(Circulation. 1995;91:1205-1212.)
© 1995 American Heart Association, Inc.
Articles |
Splanchnic Venous Pressure–Volume Relation During Experimental Acute Ischemic Heart Failure
Differential Effects of Hydralazine, Enalaprilat, and Nitroglycerin
From the Division of Cardiology, Departments of Medicine and Medical Physiology, The University of Calgary, Alberta, Canada.
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Abstract |
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Background Vasodilator drugs have variable effects on veins and arteries. However, direct measurements of their effects on the splanchnic veins, perhaps the most important volume reservoir, have not been reported. We assessed the effect of acute heart failure and the subsequent administration of hydralazine, enalaprilat, and nitroglycerin on the splanchnic venous pressure–volume relation in intact dogs.
Methods and Results Experimental acute ischemic heart failure was induced in 19 splenectomized dogs by microsphere embolization of the left main coronary artery. Embolization was repeated until left ventricular end-diastolic pressure (LVEDP) reached 20 mm Hg and cardiac output decreased by 50%. The splanchnic vascular pressure–volume relation was determined by radionuclide plethysmography during the control stage, after acute heart failure had been established, and after administration of a vasodilator (hydralazine, enalaprilat, or nitroglycerin) at a dose sufficient to reduce mean aortic pressure by approximately 20%. Induction of acute heart failure was associated with a decrease in the splanchnic vascular volume from 100% to 86±2% and an increase in LVEDP from 6±1 to 21±1 mm Hg (P<.001). There was a parallel leftward shift of the splanchnic vascular pressure–volume curve. After the administration of hydralazine, enalaprilat, and nitroglycerin, the splanchnic vascular volumes increased from 86% to 88±3%, 96±3%, and 113±3%, respectively (P=NS, P<.01, and P<.001, respectively, versus heart failure). After drug administration, the LVEDPs were 18±2, 16±1, and 13±1 mm Hg (P=NS, P<.05, and P<.001, respectively, versus heart failure).
Conclusions Acute heart failure was associated with a parallel leftward shift of the splanchnic venous pressure–volume relation (venoconstriction). Splanchnic (systemic) venoconstriction may in part explain the increased LVEDP during acute heart failure by displacement of blood to the central compartment. Subsequently administered enalaprilat and, to a greater degree, nitroglycerin produced splanchnic venodilation, thereby lowering LVEDP. Hydralazine had no significant effect on the splanchnic veins and only a modest effect on LVEDP. In this model, splanchnic capacitance changes appear to modulate change in left ventricular preload.
Key Words: heart failure • imaging • vasodilation • veins • scintigraphy
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Introduction |
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It is now clear that profound peripheral vascular abnormalities are an integral part of the syndrome of congestive heart failure (CHF).1 2 Generalized vasoconstriction is present partly because of activation of the sympathetic nervous system and the renin-angiotensin system.3 Vasoconstriction has been demonstrated in both arteries and veins, although major emphasis has been placed on the study of the arterial system over the past two decades, primarily since it was recognized that cardiac performance is enhanced by afterload reduction.4 The veins are probably the region of the cardiovascular system that has been studied the least in heart failure. One of the objectives of this investigation, therefore, was to assess the changes of the splanchnic venous pressure–volume relation during acute heart failure in an intact canine model of acute ischemic left ventricular (LV) dysfunction5 by radionuclide plethysmography, a newly described technique that uses minimal surgical intervention.6
Vasodilator drugs have become the most important pharmacological agents in the treatment of patients with CHF.7 8 9 Although the hemodynamic effects of vasodilators commonly used in the treatment of CHF have been studied extensively, studies of their effects on the venous system have been limited, confined to the peripheral (limb) veins, and often have used indirect observations (changes in central venous pressure). Direct assessment of the effects of vasodilator drugs on the splanchnic vessels, perhaps the most important venous region in terms of capacitance,10 11 12 13 14 has not been performed. The second objective of this investigation, therefore, was to assess the comparative effects of hydralazine, enalaprilat, and nitroglycerin on the splanchnic venous pressure–volume relation in a canine model of acute ischemic LV dysfunction.
