A THERMOREGULATORY ROLE FOR NITRIC OXIDE? 
Mills et al. (p. 1035) report that nonspecific inhibition of nitric
oxide synthase (NOS) by venous infusion of
NG-nitro-L-arginine methyl ester
(L-NAME) reduced sweating and
increased core body temperature in exercising horses. Conversely,
infusion of arginine, a substrate for NOS, partially reversed the
inhibitory effects of L-NAME on
sweat rate, but rectal and skin temperatures continued to increase in
running horses. Thus, by regulating sweat rate and cutaneous
circulation, NO may be involved in another mechanism or multiple
mechanisms involving temperature regulation in mammals that cool by
sweating. As endothelial and neural isoforms of NOS are known, and
because cutaneous flow was not measured, the specific mechanism by
which L-NAME restricted sweating
is uncertain. It has long been recognized that, in exercise, body temperature, total and regional blood flow, cutaneous vasodilatation, sweat rate, and other mechanisms of temperature regulation are interrelated. Now, Mills et al. provide the first data indicating a
role for NO in regulation of sweat rate during exercise. The work is
discussed in an Invited Editorial by Joyner (p. 1033).
ISCHEMIA, NOREPINEPHRINE, AND CARDIAC PERFORMANCE
During exercise, norepinephrine acts to offset the negative
effects of hyperkalemia and acidosis on cardiac performance.
O'Neill et al. (p. 1046) studied the influence of acute and
chronic myocardial ischemia on this interaction in anesthetized rabbits
in which exercise was mimicked by infusions of potassium chloride,
lactic acid, and norepinephrine. Cardiac performance was not depressed by ischemia before the infusions. Norepinephrine attenuated the negative effects of hyperkalemia and acidosis in freely perfused hearts, but this protective action was reduced in ischemic hearts. The
findings show that ischemia attenuates the protective effect of
norepinephrine and increases the depressive effects of hyperkalemia and
acidosis under the conditions of the study. Whether this action of
ischemia occurs during actual exercise remains to be determined.
HYPOCAPNIA ATTENUATES THE HYPERTENSIVE RESPONSE TO ACUTE HYPOXIA
Bao et al. (p. 1071) determined the acute pressor response to episodic
eucapnic and hypocapnic hypoxia in two strains of rats. The pressor
response was significantly influenced by the prevailing CO2 and attenuated by
1-adrenergic-receptor blockade,
probably acting at the level of the carotid chemoreceptors. Blockade of the normal bradycardic response to hypoxia did not influence the associated increase in blood pressure. A role for genetics in determining the blood pressure response to hypoxia was implicated by
the marked differences between two strains of rats in the sensitivity of their blood pressure and sympathetic responses to acute hypoxia. The
findings speak to the mechanisms responsible for individual differences
in the regulation of blood pressure in persons with sleep apnea.
HYPOXIA AND THE PULMONARY MICROCIRCULATION
It has been generally accepted that alveolar hypoxia causes
constriction of "small" pulmonary arteries but how "small"
has been a question. This is partly because it has been difficult to
make direct observations on the smallest pulmonary arteries and because
the smallest pulmonary arteries tend to have relatively little vascular
smooth muscle, raising the question as to whether they have the ability
to constrict. Hillier et al. (p. 1084) made direct videomicroscopic measurements of the diameters of subpleural pulmonary arteries in the 30- to 70-µm internal diameter range in
isolated dog lungs ventilated with normal or low
PO2 gas. They found that, at a
constant intravascular pressure, these arteries were significantly
smaller during hypoxia, suggesting the possibility that perfusion may
be matched to ventilation even on an intra-acinar scale.
N-ACETYLCYSTEINE AND RESPIRATORY MUSCLE
FATIGUE
To examine the role of oxygen-derived free radicals in the development
of respiratory muscle fatigue, Supinski et al. (p. 1119) studied the
influence of systemically administered
N-acetylcysteine (NAC), a free radical
scavenger, in well-oxygenated decerebrate rats subjected to large
inspiratory resistive loads until respiratory arrest. NAC-treated
animals tolerated loading better than controls, with larger inspiratory
pressures and tidal volumes and delayed respiratory arrest.
Diaphragmatic reduced glutathione levels fell and oxidized glutathione
levels rose during loading in the control rats, but NAC treatment
attenuated these changes. The results are consistent with a role for
free radicals in the development of respiratory muscle fatigue and
suggest that NAC may be clinically useful in the prevention or
treatment of respiratory failure.
ROLE OF CEREBELLAR NEURONS IN RESPIRATORY CONTROL
Proper modulation of the pattern of breathing is both obvious and
essential. Perturbation of cerebellar function is well known to affect
this pattern. Xu and Frazier (p. 1177) recorded
activities of neurons with respiratory-related discharge patterns in
the fastigial nucleus in anesthetized, paralyzed, and mechanically ventilated adult cats. Their discharge pattern changed concomitantly with respiratory outflow in response to hypercapnia or lung
inflation. The authors speculate that such neurons contribute to
the regulation of ventilation during stressed breathing.
