(Circulation. 1995;92:96-105.)
© 1995 American Heart Association, Inc.
Articles |
Role of Blood Doping in the Coronary Vasoconstrictor Response to Cocaine
From the Department of Medicine, Harvard Medical School, Brigham & Women's Hospital, Boston; and the New England Regional Primate Research Center, Southborough, Mass.
Correspondence to Richard P. Shannon, MD, Cardiovascular Division, West Roxbury VA Medical Center, 1400 V.F.W. Pkwy, West Roxbury, MA 02132.
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Abstract |
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Background The mechanism by which cocaine induces myocardial ischemia remains controversial. Most prior studies have postulated that cocaine-induced coronary vasoconstriction limits myocardial oxygen delivery during times of increased myocardial oxygen demand.
Methods and Results To determine the contribution of altered myocardial metabolic demands to the coronary vasoconstrictor effects of intravenous cocaine (COC 1 mg/kg), we studied 13 conscious, chronically instrumented dogs in the intact state and with heart rate held constant with atrial pacing in the presence and absence of ß-adrenergic blockade with propranolol (2 mg/kg) to limit the inotropic and chronotropic effects of cocaine on associated increases in myocardial oxygen consumption. In the intact state, COC caused a prompt increase in coronary blood flow (+30±3%, P<.01) that returned rapidly to baseline within 10 minutes, whereas coronary vascular resistance did not increase significantly (+17±6%, P<.05) until 15 minutes after COC. Notably, myocardial oxygen consumption increased (+57±4%, P<.01) to a greater extent than oxygen delivery (+42±3%, P<.01) during the first 2.5 minutes, requiring increased oxygen extraction (from 75±1% to 80±1%, P<.01), although only transiently. Thereafter, enhanced oxygen delivery matched the required oxygen consumption without further need to extract additional oxygen. Surprisingly, the enhanced oxygen delivery associated with COC in conscious dogs did not depend on persistent increases in coronary blood flow but rather was due to enhanced arterial oxygen content (+22±4%, P<.01) as a result of a significant "blood doping" effect with associated increases in circulating hemoglobin from 12.1±0.4 to 14.2±0.6 g/dL (P<.01), which persisted for 60 minutes.
Conclusions The myocardial oxygen requirements associated with COC administration have a significant impact on both the magnitude and the mechanism of the coronary vasoconstrictor effects of COC in conscious dogs. Furthermore, the enhanced myocardial oxygen delivery associated with COC administration is not dependent solely on coronary blood flow responses but is due to a significant "blood doping" effect associated with COC.
Key Words: cocaine • oxygen • blood
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Introduction |
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Despite increasing interest and intense study, the mechanisms underlying the myocardial ischemic complications associated with cocaine use are unexplained fully after consistent observations in both humans1 2 3 4 5 6 7 8 9 and experimental10 11 12 13 14 15 16 17 models of cocaine-induced vasoconstriction at both the epicardial coronary artery1 2 3 4 5 13 14 15 16 and the coronary resistance vessels.1 2 3 4 5 17 The tacit assumptions in these previous studies have been that cocaine-induced coronary vasoconstriction limits myocardial oxygen delivery at a time when myocardial oxygen demand is increasing and that this supply-and-demand imbalance provides the nidus for ischemia. However, there are several features of this generally accepted experimental paradigm that remain unproved. First, most prior studies have estimated myocardial oxygen consumption from the heart rate–blood pressure product rather than direct measures of myocardial oxygen consumption, ignoring the complex and biphasic effects of cocaine on left ventricular (LV) contractility.18 19 Second, there have been no previous studies that have measured myocardial oxygen delivery during cocaine administration to corroborate the tacit assumption that cocaine-induced coronary vasoconstriction limits oxygen delivery. Prior work from our laboratory17 found that the peak coronary vasoconstrictor effects of cocaine (1 mg/kg) did not require increased oxygen extraction across the coronary circulation, suggesting that myocardial supply and demand were balanced. In addition, most prior studies1 2 3 4 5 12 13 14 15 16 have reported the peak coronary vasoconstrictor effects of cocaine without consideration of the dynamic and transient nature of the effects after acute intravenous administration. Finally, the role of metabolically determined vasodilation associated with cocaine-induced increases in myocardial oxygen demand has often been overlooked or overshadowed by experimental studies conducted in acutely instrumented, anesthetized animal models in which the hemodynamic effects of cocaine have been shown to be altered.20
Accordingly, one purpose of the present study was to determine the extent to which the coronary vasoconstrictor response to intravenous cocaine was influenced by the dynamic changes in myocardial oxygen demand that occur simultaneously in conscious, chronically instrumented dogs. An additional goal was to determine whether cocaine-induced coronary vasoconstriction significantly limits myocardial oxygen delivery. A final goal was to examine the contribution and mechanisms contributing to enhanced myocardial oxygen delivery.
