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1 Department of Internal Medicine I and 2 Experimental Cardiology, Thoraxcenter, Cardiovascular Research Institute COEUR, Erasmus University Rotterdam, 3015 GD Rotterdam, The Netherlands
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Experimental
findings suggest a pronounced concentration gradient of norepinephrine
(NE) between the intravascular and interstitial compartments of the
heart, compatible with an active neuronal reuptake (U1) and/or an
endothelial barrier. Using the microdialysis technique in eight
anesthetized pigs, we investigated this NE gradient, both under
baseline conditions and during increments in either systemic or
myocardial interstitial fluid (MIF) NE concentration. At steady state,
baseline MIF NE (0.9 ± 0.1 nmol/l) was higher than arterial NE (0.3 ± 0.1 nmol/l) but was not different from coronary venous NE (1.5 ± 0.3 nmol/l). Local U1 inhibition raised MIF NE concentration to
6.5 ± 0.9 nmol/l. During intravenous NE infusions (0.6 and 1.8 nmol · kg
1 · min1),
the fractional removal of NE by the myocardium was 79 ± 4% to 69 ± 3%, depending on the infusion rate. Despite this extensive removal, the quotient of changes in MIF and arterial concentration (
MIF/A ratio) for NE were only 0.10 ± 0.02 for the lower
infusion rate and 0.11 ± 0.01 for the higher infusion rate, whereas
U1 blockade caused the MIF/A ratio to rise to 0.21 ± 0.03 and
0.36 ± 0.05, respectively. From the differences in MIF/A
ratios with and without U1 inhibition, we calculated that 67 ± 5%
of MIF NE is removed by U1. Intracoronary infusion of tyramine (154 nmol · kg1 · min1)
caused a 15-fold increase in MIF NE concentration. This
pronounced increase was paralleled by a comparable increase of NE in
the coronary vein. We conclude that U1 and extraneuronal uptake, and not an endothelial barrier, are the principal mechanisms underlying the
concentration gradient of NE between the interstitial and intravascular
compartments in the porcine heart.
norepinephrine; spillover; pig; myocardial interstitium
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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SEVERAL EXPERIMENTAL FINDINGS suggest that in the heart a pronounced concentration gradient for norepinephrine (NE) exists between the interstitial and intravascular compartments. Silverberg et al. (31) showed that the coronary sinus NE concentration induced by an NE infusion that led to only a small increase in the heart rate was eight times higher than that induced by stellate ganglion stimulation that caused a similar increase in heart rate. From tracer dilution experiments Cousineau et al. (8) estimated a ratio of 15% between the interstitial and arterial compartments in canine hearts. More recently, Obst et al. (29), using ultrafiltration of interstitial fluid from isolated perfused rat hearts, found ratios of interstitial transudate to arterial concentrations of NE of 0.14 to 0.77, depending on the concentration of NE administered. These investigators interpreted these findings as suggesting that the neuronal uptake of NE is the most important determinant for maintaining a concentration gradient between the circulatory and interstitial compartments. Because of the dense sympathetic innervation, especially in the heart, neuronal reuptake (U1) of NE could be an important determinant for maintaining such a gradient (17, 19). However, other investigators have suggested that the concentration gradient is caused by a physical barrier of the blood vessel wall as well (7, 8, 25, 29, 30, 33).
A profound understanding of catecholamine kinetics is invaluable when interpreting catecholamine data and their representation of sympathetic activity. Using the isotope dilution method and arteriovenous sampling, Esler et al. (16) introduced regional spillover as a kinetic parameter that aims to reflect the rate of NE entering the circulation rather than true production. In a recent study, Kopin et al. (22) have modified this technique and introduced a new method to estimate neuronal release that is based on the measurements of the specific activities of radiolabeled NE and its extraneuronal metabolite, normetanephrine, in plasma. Neuronal release of NE into the interstitial space is estimated as the sum of the spillover of NE from the interstitium to the circulation and the uptake of released NE from the interstitium. Nonetheless, the interstitial compartment can only be monitored either by estimation through the application of mathematical kinetic modeling or with the use of in vitro or semi-in vivo preparations. The microdialysis technique, however, allows for the accurate estimation of the concentration of catecholamines in the myocardial interstitial fluid (MIF) in vivo (15, 18, 32, 37). The technique should allow for measurement of the hitherto unquantifiable amount of NE that is released but taken up before reaching the vascular compartment, thus filling the gaps in existing kinetic models.