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Methods |
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Animal Preparation
Experiments were carried out in 19 mongrel dogs (weight, 13 to 22 kg). Four dogs were splenectomized 4 to 6 days before and 15 dogs were splenectomized on the day of the experiment. Splenectomy was done to avoid rapid changes of the hematocrit, which could compromise the measurements of splanchnic vascular volume (SVV) changes by blood pool scintigraphy. A pneumatic cuff was placed around the portal vein, and a small catheter was introduced into the portal vein through a small arcade vein and advanced until the tip lay upstream from the pneumatic cuff. By this means, we were able to measure portal venous pressure on the intestinal side of the cuff. In addition, a 4x4-cm sheet of lead (radiographic apron material) was sutured under the right side of the ventral abdominal wall so that the radioactivity from the ventral wall could be determined as described previously.6
On the day
of the experiment, anesthesia was induced in all dogs with
sodium pentothal (25 mg/kg IV). In 13 dogs, anesthesia was maintained
by ventilation with a mixture of oxygen and nitrous oxide (30:70) and
isoflurane (1.5%) with a constant-volume respirator (model 607,
Harvard Apparatus) and a closed breathing system. In 6 dogs that
subsequently received nitroglycerin (see below), anesthesia was
maintained by administration of 60 mg/kg IV of warm 
-chloralose,
repeated at 1-hour intervals as required. Dogs were placed in the
supine position. Body temperature was maintained by a warming blanket
and lamp. To ensure a reproducible state of hydration, dogs were given
an infusion of 3.3% dextran (15 mL/kg IV) in 0.3% NaCl at least 2
hours before the first set of data was recorded. LV pressure was
measured with an 8F micromanometer-tipped catheter with a reference
lumen (model PC-480, Millar Instruments) placed via a carotid artery.
Aortic pressure was recorded by use of a fluid-filled catheter
introduced via a femoral artery. Cardiac output was measured by
thermodilution using a triple-lumen balloon catheter placed in the
pulmonary artery via a femoral vein. Catheters for drug infusion and
blood sampling were placed into the femoral and jugular veins,
respectively. Pressures and ECGs were recorded on a multichannel
recorder (model VR-16, Electronics for Medicine–Honeywell) and a
PDP-11/23 MINC computer. Hemodynamic data were later analyzed on a VAX
11/750 computer (Digital Equipment Corp) with a custom-designed
software package (CVSOFT, Odessa Computer Systems
Ltd).
Induction of Acute Heart Failure
The model used to produce
ischemic LV dysfunction and acute
heart failure was that described by Smiseth and Mjos.5 In
brief, a 5F left coronary artery catheter was introduced via a femoral
artery and advanced into the left main coronary artery under
fluoroscopy. Polystyrene microspheres (3M Co) 50 µm in diameter were
dispersed in dextran to a concentration of 4 mg/mL. Acute heart failure
was produced by repeated bolus injections of 2.5 mL of the microsphere
suspension into the left coronary artery every 5 minutes. When LV
end-diastolic pressure (LVEDP) reached 15 mm Hg, the bolus
volume was reduced to 1 mL each. Microsphere injections were terminated
when LVEDP reached 20 mm Hg and cardiac output was lowered by
approximately 50%. Induction of acute heart failure took approximately
1 hour; during this time, 
4 to 6 mg of microspheres per kilogram
body weight was injected. To avoid their effects on vascular smooth
muscle, no antiarrhythmic drugs were used, although nonsustained
ventricular arrhythmias were observed in some animals. This model of
acute ischemic LV dysfunction has been shown to produce features
similar to those seen in patients with chronic CHF, such as significant
augmentation in LVEDP, reduction in cardiac output, and increases in
the plasma levels of catecholamines, renin, and angiotensin
II.5 15 16
Radionuclide Splanchnic Venous Volume
SVV (mesenteric and
intestinal) changes were measured by
equilibrium blood pool scintigraphy.4 6 After in vivo
labeling of the red blood cells with 99mTc, 60-second
scintigrams of the abdomen were recorded with a gamma camera (model
DYNA-MO 4, Picker) equipped with a parallel-hole, high-sensitivity
collimator and interfaced to a nuclear medicine computer system (model
DPS-3300, ADAC Laboratories). To minimize the amount of circulating
free 99mTc, scintigrams were not recorded until at least 30
minutes after red blood cell labeling.17 Once the gamma
camera was positioned over the abdomen, care was taken to maintain the
same position of the dog and the camera throughout the experiment.
