| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Vol. 84, Issue 4, 1131-1137, April 1998
Laboratoire de Physiologie, Faculté de Médecine de Nancy, 54505 Vandoeuvre-lès-Nancy, France
 |
ABSTRACT |
|---|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
Intravenous injection of dopamine (DA) has
consistently been shown to depress minute ventilation
(
E). Whereas at low dosage (
10
µg/kg) this effect may be accounted for by inhibition of the carotid
sinus nerve chemosensory discharge (CSNCD), other mechanisms appear to
be involved with large dosage (
50 µg/kg). The purpose of this study
was to elucidate the mechanisms of DA-induced E depression. The effects of
intravenous injection of DA doses ranging from 1 to 200 µg/kg were
studied in 18 anesthetized cats. DA was injected during air and
O2 breathing, after 
-adrenergic blockade by phenoxybenzamine and after baro- and chemodenervation. E and CSNCD were also simultaneously
recorded on four occasions. In contrast to that with use of low-dose
DA, E depression induced by high-dose
DA was dissociated from CSNCD, persisted during 100% O2 breathing, and was
significantly correlated with the rise in arterial blood pressure.
Although blunted, E depression was still present after complete chemo- and barodenervation but was suppressed by blocking of the concomitant vasoconstriction with phenoxybenzamine. It is concluded that reflexes of circulatory origin
contribute to the E depression induced
by large-dose DA, in addition to its effects on arterial
chemoreceptors. The contribution of baroreceptor stimulation and
peripheral vasoconstriction is discussed.
chemoreceptors; baroreceptors; vasoconstriction; blood pressure; -adrenergic blockade; phenoxybenzamine
| |
INTRODUCTION |
|---|
|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
DOPAMINE (DA) is routinely administered to patients with cardiocirculatory failure. Dosage regimens are used to induce either pure dopaminergic or dopaminergic and adrenergic effect (15). The latter effect includes prominent peripheral vasoconstriction and increased arterial blood pressure (ABP). Although the circulatory effects of DA are carefully monitored, little attention is usually given to its potential effects on ventilatory control. However, there is evidence that DA depresses ventilation in a number of mammalian species (1, 26, 35), including healthy humans (33). DA has long been shown to inhibit the chemosensory discharge from the carotid sinus nerve (CSN) (2), a mechanism that is believed to account for hypoventilation. However, some intriguing facts indicate that this may not be the only mechanism. Hypoventilation has been reported after large doses of DA during 100% O2 breathing while the CSN discharge was almost nil (35), after bilateral section of the CSNs in cats (26, 35), or after resection of the carotid bodies in goats (1). Also, DA has occasionally been reported to excite chemosensory discharge (21, 24, 27, 34), an observation that is difficult to reconcile with the depressant ventilatory effect. DA does not cross the blood-brain barrier (3, 6), and the mechanisms that may account for the ventilatory depression have not been elucidated. They could be related to the vascular effects of DA. Indeed, it has been reported that the magnitude of the ventilatory response to carotid chemoreceptor stimulation was dependent on the degree of baroreceptor stimulation in dogs (14) and cats (9). Furthermore, the stimulation of the carotid sinus baroreceptors by increasing the intracarotid pressure in vagotomized dogs was found to decrease ventilation (4). On the other hand, more recent studies suggested that distending the peripheral circulation, particularly in muscles, could represent an important source of ventilatory drive (13). The mechanism involves type III-IV somatic afferents, which have long been shown to trigger ventilatory reflexes (19, 25). The mechanosensitive fibers ending close to the vascular network could be stimulated by vascular distension, thus linking ventilation to the degree of peripheral perfusion. Taken in this context, the vasoconstriction resulting from the adrenergic stimulation by large-dose DA could also contribute to depression of ventilation.
The purpose of this study was to examine the mechanisms of the ventilatory effects of DA and to test the hypothesis that the hypertension and/or vasoconstriction induced by large-dose DA determines the magnitude of the ventilatory response.
| |
MATERIALS AND METHODS |
|---|
|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
Anesthesia and General Preparation
Experiments were performed in 18 adult cats weighing 2.5-4.0 kg. Sedation was obtained with an intramuscular injection of ketamine (25 mg/kg) or xylazine (10 mg/kg), and anesthesia was induced with a mixture of chloralose (40 mg/kg) and Urethane (250 mg/kg), administered through a saphenous vein. The animals were placed supine on a heating pad, and body temperature was measured with a rectal probe (Digi-Sense thermocouple) and maintained between 37.5 and 38.5°C.Indwelling catheters were inserted into a femoral vein for drug injection and into a femoral artery to monitor ABP by using a P23 Db Statham pressure transducer and to sample arterial blood for blood-gas measurements (Radiometer, ABL 330). The cervical trachea was dissected, cannulated, and connected to a Fleisch no. 0 pneumotachograph attached to a differential pressure transducer (Validyne MP45, ±2 hPa) to measure ventilatory flow, which was electronically integrated to volume. At the end of the experiment, the cats were euthanized by an intravenous lethal dose of pentobarbital.
