From the Cardiovascular and Pulmonary Research Institute, Allegheny
University of the Health Sciences, Pittsburgh, Pa.
Correspondence to Stephen F. Vatner, MD, George J. Magovern Professor, Director, Cardiovascular Research Institute, Allegheny University of the Health Sciences, 320 E North Ave, Pittsburgh, PA 15212.
Methods and Results—We compared responses to BAY y 5959, which
increases inotropy and decreases chronotropy, with those to
norepinephrine (NE), which coincidentally exerts the same
directional effects on inotropy and chronotropy, albeit through
different mechanisms, in the presence and absence of ganglionic
blockade both in control and in HF. Both BAY y 5959 and NE elicit
direct effects on the heart and indirect effects through activation of
reflexes, primarily the sinoaortic baroreceptor reflex. BAY y 5959
still reduced heart rate in dogs with arterial baroreceptor
denervation, but not after ganglionic blockade. HF induced classic
catecholamine desensitization to the inotropic effects of
NE and blunted reflex bradycardia. In contrast, inotropic responses to
BAY y 5959 were preserved in HF. Surprisingly, the autonomically
mediated bradycardia induced by BAY y 5959 was also preserved in HF.
Baroreflex sensitivity was assessed in control and in HF by pulse
interval–systolic arterial blood pressure (PI/SAP)
slopes constructed in response to pharmacological alterations in
arterial pressure. HF depressed the PI/SAP slope from
11.5±1.3 to 4.8±0.9 ms/mm Hg, but during BAY y 5959 infusion in HF,
the PI/SAP slope was restored to 24.1±5.2 ms/mm Hg. To assess central
versus peripheral actions of BAY y 5959, the agent was
infused with intra–carotid artery perfusion at a low dose, which acted
centrally but did not have an effect peripherally. Under
these conditions, it still decreased heart rate and restored baroreflex
sensitivity (PI/SAP slope, 12.7±2.8 ms/mm Hg).
Conclusions—Thus, the calcium promoter restores
arterial baroreflex sensitivity in HF. Based on
intra–carotid artery experiments, this occurs through a central
nervous system and vagal mechanism.
One goal of the present investigation was to determine the
regulation of heart rate by augmenting calcium levels either
systemically with intravenous (IV) infusion or selectively
in the brain with intra–carotid artery infusion of a calcium promoter
to conscious dogs before and after induction of pacing-induced heart
failure. The calcium promoter BAY y 5959 was selected for study because
it is well tolerated by conscious animals and is relatively devoid of
vascular effects.14 The drug increases both the
mean open time and mean closed time of the Ca2+
channel by binding dihydropyridine receptors in a
voltage-dependent manner, resulting in a reduced rate of
Ca2+ current activation, increased peak current,
and a prolonged tail-current decay.15 The calcium
promoter, while increasing myocardial contractility by
a direct mechanism, reduces heart rate by an indirect, autonomic
mechanism, ie, after either ganglionic blockade or atropine the
bradycardia is abolished in normal, conscious dogs without heart
failure. Interestingly, BAY y 5959 was found to elicit the same
bradycardia in heart failure as observed in normal conscious dogs
without heart failure (unpublished observations). This would imply that
the blunted arterial baroreflex sensitivity characteristic
of heart failure was not observed during the infusion of the calcium
promoter. Accordingly, the second goal of the present investigation
was to determine the effects of the calcium promoter on baroreflex
sensitivity in heart failure. To achieve this goal, baroreflex
sensitivity was assessed by pulse interval–systolic
arterial pressure (PI/SAP) slopes in conscious dogs in
control and in heart failure.
In addition, the inotropic and chronotropic effects of BAY y 5959 were
compared with those of norepinephrine, a
catecholamine that, like the calcium channel promoter,
decreases heart rate while increasing myocardial
contractility. However, norepinephrine
reduces heart rate almost entirely through the arterial
baroreflex. To evaluate the reflex components of their action,
experiments were repeated in the presence and absence of chronic
sinoaortic arterial baroreceptor denervation (SAD) and in
the presence and absence of ganglionic blockade. Ganglionic blockade
was used to verify that the mechanism was neurally mediated.