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Methods |
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Surgical Preparation and Instrumentation
Seventeen mongrel dogs of either sex (weight, 24 to 36 kg) were sedated with xyalazine (10 mg/kg), intubated, and anesthetized with halothane (1 to 1.5 vol%). With sterile technique and through an incision in the fifth left intercostal space, we implanted Tygon catheters in the descending thoracic aorta and left and right atria, and a Silastic catheter was implanted in the coronary sinus.17 21 A solid-state miniature pressure transducer (Konigsberg Instruments) was implanted in the left ventricle through the apex for high-fidelity recordings of LV pressure. A Doppler ultrasonic flowmeter was placed around the proximal portion of the left circumflex coronary artery for continuous measurement of coronary blood flow. Bipolar pacing electrodes were sutured to the surface of the left atrium. All catheters and wires were tunneled subcutaneously and externalized infrascapularly. The thoracotomy was closed in layers; analgesics were administered as needed, and antibiotics were administered daily for the first 7 days. Catheters were flushed daily with saline and heparin, and the dogs were allowed to recover for 2 to 3 weeks, during which they were trained to lie quietly on the experimental table. Animals used in the present study were maintained in accordance with the guidelines of the Committee on Animals of Harvard Medical School and the National Institutes of Health Guide for the Care and Use of Laboratory Animals (Department of Health and Human Services Publication No. [NIH] 85-23, revised 1985).
Experiment Measurements
Aortic and left atrial pressures were
measured from the
chronically implanted catheters with Statham strain-gauge manometers,
which were calibrated with a mercury manometer. LV pressures were
measured with the solid-state miniature pressure transducer calibrated
in vitro with the mercury manometer and in vivo with the left atrial
and aortic catheters. Left circumflex coronary artery blood flow was
measured using a Doppler flowmeter that measured the shift in Doppler
frequency in kilohertz Measurements of arterial and coronary sinus
hemoglobin concentrations, oxygen saturations, and oxygen content were
made using an IL-482 Co-Oximeter System (Instrumentation Laboratories).
Arterial and coronary sinus PO2,
PCO2, and pH were measured using an
IL-1306 pH and blood gas analyzer (Instrumentation Laboratories).
Experiment Protocol
All experiments were conducted after the
dogs had recovered
fully from surgery (2 to 3 weeks). After measurements were obtained in
the control state, cocaine hydrochloride (1 mg/kg) was administered
intravenously over 1 minute using a Harvard infusion pump. In 7 dogs,
hemodynamic parameters were measured for 150 minutes to establish the
duration of responses and to observe for residual effects after
parameters had returned to baseline. In addition, on a separate day,
each dog was studied with heart rate held constant at 150 beats per
minute with left atrial pacing to control the contribution of heart
rate changes to the myocardial oxygen consumption response. A separate
group of 4 dogs were instrumented similarly but received an equal
volume of intravenous normal saline (3.82 mL) over 1 minute to serve as
controls. In a separate series of 6 dogs, the response to intravenous
cocaine (1 mg/kg) was assessed with heart rate held constant at 140
beats per minute, in the presence and absence of ß-adrenergic
blockade with intravenous propranolol (2 mg/kg), so we could observe
the coronary vasoconstrictor response to the same dose of cocaine under
conditions in which the metabolic effects were limited. The efficacy of
ß-adrenergic blockade was confirmed before cocaine administration by
the absence of a heart rate response to an intravenous bolus of
isoproterenol (0.2 µg/kg).