Protocol
DA injection. Fresh DA solutions were prepared daily from dopamine chlorhydrate (DA, Nativelle) diluted to normal saline to achieve doses ranging from 1 to 200 µg/kg in a total volume of 1 ml. The drug was injected slowly into the catheter, the volume of which was 1.2 ml. After a control period of at least 1 min of regular breathing and stable blood pressure, the catheter was flushed with 2 ml normal saline, beginning at the end of an expiration.
Responses to DA in air and O2 breathing. In eight cats, one CSN was dissected, severed, and prepared for recording of the carotid chemosensory discharge, as previously described (23). The ventilatory and ABP responses to DA were studied by using the following doses: 1, 50, 100, and 200 µg/kg while the animal was breathing room air or 100% O2.
-Blockade.
Phenoxybenzamine, an irreversible blocker of
1- and
2-adrenergic receptors
(dibenzyline, SmithKline Beecham) was diluted to normal saline and
administered by slow intravenous injection, under monitoring of ABP in
12 cats. The dose ranged from 5 to 10 mg/kg. -Blockade was
considered effective when the hypertensive response to an intravenous
injection of 20-50 µg epinephrine (Aguettant) was replaced by a
decrease in ABP. Series DA injections (1, 100, and 200 µg/kg) were
performed before and after -blockade, as described above. Seven cats
were studied in these conditions, two of which were also included in
the prior experiment. The effect of -blockade was also tested after
baro- and chemodenervation, as described below.
Nerve sections. Five cats were studied as follows. The areas of the carotid bifurcations were dissected on both sides. CSNs and vagi were first exposed before control studies, during which the preparation was kept under warm isotonic saline solution. CSNs were then severed distal to their junction with the glossopharyngeal nerve. When clearly identifiable from their connections with the superior laryngeal nerve at the junction with the nodose ganglion, the aortic nerves were selectively cut. Otherwise, a vagotomy was performed. The ventilatory response to an intravenous injection of 25 µg/kg sodium cyanide was tested to attest the effectiveness of the chemodenervation.
DA (100 and 200 µg/kg) was successively injected 1) as a control, 2) after denervation, and 3) after-blockade by phenoxybenzamine administered as described above.
Arterial blood gases were checked during long-lasting experiments, and
pH was maintained by using sodium bicarbonate.
Data Analysis
Tidal volume (VT), ABP, the action potentials from the CSN, and the corresponding frequency discharge were recorded on a chart recorder (Gould TA 4000). Ventilation, ABP, and the CSN frequency discharge were also digitized at 20 Hz by using an analog-to-digital converter (MacLab 8) and a computer (MacIntosch IIsi, Chart 8 software). Volume signal and mean ABP (MABP) were processed in either of the following ways. 1) Minute ventilation (E) was computed from the digitized
VT signal over the 30-s period
before (baseline) and after the onset of DA injection (post-DA), and MABP was averaged over each epoch. The differences between post-DA and
baseline ventilation (
E) and MABP
(MABP) were calculated. 2) To
describe the relationship between CSN chemosensory discharge and
ventilation and to characterize the effects of -blockade on the
ventilatory response to DA with better time resolution, the data were
transfered off-line to text files. After an electronic drift in the
VT signal was eliminated, the
amplitude and duration of each cycle
(TT) were calculated on a
breath-by-breath basis, so as to obtain ventilation as
VT · 60/TT.
The baseline was computed as the mean of 5-10 ventilatory cycles
before DA. The breath with the lowest E
after DA was taken as the nadir of the response. Time to reach this
value and time required for E to return
to baseline were calculated. MABP or discharge frequency from the CSN
was averaged during the corresponding ventilatory cycle, and the time
course of response was similarly calculated.