Splanchnic regions of interest were defined manually on the first
abdominal scintigram, excluding the liver, kidneys, bladder, and large
blood vessels. Because the dog-camera position remained unchanged, the
same splanchnic region of interest was computer-duplicated in
subsequent scintigrams.
Relative changes in regional splanchnic venous
volumes were determined
using the changes in count rate (ie, number of counts per pixel),
corrected for physical and biological decay, in the splanchnic region
of interest in successive scintigrams. These corrections were made as
described previously,6 using the count rates of 100 µL
reference blood samples taken throughout the experiment. Additional
corrections for the contribution of the ventral abdominal wall to total
count rate were also made by subtracting the count rate in a region of
interest drawn over the lead sheet placed under the anterior abdominal
wall, as previously outlined.6 Changes of count rate, so
corrected, in the splanchnic region of interest reflect changes of the
SVV. Because 70% of the total blood volume is contained in the
veins and venules, changes in regional intravascular volume reflect
primarily changes in regional venous
volume.10 11 12 13 14 16 18 19 20
This method has been used extensively to assess regional venous volume
changes,6 14 17 21 22 23 24 25
and the results, when used in the
limbs, have correlated closely with those obtained by standard
mercury-in-rubber venous plethysmography.26 27
Furthermore, the radionuclide method has been shown to correlate well
with absolute measurements of splanchnic14 and
pulmonary28 venous capacitance. Thus, changes in
splanchnic venous volumes were assessed by measuring changes in
SVV.
Radionuclide Plethysmography
To define the splanchnic venous
pressure–volume relation,
abdominal scintigrams (to determine regional SVV changes) were recorded
at each of four portal venous pressures: baseline and 10±1,
15±1, and
20±1 mm Hg. The baseline pressure was that present in the portal
vein while the pneumatic cuff was deflated. Portal vein
"occluding" pressures were set by stepwise inflation of the
pneumatic cuff around the portal vein. The cuff was deflated for about
30 seconds between each recording. These four sets of recordings
thereby allowed us to obtain four pairs of pressure and SVV data, which
were then plotted to obtain the splanchnic vascular pressure–volume
relation. Data were fitted by linear regression as previously
reported.25 29
Study Design
Hemodynamic data included LV, aortic, right
atrial, and
portal vein pressures; heart rate; and cardiac output. Systemic
vascular resistance was calculated as mean aortic minus right atrial
pressure divided by the cardiac output. Recordings (hemodynamic and
radionuclide data) were made at three stages: (1) the control state, at
least 30 minutes after completion of instrumentation; (2) after the
induction of acute heart failure, at least 15 minutes after hemodynamic
stabilization; and (3) after administration of hydralazine,
enalaprilat, or nitroglycerin. Hydralazine and enalaprilat were
administered as an initial IV bolus injection of 1 or 0.15 mg/kg,
respectively, repeated if necessary 10 minutes later to decrease mean
aortic pressure by 20%. Nitroglycerin was administered as a
continuous IV infusion at increasing doses starting at 5
µg · kg-1 · min-1 until
mean aortic
pressure declined by 20% from the heart failure values (usual doses
between 30 and 50
µg · kg-1 · min-1). After
drug
infusion, recordings were made 10 minutes after stabilization of
hemodynamic variables.
Statistical Analysis
Hemodynamics and relative SVVs were
compared in the three stages
by ANOVA followed by the Tukey procedure when appropriate. Comparison
of data between two stages (defined a priori) were made with paired
t tests. ANOVA, with an orthogonal polynomial
decomposition,30 was used to assess the changes of SVV
produced by portal vein constriction, acute heart failure, and drug
administration. Orthogonal contrasts were used for curve fitting of the
splanchnic vascular pressure-volume relations and to examine for lack
of parallelism between the curves at control, during heart failure, and
after administration of vasodilator drugs.25 30 To
quantify the shifts of the splanchnic vascular pressure–volume
relations, we arbitrarily used the value of SVV at a portal vein
pressure of 7 mm Hg (SVV7) as a measure of vascular
capacity. In addition, we also analyzed the values of SVV at a portal
vein pressure of zero (SVV0), extrapolated from the
pressure–volume curves. Statistical significance was accepted at the
95% confidence level (P<.05). Unless otherwise noted,
group data are presented as mean±SD.