Under all experimental conditions, hemodynamic parameters were recorded continuously. In the first series of experiments, arterial and coronary sinus blood samples were collected in iced, heparinized syringes at baseline and 2.5, 10, 15, 20, 30, 60, 90, 120, and 150 minutes after cocaine administration and were used for the determination of myocardial oxygen consumption. Thereafter, both hemodynamic data and blood samples were collected for as long as 60 minutes. Plasma norepinephrine and epinephrine levels were measured at baseline and 5 and 30 minutes after cocaine infusion and were assayed using the method of Peuler and Johnson.22 Plasma cocaine levels were obtained at 5 and 30 minutes.
Data Analysis
The hemodynamic data were recorded
simultaneously on a
multichannel magnetic tape recorder (Honeywell 101) and played back on
a strip-chart recorder (Gould 3800). Mean arterial pressures and mean
left circumflex flow velocities were derived by use of electronic
filters with 2-second time constants. Mean left circumflex flows in
milliliters per minute were calculated as the product of the measured
velocity (cm/s) and the internal cross-sectional area of the coronary
vessel (cm2) at the site of implantation of the Doppler
flowmeter, obtained when the animal was euthanized. To verify that the
increases in measured Doppler velocity were truly due to increases in
flow and not simply changes in coronary artery cross-sectional area,
we confirmed the magnitude and the direction of the change in
coronary blood flow in one dog by using radioactive microspheres
(baseline, 1.05
mL · min-1 · g-1;
peak, 1.17 mL · min-1 · g-1)
and in
another dog by using a Transonic flowmeter (Transonic Instruments)
chronically implanted on the left circumflex coronary artery.
There was a close linear correlation between the two independent
measurements of coronary blood flow during cocaine infusion
[Y (Doppler)=0.96X(Transonic)+15.7,
R2=.90]. Thus, changes in Doppler flow
velocities correlated closely with two independent and direct measures
of coronary blood flow. The mean coronary vascular resistance was
calculated as the quotient of the mean arterial pressure and the mean
left circumflex coronary blood flow (in
mm Hg · mL-1 · min-1). A
cardiotachometer triggered from the LV pulse provided instantaneous and
continuous recordings of the heart rate. Continuous records of LV dP/dt
were derived from the LV pressure signals with operational amplifiers
connected as differentiators. A triangular wave signal with known slope
was substituted for the pressure signal for direct calibration of the
differentiator. An index of myocardial oxygen consumption was
calculated as the product of left circumflex coronary blood flow and
the arteriocoronary sinus oxygen content difference across the coronary
circulation17 21 (expressed in mL O2
consumed/min). An index of myocardial oxygen delivery was calculated as
the product of left circumflex coronary blood flow and the arterial
oxygen content (expressed in mL O2 delivered/min). An index
of oxygen extracted across the coronary circulation was calculated as
the quotient of the arteriocoronary sinus oxygen content difference and
the arterial oxygen content and expressed as percent extracted.
The
significant differences in the measured parameters during the
150-minute period of observation were assessed by an ANOVA with
repeated measures. The differences in the time course of the responses
of the same animals studied under differing conditions (ie, intact,
heart rate constant versus controls [Figs 1 through
4
], or heart
rate
constant and ß-adrenergic blockade [Figs 5 through
7]) were
compared using a repeated measures ANOVA. All statistical analyses were
performed using the BMDP statistical package. All data
are reported as mean±SEM.
