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SWEATING IN COMBINATION with increased skin blood flow
are two key mechanisms that can transfer heat generated by exercising skeletal muscles to the environment. These mechanisms are governed primarily by the autonomic nervous system (8). In this month's Journal, Mills and co-workers (6) report that systemic administration of the nitric oxide (NO) synthase inhibitor
NG-nitro-L-arginine
methyl ester (L-NAME) to
thoroughbred horses reduces by ~70% their sweat rate during moderate
exercise. This is an important new finding in the search to understand
the neural pathways and transmitters that govern thermoregulation in
many species. It also raises several important new issues and
highlights many unresolved ones.
First, at what site does NO "cause" thermoregulatory sweating in
the horse? Because L-NAME
crosses the blood-brain barrier, does NO play a role in the central
mechanisms that increase sympathetic outflow to sweat glands when core
temperature rises (6)? In the horse, sympathetic nerves stimulate
-adrenergic mechanisms in skin to evoke thermoregulatory sweating.
Is NO involved in this response (1, 6)? In humans, sympathetic
cholinergic fibers innervate sweat glands, and cholinergic mechanisms
predominate (5, 8, 9). What role, if any, does NO play?
The second series of issues relates to the interactions
between sweating and skin blood flow. When blood flow to one forearm of
a heated human is eliminated by inflation of an arm cuff, sweat rate in
the ischemic arm falls after a few minutes (7). This demonstrates that
if skin blood flow is reduced, sweat rate can fall. If administration
of L-NAME to the exercising
horses reduced their skin blood flow, did sweat rate fall because the
sweat glands were "underperfused"? While thermoregulatory
increases in skin blood flow during exercise in horses are modest in
comparison to humans, are high rates of sweating in the horse dependent
on marked increases in cutaneous flow?
The third series of issues relates to whether the
neural mechanisms that govern sweating and cutaneous vasodilation
during exercise (or body heating) are the same or different. If the
mechanisms are different, is there a "cross-talk" between them?
Additionally, to what extent do species differences play a role in
these mechanisms? In this context, it was thought for many years that,
in humans, sympathetic cholinergic fibers caused both sweating and
cutaneous vasodilation or that active sweat glands secreted some
substance (i.e., bradykinin) that evoked the rise in skin blood flow
(4). However, selective infusions of atropine to one forearm during body heating locally inhibited sweating but had only a modest impact on
the timing and magnitude of the rise in skin blood flow (9). This
suggested that independent mechanisms governed both the increases in
sweating and rise in skin blood flow during body heating or exercise in
humans. More recently, this issue has been revisited by Kellogg and
colleagues (5), who iontophoresed small doses of botulinum toxin into
small areas of skin before body heating in humans. Botulinum toxin
presynaptically inhibits acetylcholine release from cholinergic nerves.
This intervention locally prevented sweating and the rise in skin blood
flow during body heating, suggesting that some
substance cotransmitted with acetylcholine from sympathetic cholinergic
nerves evokes a rise in the skin blood flow during body heating in
humans (5). Is this substance NO?
In humans, infusion of L-NMMA to
one forearm via the brachial artery has little impact on either the
sweat rate or the magnitude or the forearm blood (skin blood flow)
responses to body heating (3). By contrast, local NO synthase
inhibition in the rabbit ear suppresses the neurally mediated cutaneous
vasodilation observed during body heating, suggesting that neurally
mediated NO release causes thermoregulatory cutaneous vasodilation in
this species (10). Whether the differences between humans and rabbits
represent species differences or differences in experimental design,
the extent to which NO might govern skin blood flow responses during body heating in horses is unknown. Clearly, the role of NO in neurally
mediated cutaneous vasodilation during either passive heating or
exercise-induced thermal stress needs additional attention in a wide
variety of species.
Several important experimental design issues will need to be considered
as these studies are planned and conducted. If arginine analogs are
used to block NO synthase, which analog will be used? Some arginine
analogs cross the blood-brain barrier, some are more selective for the
neural or endothelial isoforms of NO synthase, and other arginine
analogs can have anticholinergic properties (2). Because NO might be
involved at a variety of "sites" in the thermoregulatory process,
knowledge of these properties will be essential. The timing of the
arginine analog administration will also be important. Should the
subjects or animals be given the arginine analog before the onset of
exercise or thermal stress or after it has been initiated and the
neurally mediated increases in sweating and skin blood flow have
occurred (3, 10)? Again, these issues will need to be
considered as the role of NO in thermoregulation is evaluated in
additional species.
In summary, the observation that NO plays an important role in
thermoregulatory sweating during exercise in horses is provocative. This observation challenges investigators who are interested in thermoregulation and the autonomic nervous system to determine the site
or sites of action of NO as a mediator of thermoregulatory sweating in
horses. It also raises questions about the contribution of NO to the
neurally mediated regulation of sweating in other species, the role of
NO as a mediator of thermoregulatory cutaneous vasodilation, and the
possible interactions between changes in skin blood flow that might be
mediated by NO and sweating.
On a broader note, these novel findings highlight the continued
relevance of traditional systems physiology (and pharmacology) in the
study of biological adaptations in conscious animals. In the future,
molecular biology may provide useful tools to understand components of
these responses, but the need to thoroughly understand the
systems that permit conscious animals to maintain
homeostasis during stresses such as whole body exercise is unlikely to
be superseded by reductionism.
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