In a series of experiments in which either the circulatory or the interstitial NE concentration was increased, we investigated how the concentration of NE in the MIF is related to its concentration in the arterial and coronary venous circulation. The importance of U1 and extraneuronal uptake to this relationship was explored by adding desipramine [desmethylimipramine (DMI)], a well-known U1 inhibitor, to the dialysate of one of the microdialysis probes and performing experiments with isoproterenol (Iso), a catecholamine that is not handled by U1. Furthermore, NE concentrations in MIF, arterial plasma, and the coronary effluent at baseline and during infusion of NE provided an estimate of spillover, uptake, and release of NE.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Animal care. All experiments were performed in accordance with both the "Guiding Principles for Research Involving Animals and Human Beings" as approved by the Council of the American Physiological Society and the regulations of the Animal Care Committee of the Erasmus University of Rotterdam (The Netherlands).
Surgical procedure. After an overnight fast, crossbred Landrace × Yorkshire pigs of either sex (30-35 kg, n = 8) were sedated with ketamine (Ketalin; 20-25 mg/kg im) and anesthetized with pentobarbital sodium (Narcovet; 20 mg/kg iv). The animals were intubated and connected to a respirator for intermittent positive-pressure ventilation with a mixture of oxygen and nitrogen. Respiratory rate and tidal volume were set to keep arterial blood gases within the normal ranges: pH between 7.35 and 7.45, PCO2 between 35 and 45 mmHg, and PO2 between 100 and 150 mmHg.
Catheters were positioned in the superior caval vein for continuous administration of pentobarbital sodium (10-15 mg · kg1 · h1)
and Haemaccel for replacement of blood withdrawn during sampling. In
the descending aorta, a fluid-filled catheter was placed for monitoring
of aortic blood pressure and for withdrawal of blood samples. Through
the left carotid artery a micromanometer-tipped catheter (B. Braun
Medical, Uden, The Netherlands) was inserted into the left ventricle
for measurement of left ventricular pressure and, by electrical
differentiation, the maximum of its first derivative (LV
dP/dtmax).
After pancuronium bromide (Pavulon; 4 mg) was administered, a
midsternal thoracotomy was performed, and the heart was suspended in a
pericardial cradle. An electromagnetic flow probe (Skalar, Delft, The
Netherlands) was then placed around the ascending aorta for measurement
of aortic blood flow (cardiac output). A proximal segment of the left
anterior descending coronary artery (LAD) was dissected free for
placement of a Doppler flow probe. Distal to this site, a small cannula
(1.3-mm outer diameter) was inserted into the LAD for the
administration of tyramine.
The microdialysis catheters were implanted in the tissue with the help
of a steel guiding needle and split plastic tubing. Three
microdialysis probes were inserted into the left ventricular myocardium: one in the region of the left circumflex coronary artery
(LCX) and two in the area perfused by the LAD. To achieve local U1
inhibition, one of the LAD probes was coperfused with DMI (100 µM)
(36). In addition, microdialysis probes were placed in the right
carotid artery and the anterior interventricular coronary vein that
drains the territory perfused by the LAD.
Dialysis methodology.
For microdialysis, CMA/20 probes (Carnegie Medicine, Stockholm, Sweden)
were used. The polycarbonate dialysis membrane of these probes has a
cutoff value of 20 kDa, a length of 10 mm, and a diameter of 0.5 mm.