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Results |
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Time Course of Change in Coronary Hemodynamics and Myocardial Oxygen Consumption
Table 1
reveals the effects of acute
intravenous
cocaine administration (1 mg/kg) on LV, systemic, and coronary
hemodynamics in 7 conscious dogs observed for 150 minutes after
administration. Both LV systolic and end-diastolic
pressures rose significantly (P<.05) within the first
2.5 minutes (by 31±6% and 172±33%, respectively) and remained
significantly elevated for at least 30 minutes. LV dP/dt rose
significantly (13±4%, P<.05) within the first 5 minutes
and remained elevated for the first 20 minutes after cocaine
administration. In contrast, the heart rate response to cocaine peaked
rapidly (+35±7%, P<.001) over a similar period (the
first
2.5 to 5 minutes) but remained significantly elevated for 90 minutes.
The systemic pressor response to cocaine peaked at 5 minutes
(+37±6%,
P<.001) and remained significantly elevated for at least 30
minutes. In contrast, although the coronary blood flow response showed
a similar pattern of onset, increasing by 30±4% (P<.05)
over the first 2.5 minutes, coronary blood flow rapidly returned to
baseline within 10 minutes after cocaine administration, well ahead of
the corresponding changes in LV and systemic hemodynamics. As a result,
a significant coronary vasoconstrictor response to cocaine
(+17±6%, P<.05) did not occur until 10 minutes after
cocaine administration, peaking at 15 minutes (+19±3%,
P<.02) (well after the peak LV and systemic hemodynamic
effects), and remained significantly elevated for 30 minutes. No
further coronary vasoconstriction was observed subsequently. Thus,
there was a temporal dissociation between the effects of cocaine on LV
and systemic hemodynamics and the effects on coronary
hemodynamics.
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Table 2 illustrates the effects of
intravenous cocaine
administration (1 mg/kg) on myocardial oxygen consumption, delivery,
and extraction. Myocardial oxygen consumption increased promptly after
the administration of cocaine (+57±5% within 2.5 minutes,
P<.001) and returned to baseline levels within 90 minutes.
Myocardial oxygen delivery increased by 46±5% (P<.001)
within the first 2.5 minutes and thereafter declined in parallel with
myocardial oxygen demands. In contrast, myocardial oxygen extraction
increased from 75±1% to 80±1% within the first 2.5 minutes and
then
returned to baseline within 5 minutes, suggesting that myocardial
oxygen delivery kept pace with oxygen consumption for all except the
first 2.5 minutes after cocaine administration. Similarly, the coronary
sinus oxygen content fell transiently within the first 2.5 minutes from
3.8±0.2 to 3.3±0.3 vol% (P<.05) but then increased
significantly (4.3±0.3 vol%, P<.05) and remained elevated
for 60 minutes after cocaine administration.
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Of note, the arterial
oxygen content increased significantly within the
first 2.5 minutes (+12±1%, P<.01) after cocaine
administration (Table 2
), peaking at 15 minutes
(+22±4%,
P<.01), and remained significantly elevated for 90 minutes.
The sustained increase in arterial oxygen content contributed
significantly to the increase in myocardial oxygen delivery, despite
the return of coronary blood flow to baseline within 10 minutes (Table
1). Thus, despite significant increases in coronary vascular
resistance, myocardial oxygen supply and demand were well matched for
all except the first 2.5 minutes after cocaine administration.
Table
3 illustrates the factors contributing to the
prominent increase in arterial oxygen content. There was an abrupt and
sustained increase in circulating hemoglobin concentrations that was
evident within the first 2.5 minutes (11.9±0.4 to 13.4±0.6 g/dL,
P<.01) after cocaine administration, peaked at 15 minutes
(14.4±0.6 g/dL, P<.01), and returned toward baseline
levels within 90 minutes. There were minor reductions in arterial
PO2 and arterial oxygen saturation at 30, 60,
and 90 minutes after cocaine administration but no change in arterial
pH. There was a similar sustained increase in coronary sinus hemoglobin
concentration. However, there was a transient decline in coronary sinus
PO2 and oxygen saturation within the first
2.5 minutes after cocaine administration that returned to baseline
values within 30 minutes. Thus, the mechanism of the significant
increase in arterial oxygen content after cocaine administration in
conscious dogs was a significant and sustained "blood doping"
effect.