Experiments after SAD were used to pinpoint the role of the
arterial baroreflex in mediating the response to BAY y
5959. In addition, to assess the potential central neural regulation of
baroreflex sensitivity by the calcium promoter, additional experiments
were conducted in conscious dogs with heart failure, in which small
quantities of BAY y 5959 were infused to the brain through chronically
implanted carotid arterial catheters. These latter
experiments were particularly important because alterations in systemic
hemodynamics, which could affect arterial
baroreflex function per se, were avoided by the trivial levels of drug
used, which were well below the threshold for systemic
hemodynamic effects. Finally, the efferent mechanism of
the bradycardia induced by BAY y 5959 was determined by examining the
effects of the calcium promoter in the presence and absence of
ß-adrenergic receptor blockade with propranolol and
muscarinic receptor blockade with atropine before and after development
of heart failure.
In 6 dogs, SAD was performed at the time of
instrumentation.16 Briefly, the aorta was
stripped of all nerve fibers and connective tissue from the aortic root
to the second intercostal artery. The brachiocephalic and the
subclavian arteries were also stripped from the aorta cranially to the
second set of branches. Carotid sinus denervation was performed after
aortic baroreceptor denervation. Through a midline incision in the
ventral cervical region, the right and left common carotid arteries
were isolated and stripped of nerve fibers and connective tissue 2 to 3
cm distal to the bifurcation of the internal and external carotid
arteries. The denervation was confirmed by absence of reflex heart rate
in response to phenylephrine (5 to 10 µg/kg IV) and
nitroglycerin (5 to 10 µg/kg IV). In 4 SAD dogs, a 6F
micromanometer catheter (Millar Instruments) was
introduced via the femoral artery to measure LV pressure and LV
dP/dt.
In 5 dogs, internal carotid artery catheters were implanted after the
induction of heart failure. Through a midline incision in the ventral
cervical region, the right and left common carotid arteries were
isolated, and Silastic catheters (0.625-mm external diameter) were
advanced to the internal carotid artery. All dogs were allowed to
recover for at least 2 weeks before experimentation and were treated
with 1.0 g cephalothin for 10 days after surgery. All animals used
in these studies were maintained according to the Guide for the
Care and Use of Laboratory Animals of the Institute of Laboratory
Animal Resources, National Research Council (NIH publication 93-23,
revised 1985) and the Standing Committee on Animal Care of Harvard
Medical School.
Experimental Protocols
BAY y 5959 [(-)-isopropyl
2-amino-5-cyano-1,4-dihydro-6-methyl-4-(3-phenyl-quinoline-5-yl)-pyridine-3-carboxylate]15
was administered as 10-minute graded IV infusions of 5, 10, and 20
µg · kg-1 ·
min-1 via a peripheral vein while
measurements of LV pressure, LV dP/dt, mean arterial
pressure, left atrial pressure, and heart rate were recorded.
Norepinephrine was administered as 5-minute graded IV
infusions of 0.05, 0.1, and 0.2 µg ·
kg-1 · min-1. The
infusion regimen for each drug was determined by preliminary studies.