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Results |
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Twenty-two dogs were studied, but complete data were recorded in only 19 animals. The experiment was not completed in 1 animal because of failure of the pneumatic cuff around the portal vein, and 2 dogs died because of ventricular fibrillation during induction of heart failure. Acute heart failure was induced successfully in the remaining 19 dogs. After the induction of heart failure, 6 dogs received hydralazine, 7 received enalaprilat, and 6 received nitroglycerin. No fatalities occurred during drug administration.
Effects of Acute Heart Failure
The effects of acute heart
failure on hemodynamic measures and SVV
changes in all 19 dogs are noted in Table 1
, and the
effect of heart failure on the splanchnic vascular pressure–volume
relation is depicted in Fig 1. As per study design,
acute heart failure was associated with a 51% reduction of the mean
cardiac output, from 3.83±0.9 to 1.87±0.6 L/min
(P<.001),
and an increase of the mean LVEDP to 21.4±1.3 mm Hg
(P<.001). In addition, there was a significant increase of
the mean systemic vascular resistance and the average heart rate, while
the mean blood pressure decreased significantly. Portal venous pressure
increased minimally but significantly. The SVV measured without
inflation of the pneumatic cuff around the portal vein decreased by an
average of 14% (P<.001), SVV7 decreased by a
mean of 15% (P<.001), and the unstressed SVV
(SVV0) decreased by 14% (P<.001). These
changes reflected a parallel shift of the splanchnic vascular
pressure–volume relation toward the pressure axis (Fig
1); ie,
induction of heart failure produced splanchnic venoconstriction.
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The
effects of heart failure in each subgroup of dogs were similar to
those observed in the entire group (Tables 2 through
4). In dogs that received
nitroglycerin, portal vein pressure increased after induction of acute
heart failure, as in the other groups, but this did not achieve
statistical significance (Table 4). Mean arterial
pressure decreased by 30 mm Hg in animals receiving hydralazine and by
15 mm Hg in the groups that received enalaprilat and nitroglycerin;
cardiac output decreased by 59%, 44%, and 51%, respectively; and
systemic vascular resistance increased by 77%, 62%, and 77%,
respectively. Despite these differences, induction of heart failure in
the three groups of dogs was associated with almost identical levels of
elevated LVEDP, decreased SVV, and leftward shifts of the splanchnic
vascular pressure–volume relation. Tests for nonparallelism showed
that the slopes of the pressure–volume relations during heart failure
were not significantly different from the slopes of the control curves;
ie, they were parallel shifts.
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Effects of Hydralazine, Enalaprilat, and Nitroglycerin
Hemodynamic and SVV changes at the three stages (control, during
heart failure, and after drug administration) are shown in Tables 2 through
4
, and the changes of the
splanchnic vascular pressure–volume
relation are shown in Figs 2 through
4. After administration of
each vasodilator, the aortic pressure and the systemic vascular
resistance fell, albeit to different degrees, with hydralazine
having the greatest effect, followed by enalaprilat, and nitroglycerin
having the least effect. Group LVEDP also decreased after
administration of each drug, but in contrast to the effects on blood
pressure and systemic vascular resistance, nitroglycerin had the
greatest effect and hydralazine the least. Modest but significant
decreases of portal vein pressures were noted after drug
administration. Although cardiac output increased after administration
of each vasodilator, the change was significant only after
administration of hydralazine (Tables 2 through
5).
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P<.001 vs CHF.