Baseline and post-DA E and MABP were
compared by using an analysis of variance for repeated measures, and
linear correlation was used as necessary. Significant differences were
considered at P < 0.05. Data are
expressed as means ± SE.
| |
RESULTS |
|---|
|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
Responses to DA During Air and 100% O2 Breathing
Ventilatory and ABP responses to different DA doses were studied in eight cats during air and O2 breathing. Figure 1 shows meanE before and after each dose. After 1 µg/kg DA, the decrease in E was
significant in air (
67.3 ± 18.3 ml/min,
P < 0.05) but not in
O2 (7.1 ± 18.7 ml/min). In contrast, E decreased significantly after doses of from 50 to 200 µg/kg, both in air and
O2
(P < 0.05). The magnitude of
E also increased with increasing doses: after 50, 100, and 200 µg/kg DA,
E was 105.7 ± 32.4, 174.9 ± 39.0, and 281.4 ± 51.5 ml/min,
respectively, in air and 87.9 ± 12.2, 167.8 ± 60.8, and 234.0 ± 75.0 ml/min, respectively, in
O2.
|
MABP is also shown in Fig. 1. It can be seen that there was no
significant change in MABP after 1 µg/kg DA. In contrast, MABP increased significantly (P < 0.05)
after 50 µg/kg (+18.0 ± 7.8 mmHg in air and +22.7 ± 14 mmHg
in O2), 100 µg/kg (+36.3 ± 5.6 mmHg in air and +45.2 ± 10.9 mmHg in
O2), or 200 µg/kg DA (+46.3 ± 13.8 mmHg in air and +47.1 ± 18.1 mmHg in
O2). Figure
2 illustrates the relationship between
E and MABP induced by DA doses
ranging from 50 to 200 µg/kg. The correlation is significant so that
the larger the increase in blood pressure, the larger the decrease in
E (r = 0.65, P < 0.01).
|
Pattern of Carotid Chemosensory and Ventilatory Responses to DA
Simultaneous recording was possible in four fiber preparations recorded in three cats. An example is shown in Fig. 3. After a low-dose DA injection, the chemosensory activity was completely stopped for ~5 s, andE decreased for three ventilatory cycles. Both events were tightly linked: the decrease in
E occurred within one ventilatory cycle
of cessation of the chemosensory discharge, and the return of
E to baseline was within two ventilatory cycles of reonset of the chemosensory discharge (Fig.
3A). The pattern was clearly
different after the high-dose DA (100 µg/kg). In this case, the
inhibition of the chemosensory discharge was followed by a period of
stimulation, which could be explained by a rise in arterial
PCO2
(PaCO2) and a decrease in arterial
PO2
(PaO2), as shown below. Ventilation was depressed for a prolonged period of time despite the clear increase in
chemosensory discharge (Fig. 3B).
|
After low-dose DA, the mean chemosensory discharge in the four
preparations was silenced for 6.7 ± 1.0 s into the injection period
and returned to control 42.7 ± 3.8 s thereafter. After 100-200
µg/kg DA, the discharge was silenced for 7.2 ± 0.3 s into the
injection and was back to control after 22.6 ± 5.5 s. The relationship between E and
chemosensory discharge after a small and a large dose of DA is
illustrated in Fig. 3, inset.
E followed the chemosensory discharge
after the small-dose DA but was clearly dissociated from the
chemosensory discharge after the large one. The mean correlation
coefficients between E and chemosensory discharge after DA were 0.58 ± 0.05 for the small and 0.12 ± 0.05 for the large doses. The latter value reflects the hysteresis observed between E and chemosensory
discharge.
Effects of -Adrenoreceptor Blockade
E, from
768.8 ± 82.6 to 865.9 ± 70.5 ml/min
(P < 0.03).
The effects of phenoxybenzamine on the ventilatory response to small-
and high-dose DA are summarized in Fig. 4.
After the control injection of 1 µg/kg DA,
E decreased by 232.9 ± 45.8 ml/min,
11.0 ± 1.9 s into the injection, and was back to baseline after
24.6 ± 3.9 s. The pattern of response was unaltered by
phenoxybenzamine: E decreased by 277.5 ± 23.6 ml/min, 10.0 ± 1.5 s into DA injection, and
was back to baseline 23.5 ± 1.5 s thereafter. MABP did not change
significantly after 1 µg/kg DA: +5.9 ± 1.9 mmHg before and +7.5 ± 2.9 mmHg after phenoxybenzamine.
|
More prominent E changes were observed
after 100 and 200 µg/kg DA. Moreover, the amplitude and timing of
E responses and the amplitude of MABP
response to 100 and 200 µg/kg DA were significantly altered by
phenoxybenzamine (P < 0.01). In
response to 100 µg/kg DA, E dropped by
498.0 ± 71.2 ml/min at 14.5 ± 1.7 s and returned to baseline
49.7 ± 8.8 s later, whereas MABP rose by 29.7 ± 12.1 mmHg.