Because hemodynamic responses were in the steady state
10 minutes after infusion of BAY y 5959 and 5 minutes after infusion of
norepinephrine, these times were selected for data
analysis, whereas the concentrations were selected to achieve
roughly equi-inotropic effects of the 2 agents after ganglionic
blockade.14 On a separate day, the same doses of
BAY y 5959 and norepinephrine were repeated in the presence
of ganglionic blockade with hexamethonium bromide (30
mg/kg IV) and atropine (0.1 mg/kg IV). The efficacy of blockade was
confirmed by the absence of reflex heart rate responses to
arterial pressure changes induced by administration of
nitroglycerin (5 µg/kg IV) and
phenylephrine (5 µg/kg IV). In 6 dogs before heart
failure and in 3 dogs with heart failure, the efferent mechanism of the
bradycardia induced by BAY y 5959 was examined on separate days after
ß-adrenergic receptor blockade with propranolol (1 mg/kg
IV) or atropine (0.1 mg/kg IV). Baroreflex sensitivity was assessed in
7 dogs before and after pacing-induced heart failure by plotting PI/SAP
slopes.17 The PI/SAP slopes were analyzed
by relating the change in systolic pressure induced by
phenylephrine (5 to 20 µg/kg IV) and
nitroglycerin (5 to 20 µg/kg IV) to the reflex change
in R-R interval. These slopes in control and in heart failure were also
examined during infusion of BAY y 5959 (20 µg ·
kg-1 · min-1 IV).
These protocols were repeated in the same dogs with heart failure. In 5
dogs with heart failure, BAY y 5959 (0.0025 to 0.005 µg ·
kg-1 · min-1 over
10 minutes) was also administered through intra–internal carotid
artery catheters while measurements of heart rate, LV pressure, LV
dP/dt, and mean arterial pressure were recorded.
Data Analysis
Effects of Norepinephrine With and Without Heart
Failure
Effects of BAY y 5959 With Control State and With Heart
Failure
Effects of BAY y 5959 on Heart Rate in the Presence of Either
ß-Adrenergic Receptor or Muscarinic Blockade
Effects of BAY y 5959 in SAD Dogs
Alteration of Baroreflex Sensitivity With BAY y 5959
Effects of Intra–Carotid Arterial BAY y 5959
Infusion
In the present investigation, blunted inotropic responses to the
catecholamine norepinephrine were observed, but
the inotropic responses to the calcium promoter were preserved. In
addition, the bradycardia induced by the calcium promoter was also not
diminished in the presence of heart failure, in contrast to the blunted
reflex bradycardia in response to norepinephrine. This
catecholamine was selected for comparison because, like the
calcium promoter, it increases myocardial contractility
and arterial pressure while reducing the heart rate. Of
course, the mechanism for the inotropic response differs for the 2
agents, as does the bradycardia.
The bradycardia in response to norepinephrine is mediated
by the arterial baroreceptor reflex. The first goal of the
present investigation was to determine the mechanism of the
bradycardia in response to the calcium promoter. Because the
bradycardia was completely abolished by ganglionic blockade, we
concluded that the bradycardia was neurally mediated and not due to a
direct effect of the drug. However, because the bradycardia was not
abolished in the dogs with SAD, a baroreflex mechanism was not entirely
responsible for the autonomically mediated bradycardia. These data,
taken in combination, suggest that the bradycardia in response to the
calcium promoter was mediated to a major extent by a central neural
mechanism. Potentially, the drug could act to increase vagal nerve
activity, a mechanism consistent with the findings that the
bradycardia was abolished by ganglionic blockade but not by SAD. In
further support of this concept, intra–carotid artery infusions of
small quantities of BAY y 5959 elicited bradycardia without increasing
arterial pressure. However, when the same dose of the drug
was administered systemically, no effects on
hemodynamics or heart rate were observed. Furthermore,
in control dogs, the bradycardia was abolished with atropine, whereas
in the presence of heart failure, a component of the bradycardia,
presumably due to sympathetic withdrawal, persisted after muscarinic
blockade. This suggests that a component of the efferent bradycardia in
heart failure with the afferent loop in the central nervous system is
mediated by sympathetic withdrawal. A parallel situation occurs with
the arterial baroreflex control of heart rate, which is
almost entirely vagal in the control state but includes a component of
sympathetic withdrawal in heart failure.18
The fact that the calcium promoter elicited the same bradycardia in the
presence and absence of heart failure implied that the well-known
blunted arterial baroreflex sensitivity characteristic of
heart failure was actually preserved during BAY y 5959 infusion. To
confirm that depressed baroreflex sensitivity occurred in the model of
pacing-induced heart failure,7 we examined PI/SAP
slopes in response to pharmacologically induced hypotension and
hypertension. As expected, the PI/SAP slopes were depressed in heart
failure. Surprisingly, the PI/SAP slope, ie, baroreflex sensitivity,
was not only restored during the infusion of BAY y 5959 but actually
enhanced above pre–heart failure baseline levels. Thus, the calcium
promoter was able to rapidly reverse the impaired baroreflex
sensitivity in heart failure and permit the expression of the
bradycardia in response to the drug, which as noted above appeared to
be mediated by a central neural/vagal mechanism.
