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Dalton Cardiovascular Research Center and Department of Veterinary Biomedical Sciences, University of Missouri, Columbia, Missouri 65211
AT THE END OF WORLD WAR II, groups on
both sides of the Atlantic (2, 22) demonstrated that loss
of central blood volume in human volunteers resulted in a sudden
decrease in arterial pressure due to an equally sudden fall in vascular
resistance. Subsequent studies have shown that the response observed in
humans is common to a variety of conscious mammals and involves two
phases (17). In phase 1, arterial pressure is maintained
by regional sympathetic vasoconstriction. Phase 2 occurs as blood loss
approaches 25-30% of blood volume and involves a rapid fall in
arterial pressure due to global vasodilation accompanied by profound
sympathoinhibition. In contrast to the effects on sympathetic nerves,
adrenal catecholamine release, while at baseline levels during phase 1, increases dramatically in phase 2 (14, 15). Phase 2 is
sometimes referred to as the decompensatory phase. This is an
unfortunate choice, because the term implies an inability to compensate
further for the loss of blood volume. There are at least three reasons
this is not the case. First, the events associated with phase 2 are
readily reversed by a variety of centrally acting drugs such as
methysergide (18) and opiate antagonists (8,
11). Second, exposure to a sensory stressor delays the onset of
phase 2 (16). Finally, recovery of sympathetic nerve
activity after hypotensive hemorrhage is slower than recovery of
arterial pressure with (8) or without (Fig. 3 of Ref.
18) reinfusion of removed blood.
Thus the current view is that the fall in arterial pressure during
acute blood loss is actively mediated by a central sympathoinhibitory mechanism. Although the teleological question of why this happens is
very interesting, any answer would be based on conjecture rather than
facts. On the other hand, the question of how this happens is also
interesting and more amenable to experimental studies. Thus, in the
context of defining central mechanisms involved in the
sympathoinhibition associated with acute hemorrhage, many studies have
focused on pharmacological modification of the cardiovascular and
sympathetic response. The role of serotonin in this response has been
addressed in this way. One of the earliest studies showed that the
nonspecific serotonin receptor ligand methysergide aided recovery from
hypotension in anesthetized rats (5). Subsequently, Morgan
et al. (9) showed that intravenous pretreatment with methysergide abolished the decrease in sympathetic activity seen during
hypotensive hemorrhage in conscious rats. Roger Evans, John Ludbrook,
and colleagues investigated the central nervous system site of
methysergide's effects during simulated hemorrhage in conscious
rabbits. The first of their studies (7) confirmed earlier
work showing that systemic methysergide delayed the onset of phase 2. They also showed that methysergide was effective at a lower dose if it
was injected into the fourth cerebral ventricle. Thus it seemed that a
central, endogenous, serotonergic system must mediate phase 2. However,
later work from the same laboratory (6), employing
additional serotonergic agonists and antagonists, suggested that
methysergide's effects might actually be due to its agonist activity
at 5-HT1A receptors rather than to antagonism of ongoing
serotonergic activity.
The report by Dr. Scrogin (18) in this issue of the
American Journal of Physiology-Regulatory, Integrative and
Comparative Physiology deals specifically with the site of
methysergide's 5-HT1A effects in reversal of acute
hemorrhagic hypotension and sympathoinhibition. The author's first
studies in this area (20) showed that central pretreatment
with methysergide delayed or abolished the sympathoinhibition
associated with hypotensive blood loss. They also showed that the
serotonergic pathway in hemorrhage was different from that mediating
the sympathoinhibition after activation of peripheral, cardiopulmonary
5-HT3 receptors. Subsequent studies (19)
picked up where the Evans et al. study (6) left off and
addressed the assumption that methysergide's effects indicated serotonergic mediation of phase 2. Dr. Scrogin and colleagues (19) demonstrated that the effects of methysergide
were likely mediated by its 5-HT1A agonist properties
rather than its antagonist actions at another receptor subtype. The
present work (18) measured the latency and effectiveness
of the response to a specific 5-HT1A agonist, 8-OH-DPAT,
administered at different central nervous system sites. Although the
results did not identify a specific site, it does appear that the
effects of 5-HT1A receptor activation during hemorrhage in
conscious rats are mediated in the hindbrain.
A role of serotonin in the response to blood loss is supported by other
recent studies. Pelaez et al. (13) demonstrated that
hypotensive blood loss in conscious rats activates a medullary serotonergic cell group. This same cell group was not activated by
hypotension induced by the vasodilator hydralazine. In addition, Bago
and Dean (1) demonstrated in anesthetized rats that
ventrolateral periaqueductal gray (VLPAG) stimulation results in
sympathoinhibition mediated by activation of 5-HT1A
receptors in the rostroventrolateral medulla (RVLM). They also
subsequently demonstrated that the renal sympathoinhibition associated
with hypotensive hemorrhage in anesthetized rats was mediated by
activation of 5-HT1A receptors in the RVLM (4). Cavun and Millington (3) showed that
reversible chemical lesion of the VLPAG of conscious rats delays and
reduces the fall in arterial pressure during blood loss. A complicating
feature here is that Morgan and Carrive (10) recently
reported that although stimulation of the VLPAG produces hypotension in
anesthetized rats, it does not in conscious rats. A further
complication is introduced by the failure of a specific
5-HT1A antagonist to modify the response to blood loss in
conscious rats (19) and the failure of partial depletion
of central serotonin to alter the response to simulated hemorrhage in
conscious rabbits (7). There can be no doubt that
anesthesia alters the response to hemorrhage (17).
Perhaps, as Dr. Scrogin (18) suggests, some of this alteration is due to the effects of anesthesia on the actions of serotonin.
The importance of differential control of regional sympathetic nerve
activity has recently been reviewed in this journal (12). One of the best examples of differential control is the qualitative separation of activation of sympathetic nerves and the adrenal medulla
during hemorrhage (14, 15, 21). Could central serotonergic mechanisms be involved? If 5-HT1A receptor activation in
the RVLM influences activity in renal sympathetic nerves, does it also affect the adrenal medulla? Although regional vascular responses are
quite variable during hemorrhage, it is not known if these end-organ
responses involve differential sympathetic effects. Most, if not all,
studies of hemorrhage have relied on measurements of renal sympathetic
nerve activity. It is clear that many questions remain about the role
of the central nervous system in the response to acute hypotensive
hemorrhage. Perhaps the present findings (18) will lead to
future studies that identify the trigger for sympathoinhibition and
better define the central nervous system pathways contributing to the
fall in blood pressure during blood loss.
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Address for reprint requests and other correspondence: J. C. Schadt, Dalton Cardiovascular Research Center, Univ. of Missouri, Columbia, MO 65211 (E-mail: schadtj{at}missouri.edu).
10.1152/ajpregu.00746.2002
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