After phenoxybenzamine, E dropped by
393.0 ± 73.9 ml/min at 11.5 ± 2.1 s and returned to baseline
24.8 ± 6.1 s later, whereas MABP changed by 1.2 ± 2.4 mmHg. A
similar effect was seen in the response to 200 µg/kg DA. Control and
phenoxybenzamine peak decreases in E were
577.3 ± 102.7 and 304.6 ± 88.3 ml/min at 17.4 ± 3.1 and
11.5 ± 2.4 s, respectively, whereas delays to recovery were 79.9 ± 14.4 and 34.7 ± 9.4 s and changes in MABP were
43.7 ± 11.6 and 1.1 ± 1.1 mmHg, respectively. For clarity,
E responses to 100 and 200 µg/kg DA
were pooled in Fig. 4 because neither the amplitude nor the delay to
peak E responses was different between the two doses. Only the delay in E
recovery was significantly longer with 200 µg/kg DA compared with 100 µg/kg DA (P < 0.02). In summary,
after phenoxybenzamine, the ventilatory response to 100-200
µg/kg DA very much resembled that to 1 µg/kg DA.
Nerve Section Experiments
Figure 5 illustrates the main results of these experiments. As expected,E was
significantly depressed by control injections of 100 and 200 µg/kg
DA; changes in E during the
30-s period into DA were, respectively, 243.8 ± 50.0 and
291.3 ± 72.7 ml/min (P < 0.001). Although the magnitude of the response decreased after complete
baro- and chemodenervation, E was still
significantly inhibited after both doses, changing 51.6 ± 39.1 and 123.6 ± 34.8 ml/min, respectively
(P < 0.01). The average changes in
MABP were highly significant (P < 0.001) for 100 µg/kg and 200 µg/kg DA in both control conditions
(+39.1 ± 3.8 and +50.1 ± 4.9 mmHg, respectively) and after
chemo- and barodenervation (+23.1 ± 14.4 and +46.9 ± 5.3 mmHg, respectively).
|
The injection of phenoxybenzamine was associated with a significant
decrease in MABP, from 132.5 ± 13.9 to 69.2 ± 6.5 mmHg (P < 0.02), and a significant
increase in E, from 521.8 to 554 ± 61.5 ml/min (P < 0.01). In response
to DA, however, E did not change
significantly, +20.6 ± 16.5 ml/min with 100 µg/kg and 0.5 ± 13.8 ml/min with 200 µg/kg, whereas MABP decreased
significantly in response to either 100 µg/kg (16.2 ± 9.6 mmHg) or 200 µg/kg DA (13.8 ± 5.5 mmHg,
P < 0.03). Altogether, the data
indicate that chemo- and barodenervation decreased but did not abolish the ventilatory response to DA, whereas phenoxybenzamine injected thereafter suppressed the response.
Arterial Blood Gases
In 14 cats, arterial pH, PaO2, and PaCO2 measured in air at the beginning of the experiment were 7.29 ± 0.02, 94.9 ± 3.4 Torr, and 37.1 ± 1.9 Torr, respectively. In five cats breathing O2, those values were 7.26 ± 0.02, 427.6 ± 29.7 Torr, and 41.6 ± 4.0 Torr, respectively. Finally, measurements were performed in eight cats immediately before and 20-30 s into the injection of large-dose DA while ventilation was still depressed. Arterial pH, PaO2, and PaCO2 were found to change significantly, from 7.31 ± 0.02 to 7.23 ± 0.01, 99.3 ± 4.7 to 80.8 ± 4.2 Torr, and 34.2 ± 2.0 to 43.1 ± 1.9 Torr, respectively (P < 0.05).| |
DISCUSSION |
|---|
|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
The present study shows that DA depresses ventilation by different mechanisms. At low dose, DA is devoid of adrenergic effect, and the inhibition of the carotid chemoreceptor activity appears to be the main mechanism of the observed ventilatory depression. Altogether, ventilatory depression lasts a short time, and there is no evidence of change in ABP. This study adds to the well-documented evidence that low-dose DA transiently suppresses ventilation. In addition, we have described the dose-dependent relationship between carotid chemosensory discharge and ventilation after DA injection. The breath-by-breath analysis of the relationship between ventilation and CSN chemosensory discharge shows that ventilatory depression follows the decrease in chemosensory discharge within two respiratory cycles. A very similar relationship between ventilation and CSN chemosensory discharge was demonstrated during O2 tests in the pioneer work of Leitner et al. (22). The demonstration that ventilatory depression by small-dose DA is suppressed by 100% O2 breathing, shown in the present study and in a previous study (35), also favors the mechanism of carotid chemoreceptor inhibition. DA D2 receptors are located on the carotid body type I cell that is connected to afferent endings from the CSN. Because of their presynaptic location and evidence for DA synthesis by the type I cell, these receptors are believed to function as autoreceptors, regulating DA release and synthesis. The selective stimulation of these D2 receptors is thought to inhibit the chemosensory discharge (8).