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The
effects of each drug on the splanchnic vascular capacitance were
measured by changes in the regional SVV, SVV0,
SVV7 (Tables 2 through
5), and shifts of
the splanchnic
vascular pressure–volume relations (Figs 2 through
4). Nitroglycerin
had the greatest influence on the splanchnic capacitance vessels, as
reflected by a 31% increase in SVV, a 32% increase in
SVV0, and a significant rightward shift of the
pressure–volume relation, which actually went beyond the control
(pre–heart failure) curve, as quantified by a 32% increase in mean
SVV7 (Tables 4 and 5 and Fig
4). Enalaprilat also increased
SVV and SVV0 significantly (Tables 3 and
5), but to a
lesser degree, and it produced a significant rightward shift of the
splanchnic vascular pressure-volume relation noted by a 14% increase
in SVV7 (Fig 3). Finally, hydralazine had no
significant
effects on SVV or SVV0 (Tables 2 and
5) or on the
splanchnic vascular pressure–volume relation, with only a 3% increase
(P=NS) in the average SVV7 (Fig 2).
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Discussion |
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The results of this investigation showed, first, that experimental acute heart failure produced a reduction of splanchnic venous volume by displacing the splanchnic venous pressure–volume relation toward the pressure axis (venoconstriction) without significant change in the slope. Second, nitroglycerin and enalaprilat both increased splanchnic venous volume by displacing the splanchnic venous pressure–volume relation away from the pressure axis (venodilation), with nitroglycerin having a greater effect. Hydralazine, given at doses that had even larger effects on mean aortic pressure, cardiac output, and systemic vascular resistance, had no effect on the splanchnic venous volume or the splanchnic venous pressure–volume relation. Third, our results also showed that during acute heart failure, the reduction of SVV was associated with an increase in LVEDP, which in turn was reduced by administration of all three vasodilators. The drug with the greatest effect on SVV (nitroglycerin) also had the greatest effect on LVEDP, and the drug with the least effect on SVV (hydralazine) also had the least effect on LVEDP. These observations suggest that changes in LVEDP during acute heart failure and the subsequent administration of vasodilator agents are mediated, at least in part, by displacement of blood from the splanchnic veins to the central compartment and from the central compartment to the splanchnic veins, respectively.
The splanchnic venous bed is an important region in terms of
vascular capacitance in
animals12 13 14 31 and
probably in
humans.10 11 12 13 19 20 23 24 25
Studies of the splanchnic venous
bed, however, have been limited by the use of techniques that use
extensive preparatory surgery.14 31 32
This study was
carried out in anesthetized dogs with radionuclide plethysmography, a
newly described method that uses minimal surgery.6
Moreover, because regional venous volume changes may occur passively,
as a result of changes in venous distending pressure (stressed venous
volume), or actively, as a result of changes in venous smooth muscle
tone (unstressed venous volume), changes in venous capacitance are best
defined by changes in the regional venous pressure–volume
relations.* The use of radionuclide plethysmography
allowed us to study the splanchnic capacitance changes and to
distinguish the active and passive components of these changes. The
spleen was removed in all dogs before the experiment to facilitate
radionuclide recordings of the mesenteric and intestinal
regions.6 Although the spleen of the dog contributes only
4% to 7% of the total systemic vascular capacity, it contains 30%
to 35% of the total blood volume.38 The main limitation
of the radionuclide method used is that relative volumes are obtained
rather than volume in absolute units. Although attenuation correction
methods have been suggested14 28 to obtain absolute
volumes, we have not validated those techniques in our laboratory. We
have chosen, therefore, to present our findings as relative
volumes.
Effects of Acute Heart Failure
Acute heart failure was
associated with a significant reduction of
the SVV despite an increase, albeit small, of the distending portal
vein pressure. Thus, active splanchnic venoconstriction, reflected by a
14% leftward displacement of the splanchnic vascular pressure–volume
relation and SVV0, predominated over and was far
greater than the passive increase in volume due to the increase in
pressure. Because CHF induction was associated with an increase in
portal venous pressure, the potential passive changes of SVV would have
been in the opposite direction, ie, venodilation. We estimated this to
be <1%, which is in agreement with the findings of Rutlen et
al,39 who reported that there is no significant passive
effect of acute heart failure on mesenteric-intestinal intravascular
volume.