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Effects of Altered Myocardial Oxygen Consumption on Coronary
Vasoconstrictor Effects of Cocaine
Table 4 reveals the
time course of the coronary
hemodynamic and myocardial metabolic responses with heart rate held
constant at 150 beats per minute to minimize the chronotropic effects
and thus limit the increases in myocardial oxygen consumption
associated with cocaine administration.
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Fig 1 compares
the effects of intravenous cocaine (1
mg/kg) on mean arterial pressure, coronary blood flow, and coronary
vascular resistance in the same 7 dogs studied in the intact state and
under conditions in which heart rate was held constant compared with 4
that received control saline infusions. Although the mean arterial
pressure responses were comparable, the coronary blood flow response
was consistently and significantly less (P<.01) and the
coronary vasoconstrictor response was consistently and significantly
more (P<.01) under circumstances in which heart rate was
held constant compared with the intact state. These differences
occurred despite comparable peak increases in plasma cocaine
concentration (intact, 614±111 ng/mL; heart rate constant,
589±168
ng/mL; n=4) and plasma norepinephrine concentration (intact,
407±52
pg/mL; heart rate constant, 364±143 pg/mL; n=4), suggesting that
neither cocaine pharmacokinetics nor norepinephrine release was altered
by holding heart rate constant during drug administration. Control
saline infusion had no significant effect on these parameters. Fig
2 reveals the differences in the time course and the
extent of the response of myocardial oxygen consumption, oxygen
delivery, and extraction under the three experiment conditions. The
early myocardial oxygen consumption response was significantly less in
the absence of a chronotropic response to cocaine, particularly during
the first 20 minutes after cocaine administration. Similarly,
myocardial oxygen delivery was significantly less and required
consistently greater increases in the extraction of oxygen to meet
metabolic demands under conditions in which heart rate was held
constant. Control saline infusions had no effect on these parameters.
The limitation in myocardial oxygen delivery was not attributable to
differences in arterial oxygen content (Fig 3) or to
differences in the blood doping effects (Fig 4).
However, with heart rate held constant, both coronary sinus oxygen
content (Fig 3) and coronary sinus oxygen saturation (Fig
4) were
significantly reduced to a greater extent and for a longer period of
time than under circumstances in which heart rate was allowed to
increase. Thus, during the first 20 minutes after cocaine
administration, the greater coronary vasoconstrictor effects of cocaine
under circumstances in which heart rate was held constant were
attributable to reductions in myocardial oxygen demands. Furthermore,
the enhanced vasoconstrictor response was sufficient to limit the
coronary blood flow response and myocardial oxygen delivery, despite a
comparable blood doping effect, requiring enhanced oxygen
extraction.
To examine further the effects of altered myocardial oxygen
demands on
the coronary vasoconstrictor effects of cocaine, both the inotropic and
the chronotropic effects of cocaine were eliminated by holding heart
rate constant with atrial pacing in the presence and absence of
ß-adrenergic blockade with propranolol (2 mg/kg) in 6 separate dogs
that had been instrumented similarly. Table 5 reveals
the baseline and peak responses to cocaine in the presence and absence
of ß-adrenergic blockade with heart rate held constant. Fig
5 reveals that the mean arterial pressure response to
cocaine (1 mg/kg) was similar in the presence and absence of
ß-adrenergic blockade. However, the coronary blood flow response was
attenuated significantly (P<.01) in the presence of
ß-adrenergic blockade with heart rate held constant compared with
holding heart rate constant alone. Consequently, the coronary
vasoconstrictor response to cocaine (Fig 5) was enhanced
significantly
(P<.01) in the presence of ß-adrenergic blockade. Fig
6 reveals the myocardial metabolic response to cocaine
with heart rate held constant in the presence and absence of
ß-adrenergic blockade. Both the myocardial oxygen consumption
(P<.01) and oxygen delivery (P<.05) responses
to cocaine were attenuated significantly (P<.05) in the
presence of ß-adrenergic blockade, consistent with abolishing both
the chronotropic and the inotropic responses to cocaine. However,
despite the enhanced coronary vasoconstrictor response to cocaine in
the presence of ß-adrenergic blockade, increased oxygen extraction
was required for only the first 10 minutes after cocaine administration
in contrast to the sustained requirements for enhanced oxygen
extraction with heart rate held constant in the absence of
ß-adrenergic blockade. This was due to myocardial oxygen delivery
keeping pace with the reduced myocardial oxygen consumption
requirements in the presence of ß-adrenergic blockade. In turn, the
increase in myocardial oxygen delivery response was sustained in the
absence of an increase in coronary blood flow by the blood doping
effect (Table 5), which was unaffected by ß-adrenergic
blockade.