Large doses of DA were associated with very different patterns of
ventilatory response. Ventilation was depressed well beyond the
short-lasting cessation of chemosensory discharge, at a time when
chemoreceptor activity was already above control (Fig. 3). Indeed, it
is worth noting that, despite an average ~20 Torr decrease in
PaO2 and ~10 Torr increase in
PaCO2, 30 s into DA injection ventilation was depressed for up to at least 1 min, and the concomitant rise in chemosensory discharge was clearly ineffective in restoring ventilation. Moreover, large-dose DA also induced a significant ventilatory depression during O2
breathing, a further indication that suppressing the carotid
chemosensory discharge was not the determinant mechanism to this
hypoventilation. Similar conclusions can be drawn from other studies
dealing with the effects of DA on the arterial chemoreflex. For
example, Zapata and Zuazo (35) demonstrated that intracarotid injection
of DA induced a rapid decrease in both
VT and breathing frequency in
cats. This response was abolished after sectioning of the ipsilateral
carotid nerve. However, the ventilatory depression provoked by an
intravenous injection of 20 µg/kg DA did not change after bilateral
carotid neurotomy (35). Similar findings were reported by Nishino and Lahiri (26) in the same species, in which bilateral section of the CSNs
diminished but did not abolish the hypopnea induced by intravenous
infusion of 10 µg · kg
1 · min1
DA. A non-chemoreceptor-related mechanism must therefore be proposed to
account for part of the "high-dose" DA-induced ventilatory depression. The present study brings definitive evidence for such a
dual mechanism to the ventilatory effect of DA.
The significant correlation between the increase in blood pressure and
the decrease in ventilation suggests the possibility of a link between
respiratory and circulatory events. Various sites of the cardiovascular
system primarily devoted to the control of circulation, i.e., the
arterial baroreceptors (4, 14) and the receptors located in the heart
(17) or the pulmonary circulation (18), contribute to the regulation of
breathing (32). Such a circulatory-ventilatory coupling relies on the existence of direct synaptic connections between neurons involved in
regulation of breathing and circulation at the brain-stem level, like
in the nucleus tractus solitarii (29), a major relay for cardiovascular
and respiratory afferents. Exogenous DA has a variety of cardiovascular
dose-dependent effects. With infusion at a dosage above 10-20
µg · kg1 · min1,
both a 
- and an -mimetic effect are obtained, consisting of a
rise in cardiac output and peripheral resistance, leading to an
increase in systemic blood pressure. Such circulatory changes could
have affected the level of ventilation. An increase in cardiac output
could have stimulated mechanoreceptors located in the right heart (10)
and thus triggered ventilatory responses (17). The afferent arm of this
reflex travels through the vagus and/or sympathetic nerve (10).
However, this mechanism should, if anything, stimulate rather than
inhibit breathing during DA infusion. A similar effect is expected from
stimulation of mechanoreceptors located in the pulmonary circulation
because distending the pulmonary artery and its main branches appears
to increase ventilation (18). In contrast, stimulation of
mechanoreceptors located in the left ventricle can depress ventilation,
a response that persists after bilateral destruction of the stellate
ganglia but is suppressed by vagotomy (20). It is unlikely that the
conditions required to trigger this hypoventilation, i.e., an acute and
dramatic distension of the left ventricle, could result from DA
injection. Lung receptors, mostly those with unmyelinated fibers, have
long been shown to respond to local circulatory changes (5) and can
produce rapid shallow breathing and apneusis. However, it is difficult
to predict whether C fibers could have been stimulated through a
possible increase and/or redistribution of intrapulmonary blood
flow during DA injection. Moreover, in no instance did the observed
changes in breathing pattern provoked by DA resemble that occurring
with pulmonary C-fiber stimulation. Finally, the persisting ventilatory depression after vagotomy is a strong argument to a non-vagally mediated reduction in breathing, independent therefore of the mechanoreceptors located in the left heart or the lungs.