The probes were perfused with an isotonic Ringer solution at a rate of
2 µl/min using a CMA/100 microinjection pump. Dialysate volumes of 20 µl (sampling time 10 min) were collected in microvials containing 20 µl of a solution of 2% (wt/vol) EDTA and 150 nM Epinine as internal
standard in 0.08 N acetic acid. Sampling was started
immediately after the catheters were inserted. The plasma samples were
drawn into chilled heparinized tubes containing 12 mg of glutathione,
and, like the microdialysis samples, stored at 
80°C and
analyzed within the next 5 days (5).
Determination of in vivo probe recovery.
Probe recovery is defined as the quotient of dialysate catecholamine
concentration and the actual catecholamine concentration in the medium
that is dialyzed. In vivo probe recovery was determined separately for
blood as well as myocardial intercellular fluid. Probe recovery for
blood was estimated by comparing catecholamine concentrations in plasma
with catecholamine concentrations in the corresponding dialysate of the
microdialysis probe in the carotid artery (Fig.
1).
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-methylnorepinephrine
(AMN) was chosen as the calibrator for probe recovery for NE. This AMN
isomer is considered to be a "false transmitter"; it is handled
like NE, although it does not share its pharmacodynamic effects.
Retrodialysis was performed in four animals for the length of the whole
experiment. The average percentage of loss of AMN, i.e., in vivo probe
recovery for NE in MIF, was based on the data derived from the LAD and LCX probes of all four animals. This method revealed a probe recovery of 52 ± 1% (2 probes in 4 animals). Comparison of the
concentration of NE in arterial plasma with the NE concentration in the
dialysate obtained from the probe positioned in the carotid artery
showed a similar value for probe recovery of NE (52 ± 4%, Fig. 1).
For Iso, using a similar approach, the in vivo probe recovery was 37 ± 3% (Fig. 1).
Protocol.
After 120-150 min, steady-state conditions were reached at
baseline. Thereafter, NE and Iso were intravenously infused
consecutively for 30 min for each dose, followed by a 30-min
intracoronary infusion of tyramine. After each infusion, a 30-min
stabilization period was introduced, allowing for a complete washout of
the infused substances and return to baseline conditions. The infusion
rates of Iso (0.16 and 0.48 nmol · kg1 · min1)
and tyramine (154 nmol · kg1 · min1)
were chosen to correspond with the hemodynamic response of the NE
infusions (0.6 and 1.8 nmol · kg1 · min1)
(21). At the end of the experiments, the pigs were killed with an
overdose of pentobarbital.
Analytic procedure. Plasma catecholamines were determined by HPLC with fluorimetric detection after liquid-liquid extraction and derivatization with the fluorogenic agent N,N'-diphenylethylenediamine (DPE) (34). For microdialysis samples, the catecholamines were not extracted before fluorimetric detection with HPLC but were directly derivatized according to the procedure described by Alberts et al. (3). This method suppresses the interference of in vivo factors on derivatization, thereby improving sensitivity.
Reagents and pharmaceuticals. Ketalin and Narcovet were obtained from Apharmo (Arnhem, The Netherlands), Pavulon from Organon Teknica (Boxtel, The Netherlands), Ringer solution from Baxter (Uden, The Netherlands), Haemaccel from Behringwerke (Marburg, Germany), and Epinine from Zambon (Milan, Italy). Tyramine, NE, and Iso for infusions were obtained from the Department of Pharmacy (University Hospital, Rotterdam, The Netherlands). DMI, bicine, NE, and AMN were purchased from Sigma (St. Louis, MO); EDTA, N-ethylmaleimide (NEM), and hydrochloric acid were from Merck (Darmstadt, Germany); potassium ferricyanide was from Aldrich (Bornem, Belgium); L-glutathione was from Fluka (Buchs, Switzerland); and acetic acid and acetonitrile were from Baker (Deventer, The Netherlands). DPE was prepared as reported previously (34).