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Discussion |
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In the present study, we identified the time course and the extent to which the coronary vasoconstrictor response to cocaine in conscious dogs was influenced by alterations in myocardial oxygen consumption and the degree to which coronary vasoconstriction limited myocardial oxygen delivery. We documented for the first time that in the intact state, the coronary vasoconstrictor response to cocaine is insufficient to limit myocardial oxygen delivery, except for the first 2.5 minutes after drug administration, when increased oxygen extraction was required. When the myocardial oxygen consumption response was limited by holding heart rate constant in the presence and absence of ß-adrenergic blockade, the coronary vasoconstrictor response to the same dose of cocaine was enhanced significantly, requiring enhanced oxygen extraction for longer periods. Finally, we observed an important blood doping effect of cocaine that contributes significantly to myocardial oxygen delivery response despite limitations in coronary blood flow, which has previously been unrecognized as a feature of the cardiovascular actions of cocaine.
There are several important methodological features that account for the novel findings reported here. First, our experiments were carried out in conscious, chronically instrumented dogs in which the full effects of moderate doses of cocaine (1 mg/kg) on coronary hemodynamics and oxygen consumption were unadulterated. Prior studies in experimental canine models studied with the animals under anesthesia12 13 14 15 16 have observed conflicting effects on blood pressure, heart rate, and coronary blood flow, thereby masking the influence of myocardial oxygen demands on the coronary vasoconstrictor response. Second, prior studies1 2 3 4 5 have failed to calculate myocardial oxygen consumption but rather have extrapolated from changes in the heart rate–blood pressure product. Both Abel et al23 and Zimring et al24 measured myocardial oxygen consumption but found significant declines after cocaine administration in anesthetized dogs that were never observed in our conscious animals. Third, most prior studies have reported only peak hemodynamic and coronary vasoconstrictor responses, which fail to consider both the dynamic and the transient effects of acute cocaine administration. Thus, the experimental design using conscious, chronically instrumented dogs studied under conditions in which determinants of myocardial oxygen consumption were controlled coupled with multiple and simultaneous measurements of coronary hemodynamics and myocardial oxygen consumption allowed us to determine the role of metabolic vasodilatation in opposing the coronary vasoconstrictor response to cocaine.
It is important to note that prior studies have reported that cocaine
in comparable doses causes coronary vasoconstriction in both
humans1 2 3 4 5
and experimental
models.10 17 18 32
This consistent observation coupled with associated increases in both
heart rate and blood pressure has led to the prevailing notion that a
supply-and-demand imbalance underlies that predisposition to ischemic
insults that has been reported after cocaine use in
humans.1 6 7 8 9
However, our data demonstrated that in
animals in the intact state, myocardial oxygen delivery was
insufficient to meet myocardial oxygen consumption for only the first
2.5 to 5 minutes after cocaine administration, when a transient
increase in oxygen extraction was required. Thereafter, myocardial
oxygen delivery met myocardial oxygen consumption, including during the
period of peak coronary vasoconstriction in the intact state (Tables
1 and 2).