In contrast, it has long been recognized that ventilation can be
decreased through the arterial baroreflex when ABP rises. The precise
characteristics of this baroreceptor-mediated effect on ventilation
have been described by using the isolated carotid sinus preparation in
vagotomized dogs. Brunner et al. (4) have found that the slope of the
relationship between the decrease in ventilation and the increase in
carotid sinus pressure averaged 0.65 ml · min1 · kg1 · mmHg1
when intrasinus pressure was increased 100 mmHg above normal resting level. Beyond this value, the slope appeared to flatten, resulting in a pseudosigmoidal shape over the whole range of intrasinus pressure studied (4). The gain of ventilatory-to-blood pressure change
depends on many factors, including the level of chemoreceptor activity
and the integrity of vagal feedback loops. This aspect is obvious in
the study by Heistad et al. (14), in which a fivefold potentiation of
the slope of the relationship between carotid perfusion pressure and
E was observed after vagotomy. It becomes therefore impossible to evaluate the contribution of vagally mediated information to the observed ventilatory inhibition of breathing by
cutting the vagi because the interaction between vagal and other inputs
to the brain-stem respiratory neurons is simply not that expected from
a linear function. Similarly, the gain of the relationship between
ventilation and carotid sinus pressure (0.24 ml · min1 · kg1 · mmHg1)
reported by Heistad et al. increased 5 to 10 times during arterial chemoreceptor stimulation by nicotine. The inverse relationship between
systemic blood pressure and ventilatory changes reported in the present
study in intact animal displayed a much higher slope (1.5 ml · min1 · kg1 · mmHg1)
than in any study in which discrete pressure changes were applied at
the level of the baroreceptors (4, 14). Interestingly, the gain was
still ~1
ml · min1 · kg1 · mmHg1
during 100% O2 breathing, a
condition in which the ventilatory component of the arterial baroreflex
is expected to be dramatically blunted (14). More importantly, after
complete barodenervation, the gain of the ventilatory response (0.8 ml · min1 · kg1 · mmHg1)
was still above that reported for the relationship between intrasinus pressure and ventilation in dogs (4). In other words, although complete
barodenervation blunted the magnitude of DA-induced hypoventilation, the ventilatory depression remained and was only abolished after -blockade.
It remains unclear what other structure could be involved to account
for the E inhibition after section of
sinus and aortic nerves because the arterial baroreceptors are not
operative anymore, but the ventilatory depression to DA remains. A
central mechanism is unlikely to explain the depressant effect of DA on
ventilation after arterial baro- and chemodenervation because DA does
not cross the blood-brain barrier. Moreover, DA acting on the central nervous system should, if anything, produce an opposite effect on
ventilation because the DA-receptor blocker haloperidol acts centrally to inhibit ventilation (16, 28). Furthermore, any reduction
in cerebral blood flow, which is likely to occur during high-dose DA
injection, will yield a rise in ventilation through local accumulation
of CO2 (6).
We have recently reported that high-dose DA injected into the isolated hindlimb circulation of an anesthetized sheep after injection of a vasodilatory agent can produce a ventilatory depression despite the lack of increase in systemic blood pressure and therefore the lack of involvement of any of the known receptors located in the central circulation (12). It was therefore postulated that the status of the peripheral circulation could be sensed by slow-conducting afferent fibers and contributes to control breathing. Indeed, stimulation of group III and IV muscle receptors evokes strong cardiac and ventilatory responses (25). They are found close to or within the adventitia of arterioles and venules (30, 31). Many receptors respond to low-threshold mechanical stimuli (19) and could plausibly encode the distension of the peripheral vascular network. High-dose DA could therefore inhibit ventilation by reducing peripheral blood flow the same as after occlusion of the arterial supply to the hindlimb circulation (11). This inhibitory effect on ventilation does not depend on arterial baro- and/or chemoreceptors and is expected to disappear with blockade of the vasoconstriction, as observed in this study.
It is concluded that the depression of ventilation by DA is explained by a depression of the arterial chemoreceptor discharge at low (dopaminergic) doses. The increase in blood pressure as well as the vasoconstriction resulting from the adrenergic effect are likely to contribute to the ventilatory inhibition observed with large doses. The clinical relevance of these mechanisms must be considered because DA is usually administered to patients with low blood pressure and probably a dramatic decrease in peripheral vascular conductance. The above concept implies that infusion of an agent that would further reduce peripheral perfusion could plausibly lead to hypoventilation, independent of, or in addition to, the effect of reloading the arterial baroreceptors. Although the ventilatory effects of DA under experimental conditions have been described for several years, there is precious little clinical data in subjects with circulatory failure. Such studies may be of importance in improving the management of those patients.
| |
ACKNOWLEDGEMENTS |
|---|
The authors are grateful to Professor H. Sundell for advice and discussion and to SmithKline Beecham for providing the dibenzyline. They also gratefully acknowledge the technical assistance of N. Bertin, J. Beyrend, B. Chalon, C. Creusat, and G. Colin.
| |
FOOTNOTES |
|---|
This study was supported by Université Henri Poincaré de Nancy I Grant JE 2164.
Address for reprint requests: F. Marchal, Laboratoire de Physiologie, Faculté de Médecine de Nancy, Université Henri Poincaré de Nancy I, 9 Ave. de la Forêt de Haye, BP 184 F-54505 Vandoeuvre-lès-Nancy, France.
Received 27 June 1997; accepted in final form 5 December 1997.
| |
REFERENCES |
|---|
|
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References
|
|---|
1.