There have been no previous studies of splanchnic (intestinal and mesenteric) vascular capacitance changes during acute heart failure. Our results, however, are in agreement with the findings of Ogilvie et al,40 who also reported a reduction in unstressed (total) venous volume without change in compliance in dogs with pacing-induced chronic CHF. Gay et al41 and Raya et al42 reported a reduced total vascular capacitance in rats with CHF 3 weeks after acute myocardial infarction, although unstressed vascular volume was unchanged. The partial discrepancy with our results may be related to the different animal species, methods, and models of heart failure used. Thus, we have shown for the first time that acute heart failure in dogs produces vasoconstriction of the splanchnic capacitance vessels by an active parallel displacement of the pressure–volume relation to the left, quantified by a 14% reduction of the unstressed splanchnic vascular (venous) volume. Passive changes in splanchnic vascular (venous) volume in this setting appear to be negligible.
The mechanisms
causing the significant leftward displacement of
the splanchnic vascular pressure–volume relation cannot be determined
from our study. Active contraction of the canine splanchnic capacitance
vessels has been shown by -adrenergic stimulation,14
angiotensin,43 pressure changes at the level of the
carotid sinus and aortic arch
baroreceptors,36 44 45
administration of catecholamines,45 and indirect
sympathetic stimulation.46 Since CHF is usually associated
with an enhanced sympathetic tone, activation of the renin-angiotensin
system, elevated serum catecholamine levels,
etc,3 11 12 15 19
any of the above or most likely a
combination of them may play important roles in the mechanism of active
splanchnic venoconstriction in CHF.
Other hemodynamic changes produced by acute heart failure were the same as those reported previously5 15 and include characteristic abnormalities seen in this syndrome in dogs, other animals, and humans. We wish to point out, however, that the association between splanchnic venoconstriction and elevation of LVEDP is compatible with the hypothesis advanced by several investigators* that splanchnic capacitance volume changes modulate LV preload.
Effects of Hydralazine, Enalaprilat, and Nitroglycerin
Although the hemodynamic effects of hydralazine, enalapril, and
nitroglycerin have been studied extensively in both animal and human
experiments, to the best of our knowledge the effects of these drugs on
the splanchnic capacitance vessels in the setting of acute heart
failure have not been studied previously. Our results indicate that all
three vasodilator agents produced favorable hemodynamic changes.
However, there were important differences between drugs in terms of
their effects on the splanchnic capacitance vessels. Nitroglycerin had
the greatest effect, increasing SVV7 by 32%
(P<.0001), and hydralazine had the least effect, increasing
SVV7 by only 3% (P=NS). The effect of
enalaprilat was intermediate; it increased SVV7 by 14%
(P<.001). The second most important finding of our
investigations was the close relation between the degree of splanchnic
venodilation and the reduction in LVEDP. Nitroglycerin, which had the
greatest splanchnic venodilatory effect, also had the greatest effect
on LVEDP (-42%, P<.0001), whereas hydralazine, which had
the least dilatory effect on the splanchnic capacitance vessels, also
had the least effect in reducing LVEDP (-13%, P<.05). The
effect of enalaprilat, which was intermediate in dilating the
splanchnic veins, also was intermediate in reducing LVEDP (-25%,
P<.01). These results further support the concept that
splanchnic capacitance volume changes modulate LV
preload* by means of redistribution of blood between
the central and the peripheral compartments. It is possible, however,
that changes in the LVEDP could have been mediated through drug-induced
changes in LV compliance, but we are unaware of any information to
suggest that the vasodilators used in this investigation change LV
compliance acutely.
Although there are no previous studies on the effects of hydralazine, enalaprilat, or nitroglycerin on the splanchnic capacitance in the setting of acute heart failure, a number of studies with data supporting our findings have been published. Hydralazine has been shown to have no significant effect on the venous system or LVEDP in rats with42 or without48 acute heart failure in studies in which the venous system was assessed by measurements of mean circulatory pressure and total blood volume. Raya et al42 reported an increase in total capacitance volume and a significant reduction of LVEDP after captopril administration. Enalaprilat increased the unstressed hepatic vascular (capacitance) volume when administered to dogs with acute ischemic LV dysfunction.49 The data presented by Ogilvie from experiments in dogs without heart failure50 showed that hydralazine had no significant effect on total venous volume or central blood volume, whereas captopril increased total venous volume and decreased blood volume in the central compartment. Hydralazine, even at high concentrations, failed to reduce portal vein tone.51 Moreover, hydralazine was shown to have no effect on the veins of the human limbs.52 The results of our study further support the concept that hydralazine is an arterial vasodilator with no effect on the veins, even though hydralazine was given at doses that produced the greatest changes in aortic pressure and cardiac output.
