associated with changes in muscle metabolism. NO also attenuates sympathetic vasoconstri-cion in an action known as "sympatholysis": Again, this mechanism is not fully understood, but this aspect of the contribution of NO to vasodilation also appears likely to involve Katp channels. Whether they are located on SMCs, ECs, or the skeletal muscle fibers remains to be determined.
It has also been shown that the arteriolar dilation to muscle contraction is partially blocked by indomethacin, implicating prostaglandins in the regulation of this function. As both NO and prostaglandins have been implicated in flow-dependent responses in skeletal muscle, a challenge will be to sort out which aspects of this pathway are primary versus secondary as a consequence of local changes in the prevailing flow that are themselves a consequence of local changes in arteriolar tone. Recent work has shown, not surprisingly, that multiple local vasoactive pathways can be activated simultaneously upon contraction of skeletal muscle, and at least some of these are independent of any local hemody-namic changes.
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