Bisgaard, G. E.,
H. V. Forster,
J. P. Klein,
M. Manohar,
and
V. A. Bullard.
Depression of ventilation by dopamine in goats. Effects of carotid body excision.
Respir. Physiol.
41:
379-392,
1980.
2.
Black, A. M. S.,
J. H. Comroe,
and
L. Jacobs.
Species difference in carotid body response of cat and dog to dopamine and serotonin.
Am. J. Physiol.
223:
1097-1102,
1972.
3.
Bloom, F. E.
Neurohumoral transmission and the central nervous system.
In: The Pharmacological Basis of Therapeutics, edited by A. Goodman Gilman,
T. W. Rall,
A. S. Nies,
and P. Taylor. New York: McGraw-Hill, 1992, p. 244-268.
4.
Brunner, M. J.,
M. S. Sussman,
A. S. Greene,
C. H. Kallman,
and
A. A. Shoukas.
Carotid sinus baroreceptor reflex control of respiration.
Circ. Res.
51:
624-636,
1982
5.
Coleridge, H. M.,
and
J. C. G. Coleridge.
Reflexes evoked from tracheobronchial tree and lungs.
In: Handbook of Physiology. The Respiratory System. Control of Breathing. Bethesda, MD: Am. Physiol. Soc., 1986, sect. 3, vol. II, pt. 1, chapt. 12, p. 395-429.
6.
Esson, C. V.
Effect of dopamine, noradrenaline and 5-hydroxytryptamine on the cerebral blood flow in the dog.
J. Pharm. Pharmacol.
24:
668,
1972[Medline].
7.
Franz, D. N.
Drugs for Parkinson's disease.
In: The Pharmacological Basis of Therapeutics, edited by A. Goodman Gilman,
T. W. Rall,
A. S. Nies,
and P. Taylor. New York: McGraw-Hill, 1992, p. 227-244.
8.
Gonzalez, C.,
L. Almaraz,
A. Obeso,
and
R. Rigual.
Carotid body chemoreceptors: from natural stimuli to sensory discharges.
Physiol. Rev.
74:
829-898,
1994
9.
Grunstein, M.,
J. Derenne,
and
J. Milic-Emili.
Control of depth and frequency of breathing during baroreceptor stimulation in cats.
J. Appl. Physiol.
39:
395-404,
1975
10.
Hainsworth, R.
Reflexes from the heart.
Physiol. Rev.
71:
617-658,
1991
11.
Haouzi, P.,
J. J. Hirsh,
J. P. Gille,
B. Chalon,
F. Marchal,
J. P. Crance,
and
B. J. Whipp.
Vascular distension in muscles contributes to respiratory control in sheep.
Respir. Physiol.
99:
41-50,
1995[Medline].
12.
Haouzi, P.,
J. J. Hirsh,
J. P. Gille,
F. Marchal,
J. P. Crance,
and
A. Huszczuk.
Papaverine injection into the hindlimb circulation stimulates ventilation in sheep.
Respir. Physiol.
105:
143-153,
1996[Medline].
13.
Haouzi, P.,
F. Marchal,
and
A. Huszczuk.
Muscle perfusion and control of breathing. Is there a neural link?
In: Modeling and Control of Ventilation, edited by S. J. G. Semple,
L. Adams,
and B. J. Whipp. New York: Plenum, 1995, p. 363-368.
14.
Heistad, D. D.,
F. M. Abboud,
A. L. Mark,
and
P. G. Schmid.
Effect of baroreceptor activity on ventilatory response to chemoreceptor stimulation.
J. Appl. Physiol.
39:
411-416,
1975
15.
Hoffman, B. B.,
and
R. J. Lefkowitz.
Catecholamines and sympathomimetic drugs.
In: The Pharmacological Basis of Therapeutics, edited by A. Goodman Gilman,
T. W. Rall,
A. S. Nies,
and P. Taylor. New York: McGraw-Hill, 1992, p. 187-220.
16.
Hsiao, C.,
S. Lahiri,
and
A. Mokashi.
Peripheral and central dopamine receptors in respiratory control.
Respir. Physiol.
76:
327-336,
1989[Medline].
17.
Jones, P. W.,
A. Huszczuk,
and
K. Wasserman.
Cardiac output as a controller of ventilation through changes in right ventricular load.
J. Appl. Physiol.
53:
218-224,
1982
18.
Kan, W. O.,
J. R. Ledsome,
and
C. P. Bolter.
Pulmonary arterial distension and activity in phrenic nerve of anesthetized dogs.
J. Appl. Physiol.
46:
625-631,
1979
19.
Kaufman, M. P.
Afferents from limb skeletal muscle.
In: Regulation of Breathing, edited by J. Dempsey,
and A. I. Pack. New York: Dekker, 1995, p. 583-616.
20.