In contrast, when the metabolic alterations associated with cocaine administration were limited by holding heart rate constant, an earlier and more intense coronary vasoconstrictor response was observed that virtually eliminated the coronary blood flow increases and required sustained increases in myocardial oxygen extraction. These findings are consistent with cocaine-induced, adrenergically mediated coronary vasoconstriction predominating over vasodilatory influences associated with cocaine-induced increases in myocardial oxygen consumption under circumstances in which the metabolic vasodilatory effects were limited.25 26 27
Furthermore, although the enhanced coronary vasoconstrictor response to
cocaine observed in the presence of ß-adrenergic blockade has been
reported previously,2 our findings suggested that the
limited metabolic demands associated with cocaine administration in the
presence of ß-adrenergic blockade resulted in virtually unopposed
increases in coronary vascular resistance, as has been noted by
others.28 29 Of importance, altering myocardial
oxygen
consumption by eliminating the heart rate response to cocaine with
atrial pacing or the inotropic response with ß-adrenergic blockade
did not alter either the pharmacokinetics of acute cocaine
administration or the plasma catecholamine response, arguing that the
difference in the coronary vasoconstrictor effects was attributable to
the observed differences in myocardial oxygen consumption (Fig
7).
Perhaps of greatest interest was the novel observation that acute
cocaine administration caused a significant and sustained increase in
arterial oxygen content, the mechanism of which was a significant
increase in circulating hemoglobin concentration of >2 g/dL for as
long as 60 to 90 minutes after cocaine administration. This finding
contributed in a significant way to the observed coronary vascular
effects of cocaine by maintaining oxygen delivery when coronary blood
flow returned to baseline (Fig 8). Furthermore, this
blood doping effect of cocaine was dependent on its systemic
hemodynamic effects as it was abolished by pretreatment with combined
- and ß-blockade,17 combined ganglionic blockade, or
splenectomy (unpublished observation). The blood doping effect of
cocaine may provide a previously unrecognized physiological boost to
drug abusers that appears to outlast its transient
psychological30 31 32 or
hemodynamic17 18 20 33 34
effects. It is important to
recognize that these findings were observed in a canine model noted for
its prodigious splenic function and have not been investigated in
humans. However, there are several lines of evidence that support the
possibility that cocaine-induced blood doping may play a role in
humans. First, blood doping due to splenic contraction has been
reported during hypoxia in divers35 and during endurance
training in athletes.36 Second, we have observed
cocaine-induced blood doping in conscious, chronically instrumented
baboons, although of a lesser magnitude than reported here (unpublished
observations). Finally, the finding of significant blood doping in
response to cocaine in dogs and its role in the maintenance of oxygen
delivery are of considerable relevance, given that the canine model is
the most commonly used animal model in the study of the effects of
cocaine on the coronary circulation.
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In summary, our findings suggest that acute cocaine administration in moderate doses (1 mg/kg) did not limit myocardial oxygen delivery, despite marked coronary vasoconstriction. Rather, the effects of cocaine were best understood in terms of the competition between metabolically mediated increases in coronary blood flow and adrenergically mediated increases in coronary vascular resistance. Furthermore, although the effects on the coronary circulation were transient, there was a significant and sustained blood doping effect that played an important role in sustaining myocardial oxygen delivery in the absence of significant increases in coronary blood flow, thus providing an important compensatory reserve in the face of cocaine-induced coronary vasoconstriction. Whether these dynamics are altered with more long-term or sustained use remains the subject of further investigation.
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Acknowledgments |
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This work was supported in part by US Public Health Service grants DA-06036, HL-33107, HL-38070, and RR-00168. Dr Shannon was the recipient of a Clinician-Scientist Award from the American Heart Association. We thank Gail Smygelski for her expert assistance in the preparation of the manuscript.
Received August 29, 1994; revision received December 13, 1994; accepted December 18, 1994.
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