Statistics and calculations. Results are expressed as means ± SE. NE and Iso concentrations obtained with microdialysis were corrected for probe recovery. Baseline values were determined by averaging the data from the steady state before the infusions. During the infusions of NE and Iso, the cardiac extraction (E) was calculated as
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(1) |
A and V are the changes from baseline of arterial and coronary
venous concentrations, respectively. The ratio of interstitial NE to
arterial plasma NE is presented as
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(2) |
MIF is the change from baseline of the myocardial interstitial fluid concentration.
The percentage of NE that can be recovered from the MIF and taken up by
U1 (Fx U1) can be calculated from the difference between the
MIF/A ratio with and without U1 inhibition as
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(3) |
MIF/ADMI is the MIF/A
ratio with U1 inhibition. The percentage of MIF NE that is originating
from the circulation (MIF NEA)
at baseline can be estimated as follows
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(4) |
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(5) |
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(6) |
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(7) |
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(8) |
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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NE infusions.
Steady-state concentrations of MIF NE were observed 120-150 min
after the probes were placed and microdialysis was started. The
baseline arterial plasma NE concentration was about three times lower
than the MIF NE concentration (P < 0.001, Fig. 3). MIF NE concentrations in
the LAD and LCX regions were similar, and values did not differ from
those in the coronary vein. During U1 blockade, MIF NE concentration
increased more than sixfold (P < 0.01, Fig. 3).
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MIF/A ratio
(Eq. 2) was 0.10 ± 0.01 for the
lower infusion rate and 0.11 ± 0.01 for the higher NE infusion
rate, whereas DMI caused the MIF/A ratio to rise to 0.21 ± 0.02 and 0.36 ± 0.05, respectively (P < 0.05).
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NE values to baseline between the lower
and higher NE doses, the kinetic parameters for NE remained unchanged
(Table 2).
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Isoproterenol infusions.
Systemic Iso infusions caused dose-dependent increments in arterial and
venous Iso concentrations (Fig. 3 and Table 1). Circulatory and MIF Iso
concentrations at 20 and 30 min after the start of both systemic Iso
infusions did not differ significantly, suggesting that a steady state
was reached within 20 min (Fig. 3). The extraction of arterially
delivered Iso in the coronary circulation was 24 ± 5% with both
the low and the high infusion rates. MIF Iso concentrations were lower
than arterial and coronary venous concentrations, and values did not
alter in the presence of U1 blockade. The MIF/A ratio for Iso was
0.37 ± 0.02 with the low infusion rate and 0.34 ± 0.02 with the
high infusion rate.
Tyramine infusion.
Tyramine, like NE, is taken up by neurons through U1, and it
subsequently displaces NE from the nerve terminals because of its
higher affinity for the neuronal storage proteins (37). Consequently,
the degree of attenuation of tyramine-induced NE release is a measure
of the degree of U1 blockade. Without U1 blockade, infusion of tyramine
in the LAD caused a 15-fold rise in the MIF NE concentration in the LAD
region, accompanied by a similar increase of the NE concentration in
the coronary vein (Fig. 5). Under U1 blockade, this
response was almost completely abolished, indicating that the blockade
of U1 was virtually complete with the dose of DMI used. Tyramine
infusion in the LAD was also associated with a fivefold increase in the
MIF NE concentration in the LCX region. Because the systemic arterial
NE concentration also slightly increased during intracoronary tyramine
infusion, this increase was most likely caused by overflow of tyramine
from the coronary into the systemic circulation. The hemodynamic
response to tyramine was mainly confined to the heart; LV
dP/dtmax
increased almost threefold to 3,933 ± 465 mmHg/s, comparable to the
increase seen during the infusions of NE and Iso.
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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We investigated to what extent the concentration of NE in the myocardial intercellular space was related to its concentration in the arterial and coronary venous circulation at baseline and after increments in plasma or interstitial NE concentration induced by either systemic infusions of NE or an intracoronary infusion of tyramine. In addition, the importance of the U1 mechanism for the MIF NE concentration was assessed by perfusing one of the probes with the U1 inhibitor DMI and performing studies with Iso, a catecholamine that is not handled by U1. Finally, adaptation of the method introduced by Kopin et al. (22) provided an estimate of spillover, uptake, and, consequently, release of NE.