Kostreva, D. R.,
F. A. Hopp,
E. J. Zuperku,
and
J. P. Kampine.
Apnea, tachypnea, and hypotension elicited by cardiac vagal afferents.
J. Appl. Physiol.
47:
312-318,
1979
21.
Lahiri, S.,
and
T. Nishino.
Inhibitory and excitatory effects of dopamine on carotid chemoreceptors.
Neurosci. Lett.
20:
313-318,
1980[Medline].
22.
Leitner, M.,
B. Pages,
R. Puccinelli,
and
P. Dejours.
Etude simultanée de la ventilation et des décharges des chémorécepteurs du glomus carotidien chez le chat. I
Au cours d'inhalations brèves d'oxygène pur.
Arch. Int. Pharmacodyn. Ther.
154:
421-426,
1965[Medline].
23.
Marchal, F.,
A. Bairam,
P. Haouzi,
J. P. Crance,
C. Di Giulio,
P. Vert,
and
S. Lahiri.
Carotid chemoreceptor response to natural stimuli in the newborn kitten.
Respir. Physiol.
87:
183-193,
1992[Medline].
24.
Marchal, F.,
A. Bairam,
P. Haouzi,
J. M. Hascoet,
J. P. Crance,
P. Vert,
and
S. Lahiri.
Dual responses of carotid chemosensory afferents to dopamine in the newborn kitten.
Respir. Physiol.
90:
173-183,
1992[Medline].
25.
Mitchell, J. H.,
and
R. F. Schmidt.
Cardiovascular reflex control by afferent fibers from skeletal muscle receptors.
In: Handbook of Physiology. The Cardiovascular System. Bethesda, MD: Am. Physiol. Soc., 1983, sect. 2, vol. III, pt. 2, chapt. 17, p. 623-637.
26.
Nishino, T.,
and
S. Lahiri.
Effects of dopamine on chemoreflexes in breathing.
J. Appl. Physiol.
50:
892-897,
1981
27.
Okajima, Y.,
and
K. Nishi.
Analysis of inhibitory and excitatory actions of dopamine on chemoreceptor discharges of carotid body of cat in vivo.
Jpn. J. Physiol.
31:
695-704,
1981[Medline].
28.
Smatresk, N. J.,
M. Pokorski,
and
S. Lahiri.
Opposing effects of dopamine receptor blockade on ventilation and carotid chemoreceptor activity.
J. Appl. Physiol.
54:
1567-1573,
1983
29.
Spyer, K. M.
Central nervous integration of cardiorespiratory control.
In: Comprehensive Human Physiology, edited by R. Greger,
and U. Windhorst. Berlin: Springer-Verlag, 1996, vol. 2, p. 2129-2144.
30.
Stacey, M. J.
Free nerve endings in skeletal muscle of the cat.
J. Anat.
105:
231-254,
1969[Medline].
31.
Von During, M.,
and
K. H. Andres.
Topography and ultrastructure of group III and IV nerve terminals of cats gastrocnemius-soleus muscle.
In: The Primary Afferent Neuron: A Survey of Recent Morpho-Functional Aspects, edited by W. Zenker,
and W. L. Neuhuber. New York: Plenum, 1990, p. 35-41.
32.
Ward, S. A.,
and
B. J. Whipp.
Coordination of circulation and respiration during exercise.
In: Comprehensive Human Physiology, edited by R. Greger,
and U. Windhorst. Berlin: Springer-Verlag, 1996, vol. 2, p. 2145-2176.
33.
Welsh, M. J.,
D. D. Heistad,
and
F. M. Abboud.
Depression of ventilation by dopamine in man.
J. Clin. Invest.
61:
708-713,
1978.
34.
Zapata, P.
Effects of dopamine on carotid chemo and baroreceptors in vitro.
J. Physiol. (Lond.)
244:
235-251,
1975
35.
Zapata, P.,
and
A. Zuazo.
Respiratory effects of dopamine-induced inhibition of chemosensory inflow.
Respir. Physiol.
40:
79-92,
1980[Medline].
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |
) and
O2 (
). B, baseline; D, DA.
After 1 µg/kg DA ventilation decreases significantly in animals
during air but not O2 breathing.
Note lack of change in blood pressure after above-mentioned dose in
either condition. Larger doses are associated with significant decrease
in ventilation and rise in blood pressure in animals during both air
and O2 breathing. * P < 0.05. 
P < 0.01.
)-dose DA. Arrows, time course. Relationship
between small and large doses is similar at onset but clearly different
at recovery. Although ventilation and discharge frequency are related
during recovery from small dose, recovery of chemosensory activity does
not induce any increase in ventilation after large dose. Imp,
impulses.
P = 0.01;
§ P < 0.05.