INTRACRANIAL PRESSURE DYNAMICS
Pressure-volume index (PVI) tests provide information about
intracranial pressure dynamics in patients with severe brain damage. In
this test, intracranial volume is increased or decreased by a small
amount, and the resultant intracranial pressure changes are monitored.
To elucidate the mechanisms responsible for the observed pressure
transients after PVI tests, Ursino and Lodi (p. 1256) mathematically
simulated factors influencing intracranial pressure. The model reveals
that intracranial pressure may become unstable in subjects with
elevated cerebrospinal fluid flow resistance and decreased intracranial
compliance, that moderate arterial hypertension may have completely
different effects on pressure, and that response to a PVI test is
dependent on autoregulation of cerebral hemodynamics. A companion
manuscript by the same authors (p. 1270) describes the correspondence
between predicted and observed intracranial pressure transients during
PVI tests in 20 patients with severe brain damage. Patients were
classified into two groups: those showing little autoregulation and
those having strong autoregulation of the cerebral vasculature.
Correlation between calculated and observed parameters was
significantly different in the two groups of patients, suggesting that
different mechanisms may be responsible for the pressure transients in
the presence and absence of strong autoregulation.
TEMPORAL PATTERNS OF PULMONARY CAPILLARY PERFUSION
On studying red cell movement through individual subpleural capillary
pathways, Hanger et al. (p. 1283) were struck by the erratic temporal
pattern of this traffic under ostensibly constant conditions of
upstream pressure and flow. To examine whether such erratic traffic
reflects random events, they developed a computer-assisted model to
determine all the possible perfusion patterns for a given subpleural
alveolar facet. Comparison of the observed patterns of flow with those
predicted by the model indicated that, although the traffic appears
quite erratic, there are some preferential routes that are perfused
nonrandomly.
MODELING PULMONARY NITRIC OXIDE EXCHANGE
Nitric oxide (NO) is normally produced in several parts of the
respiratory system, and low concentrations of NO appear in expired gas.
In disease states such as asthma and in sepsis, exhaled NO levels rise.
Hyde and co-workers (p. 1290) point out that NO produced in the airways
and lungs will diffuse into pulmonary capillary blood, reducing exhaled
NO levels. Equations derived relating NO production to exhaled levels
and capillary uptake, point out that, in disease, reduced capillary
NO uptake (rather than just increased NO production alone) may
contribute to higher exhaled concentrations of the gas.
Their equations also permit a calculation of NO production in the
lungs, allowing for capillary uptake, which may prove useful in
studying the significance of NO production in pulmonary disease.
EXHALED NITRIC OXIDE DURING EXERCISE
Endogenous nitric oxide (NO) is a multipurpose messenger molecule
implicated in a wide variety of biological processes. Previous work has
shown that NO is continuously released in the exhaled air, the amount
influenced by exercise in a manner not fully understood. Chirpaz-Oddou
and co-workers (p. 1311) evaluated exhaled NO output rates in groups of
sedentary women, sedentary men, and active sportsmen during an
incremental exercise test to exhaustion. The rate of NO released in the
expired air increased proportionally to power output, from ~5
nmol/min at rest to a peak rate of ~20-40 nmol/min at
exhaustion, and decreased rapidly during recovery. NO output rates were
similar across groups at the same absolute oxygen consumption. Thus
variations in peak NO output rates among individuals were related to
differences in peak aerobic work capacity. The authors conclude that
exhaled NO output is mainly related to the magnitude of aerobic
metabolism and not directly affected by gender or by appreciable
differences in the level of physical training.
MECHANISM OF MUSCLE WEAKNESS AFTER BURN INJURY
Tissue burns can elicit a marked deficit in muscle contractile
strength at sites removed from the region of injury. Clinically relevant consequences of this phenomenon include
ventilatory failure and increased difficulty in weaning
patients from respirators. Although the molecular etiology of this type
of muscle weakening is unknown, the upregulation of skeletal muscle
nicotinic acetycholine receptors (AChRs) suggests a commonality between
this phenomenon and denervation-induced muscle weakness. Nosek and
Martyn (p. 1333) demonstrated in rats that, unlike denervation-induced
muscle weakness, muscle at sites distant from burn injury shows no
evidence for increases in mRNA levels of myogenin, AChR -subunit, or
the immature sodium channel isoform SkM2. The authors also conclude that AChR upregulation secondary to burn insult is
posttranscriptionally regulated.
A THERMOREGULATORY ROLE FOR NITRIC OXIDE?