In agreement with the results of other studies using the microdialysis technique, steady-state MIF NE concentrations were observed 120-150 min after the probes were inserted and microdialysis was started. Basal MIF NE concentrations measured in this study were similar to those reported by Akiyama et al. (1, 2), who performed microdialysis in feline hearts. At baseline, MIF NE concentrations in the LCX and LAD regions were similar, suggesting no important regional differences in myocardial sympathetic activity. In contrast to various other microdialysis studies that reported arterial plasma levels at baseline to be similar to or even higher than interstitial NE levels (1, 27, 28), MIF NE concentrations in the present study were three times higher than arterial plasma concentrations. These results are in keeping with estimates made in other studies reporting that the concentration of NE at sites of release is about three- to fivefold higher than in plasma (10, 23, 26). This concentration gradient is the driving force behind the exchange of NE from the interstitial compartment to the circulation. Accordingly, one would expect this gradient to be reflected in somewhat higher NE concentrations in MIF than in the coronary vein. In contrast, NE concentrations in the coronary vein were similar to those in MIF, both under baseline conditions and during intracoronary infusion of tyramine, which induced a 15-fold increase in the MIF NE concentration. A possible explanation for this unexpected finding is that the NE concentration measured around the membrane of the microdialysis probe underestimated to some extent the concentration of NE at sites of release.
The observed absence of an NE gradient between the MIF and coronary vein does not support previous suggestions of the existence of an endothelial barrier for the diffusion of NE from the interstitial to the intravascular compartment (7, 25, 29, 30, 33). The presence of such an endothelial barrier could provide an explanation for the well-known difference in the relation of blood pressure response and plasma NE concentration observed for exogenously administered NE or for tyramine-induced endogenously released NE (4, 6). If an endothelial barrier for the diffusion of NE is present, MIF NE concentration and the NE concentration in the coronary vein, as a reflection of the NE concentration in the myocardial capillaries, should be different. However, both at baseline and during infusion of tyramine through the LAD, MIF NE concentrations in the LAD region and coronary vein were similar, indicating an unhindered exchange of endogenous NE from the interstitial to the vascular compartments. The considerable gradient between NE concentrations in the coronary vein and MIF that was seen during systemic infusion of NE was absent under U1 blockade and therefore is attributable to U1. Thus no endothelial barrier to the diffusion of NE appears to be present in the porcine heart.
Experimental studies and studies in humans with the use of labeled
infusions of NE have shown that 60-80% of arterially delivered NE
is removed by the myocardium (11, 13, 19). With the use of unlabeled NE
in the present study, the extraction of NE ranged from 79 to 69%,
depending on the infused dose (Table 1). Notwithstanding this high
fractional removal, the MIF NE concentration remained extremely low as
reflected by a MIF/A ratio of ~0.10. This value is close to the
MIF/A ratio of 0.15 reported for the canine myocardium by Cousineau et
al. (8) using the capillary-interstitium concentration model developed
by Ziegler and Goresky (38). The important role of U1 in
the removal of NE from the MIF was confirmed by comparing the MIF NE
concentrations in the microdialysis probes in the LAD region with and
without the U1 inhibitor DMI. Although the two probes were placed no
more than 1 cm apart, no interprobe interference was observed. Basal
MIF NE concentrations increased more than sixfold during U1 inhibition,
whereas the increases in MIF NE concentration due to infusion of NE
were also markedly augmented. Local U1 inhibition in the LAD probe with
DMI increased the MIF/A ratio to 0.21-0.36. Especially under
U1 blockade, the MIF/A ratio for unlabeled NE is likely to be
affected by NE that is released by or has leaked from the
neurons. Considering this artifact, our results with DMI
are quite comparable to the MIF/A ratio under U1 blockade as estimated
by Cousineau et al. (8). From the differences in the MIF/A ratios
measured in the probes with and without U1 inhibition, we calculated
that 67 ± 5% of MIF NE is removed by U1 (Eq. 3). This value is in close agreement with values
reported for the rabbit (10) but is lower than those observed in the
human myocardium (12, 19).