Our results showed, for the first time, that enalaprilat significantly dilated the splanchnic capacitance vessels in an animal model of acute heart failure by a parallel rightward displacement of the splanchnic vascular pressure–volume relation. Using the same model, Hall and Karlberg15 observed an increase in the concentration of plasma angiotensin II, a response that was attenuated by administration of enalaprilat. Also, Smiseth et al43 showed that angiotensin II decreased splanchnic blood volume and increased LVEDP in dogs without heart failure. Although our investigation was not designed to assess the mechanism of the effect of enalaprilat on SVV, a reduction of the levels of angiotensin II was the most likely mechanism for the splanchnic venodilation noted after enalaprilat administration. Of course, other mechanisms may also be involved.53 In a dog model of acute heart failure similar to ours, Risoe et al49 showed that enalaprilat dilated the hepatic veins but not the splenic veins. Our results are also in agreement with previous studies that showed that another converting enzyme inhibitor, captopril, had significant venodilator properties in normal dogs50 and in rats with myocardial infarction.42 Human studies of the venous response to converting enzyme inhibitors are sparse, conflicting, and limited to the limbs.54 55 56 57 Although much has been written on the lack of venodilating properties of converting enzyme inhibitors in humans,58 59 only one study actually documented this.55
Conversely, all previous human and animal studies that assessed preload have shown that converting enzyme inhibitors decrease LVEDP and/or LV end-diastolic volume. Our findings are in agreement with this observation; we, too, found that enalaprilat significantly decreased LVEDP in dogs with acute heart failure. Furthermore, our results suggest that splanchnic venodilation is, at least in part, involved in the mechanism to reduce the LV filling pressure by pooling blood in the capacitance vessels. Further studies to assess the effect of converting enzyme inhibitors on the human splanchnic veins are needed, since there is skepticism that converting enzyme inhibitors have any venodilator effect.58 59
To the best
of our knowledge, every study that assessed the effect of
nitroglycerin on the veins of any region, in animals and in humans,
with or without heart failure, showed that nitroglycerin is a potent
venodilator. In a recent publication, for instance, Morse and
Rutlen60 reported that nitroglycerin produced active
venodilation of the intestinal and mesenteric regions in dogs without
CHF. Interestingly, they quantified this venodilation at 12.9%,
similar to our results of 13% (Table 4) if we compare the SVV
after
nitroglycerin (113%) with the SVV at control, before CHF (100%).
Furthermore, ample documentation is also available showing that
nitroglycerin reduces LVEDP in the setting of CHF. Our results showed
for the first time that nitroglycerin increased splanchnic vascular
capacitance by an active parallel displacement of the splanchnic
vascular pressure–volume relation in dogs with acute heart failure and
that this effect was associated with a simultaneous reduction of LV
filling pressure. Only one previous study has assessed the effects of
nitroglycerin on the splanchnic veins in terms of pressure–volume
relation.25 In that study, nitroglycerin produced a 9.4%
rightward shift of the pressure–volume relation in humans without CHF.
Despite effects on the arterial blood pressure and systemic vascular
resistance that were modest relative to the changes produced by
hydralazine and enalaprilat, nitroglycerin produced the greatest
splanchnic venodilation and the greatest reduction of LVEDP. The
results of our study thus further support the concept that
nitroglycerin is a potent venous vasodilator with relatively little
effect on the arteries.