As expected, because Iso is not taken up by U1, similar MIF Iso
concentrations were measured in the probes with and without the U1
inhibitor DMI. The MIF/A ratios for Iso were very similar to the
MIF/A ratios for NE during the high infusion rate of NE and local
inhibition of U1 by DMI.
Because Iso is not taken up by U1, the difference in removal of NE and
Iso over a certain vascular bed has been proposed to be a useful
measurement of U1 activity (19, 20). Although there is some debate
about the validity of the comparison of the pharmacokinetics of Iso and
NE during U1 blockade (8, 9), the present findings suggest that such an
approach will indeed provide a reliable estimation of U1 activity.
Despite similar extractions of NE, the extraction of Iso in the porcine
heart (24%) was considerably higher than that reported for the human heart (14%). This difference in extraction suggests that the cardiac extraneuronal uptake of NE is more important in the porcine than in the
human heart. As proposed by Goldstein et al. (19), the proportionate
fractional tissue removal of NE by U1 can be calculated by subtracting
the percent removal of Iso from the percent removal of NE and dividing
this difference by the percent removal of NE. With the application of
this equation in the present study, it appears that ~66% of NE in
the porcine myocardium is removed by U1. Although considerably lower
than the value reported for the human heart (82%), this value agrees
well with the proportionate fractional tissue removal of NE by U1
derived from the differences in the MIF/A ratios with and without
local U1 inhibition.
Because of the active U1 of NE in the myocardium, the MIF concentration of NE during systemic NE infusions remained relatively low compared with the arterial NE concentration. This explains why the relationship between LV dP/dtmax and changes in MIF NE concentration was much steeper than the relationship between LV dP/dtmax and changes in arterial NE concentration. Accordingly, because Iso is not taken up by U1, the difference in relationships between LV dP/dtmax and interstitial or arterial Iso concentrations during Iso infusions was less distinct.
Studies performed in humans and dogs have shown that <5% of the NE that is released into the myocardial interstitium spills over into the circulation (22). In the present study, the calculated proportional spillover (~15%) was considerably higher. Because cardiac spillover in our experiments is similar to the value measured in dogs (14), it seems likely that proportional spillover was relatively high because the calculated uptake of NE was relatively low. As shown in Eq. 6, the calculated uptake of NE strongly depends on the ratio of RA to RMIF. Although microdialysis is a more direct technique for measuring interstitial NE concentrations than the estimates based on the isotope dilution technique, it will only provide information about the mean interstitial NE concentration and not about the concentration at sites of release. Because of the downward concentration gradient of NE from the site of entry in the interstitial fluid to the sites of uptake, RMIF based on the mean interstitial NE concentration during systemic infusion of NE will be higher than RMIF at the sites where uptake of NE takes place. On the basis of Eq. 6, overestimation of RMIF will lead to the underestimation of the calculated uptake of NE.
In conclusion, microdialysis is a valuable tool for measuring as well as modifying local sympathetic activity. The present in vivo experiments largely confirm the information about NE kinetics obtained by more indirect methods. We conclude that U1 as well as extraneuronal uptake, and not an endothelial barrier, are the principal mechanisms underlying the concentration gradient of NE between the interstitial and intravascular compartments in the porcine heart.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: T. W. Lameris, Dept. of Internal Medicine I, Rm. L 257, Univ. Hospital Dijkzigt, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands (E-mail: twl{at}mediaport.org).
Received 9 December 1998; accepted in final form 25 May 1999.
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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, Carotid artery; 
, coronary
vein; 
, myocardial interstitial fluid (MIF) left anterior descending
coronary artery (LAD) region; 
, MIF LAD region under neuronal uptake
(U1) blockade; ×, MIF left circumflex coronary artery (LCX)
region. Data are presented as means ± SE for 8 animals.