We did not detect significant changes, compared with control values, in the slopes of the splanchnic vascular pressure–volume relations after the induction of acute heart failure or after administration of vasodilator agents in either individual or group results. These results support the concept that venoconstriction and venodilation occur mainly by changes in unstressed volume.12 25 31 33 34 Moreover, individual slopes of the pressure–volume relation often differed from one dog to the next, but the individual curves remained parallel after each intervention, which supports the view that changes in venous compliance may be relatively unimportant during acute or short-term interventions.6 25 29
Potential Limitations
Were our results spurious because of
the different anesthetics
used? As noted above, anesthesia was maintained by intravenous
-chloralose in dogs receiving nitroglycerin and by ventilation with
a mixture of oxygen, nitrous oxide, and isoflurane in dogs that
received hydralazine and enalaprilat. A different effect of these
anesthetic agents on the SVV or their control probably did not play an
important role in our results. We make this assertion because one
intervention, induction of acute heart failure, produced exactly the
same response independent of whether the dogs received -chloralose
or isoflurane: venoconstriction, quantified by a reduction of SVV by
16%, 16%, and 15% in the groups that subsequently received
nitroglycerin, hydralazine, and enalaprilat, respectively.
As in most plethysmographic methods, various levels of portal vein pressure (manipulated with the portal vein cuff) reflect the pressure in large splanchnic veins well, but we do not know how well portal vein pressure reflects pressure in small splanchnic veins and venules. However, concerns that large pressure differences exist between small and medium-sized veins have not been confirmed in studies by Shoukas and Bohlen.34 They found insignificant distending pressure differences in first-, second-, and fourth-order intestinal venules in rats. Moreover, they found that these venules all responded similarly to interventions producing venoconstriction or venodilation.34 Also, we do not feel that concerns related to flow-mediated changes in capacitance volume are valid. If flow-mediated changes were important, we would expect that interventions that increase flow would result in increased capacitance volume. All three vasodilators used in this study increased cardiac output and presumably increased splanchnic blood flow, and all three increased or tended to increase SVV. However, the drug that increased cardiac output the most, hydralazine (+47%; P<.001), produced the least change in SVV (+3%; P=NS); the drug that produced the greatest splanchnic venodilation, nitroglycerin (+32%; P<.001), increased cardiac output by only 11% (P=NS). Thus, our data suggest that flow-mediated changes in splanchnic capacitance volume are quantitatively unimportant and did not influence our results in a significant way.
Finally, the animal model used in this study was one that could best be defined as acute ischemic LV dysfunction leading to a syndrome of acute heart failure. Therefore, our findings may apply only to subjects with acute heart failure syndromes caused by conditions such as acute myocardial infarction or acute mitral regurgitation. They may not apply to subjects with chronic heart failure. In chronic CHF, a "congestive" status is present owing to the sodium and water retention secondary to activation of the renin-angiotensin-aldosterone system.
Conclusions
In a canine model of acute ischemic LV
dysfunction, heart failure
produced a 14% splanchnic venoconstriction and a leftward shift of the
pressure–volume curve. This was associated with a significant increase
of LVEDP. Both enalaprilat and nitroglycerin, administered
subsequently, produced splanchnic venodilation and reduction of LVEDP,
with nitroglycerin having the greatest effects. Hydralazine had no
significant effect on splanchnic veins, and its effect on LV filling
pressure was modest. These data support the concept that (splanchnic)
capacitance volume changes are responsible, at least in part, for
modulating changes in LV preload.
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Acknowledgments |
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This study was supported by grants from the Alberta Heritage Foundation for Medical Research, Edmonton, Canada, and the Alberta Heart and Stroke Foundation, Calgary, Canada. The authors gratefully acknowledge Gerald Groves, Perry Anderson, and Cheryl Meek for their skillful technical assistance; Theresa Price for her efficient secretarial assistance; and Dale Bergman and Dr Douglas Hamilton for developing the software necessary for data acquisition and analysis.
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Footnotes |
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Reprint requests to Dr Dante E. Manyari, Division of Cardiology, Foothills Medical Centre, 1403 - 29th Street NW, Calgary, Alberta T2N 2T9, Canada.
1 References 12, 13, 17-20, 24, 25, 29, 32-37. 
2 References 10-14, 16, 19, 24, 31, 35, 38, 40-43, 46, 47.
3 References 10-14, 16, 19, 24, 31, 35, 38, 40-43, 46, 47.
Received June 20, 1994; revision received September 14, 1994; accepted September 28, 1994.
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