The next goal of the present investigation was to determine the
mechanism of action of the drug on baroreflex sensitivity. It is
conceivable that the calcium promoter affected the arterial
baroreflex directly at the site of receptors in the carotid sinus and
aortic arch or at the level of central neural integration. To address
this question, low doses of the calcium promoter were infused to the
brain through a chronically implanted internal carotid
arterial catheter with the tip distal to the baroreceptors.
In these experiments, when BAY y 5959 was infused to the brain and
PI/SAP slopes were constructed during the infusion, the PI/SAP slope,
ie, baroreflex sensitivity, was restored. As noted above, when these
small quantities of drug were infused systemically, there was no
effect. Thus, it was the central neural effect of the calcium promoter
that was able to restore baroreflex sensitivity in the presence of
heart failure. The results from other studies with central nervous
system injection of either calcium, calcium agonists, or
dihydropyridine derivatives have been
controversial; ie, both increasing and decreasing calcium has been
shown to result in bradycardia.19 20 21 22
In summary, the calcium promoter BAY y 5959 elicits autonomically
mediated bradycardia through the central nervous system rather than
through the arterial baroreceptor reflex. Importantly, this
action is preserved in heart failure. The calcium promoter not only
restores but also enhances baroreflex sensitivity in heart failure
above the control, pre–heart failure levels. These actions, in
addition to the lack of desensitization of its inotropic effects, make
this class of drugs important candidates to consider therapeutically in
heart failure.
Received January 15, 1998;
revision received March 27, 1998;
accepted April 21, 1998.
2.
Eckberg DL, Drabinsky M, Braunwald E. Defective
cardiac parasympathetic control in patients with heart disease.
N Engl J Med. 1971;285:877–883.
3.
Osterziel KJ, Hanlein D, Willenbrock R, Eichhorn C,
Luft F, Dietz R. Baroreflex senstivity and
cardiovascular mortality in patients with mild to
moderate heart failure. Br Heart J. 1995;73:517–522.
4.
Sleight P, La Rovere MT, Mortara A, Pinna G, Maestri
R, Leuzzi S, Bianchini B, Tavazzi L, Bernardi L. Physiology and
pathophysiology of heart rate and blood pressure variability in humans:
is power spectral analysis largely an index of baroreflex gain?
Clin Sci. 1995;88:103–109.[Medline]
[Order article via Infotrieve]
5.
Himura Y, Liang C, Delehanty JM, Hood WB Jr.
Nitroprusside infusion improves arterial baroreflex control
of heart rate in dogs with chronic congestive heart failure.
J Cardiovasc Pharmacol. 1994;24:702–706.[Medline]
[Order article via Infotrieve]
6.
Grima EA, Moe GW, Howard RJ, Armstrong PW. Recovery of
attenuated baroreflex sensitivity in conscious dogs after reversal of
pacing induced heart failure. Cardiovasc Res. 1994;28:384–390.
7.
Wang W, Chen JS, Zucker IH. Carotid sinus baroreceptor
sensitivity in experimental heart failure. Circulation. 1990;81:1959–1966.
8.
Wang W, Chen JS, Zucker IH. Postexcitatory depression
of baroreceptors in dogs with experimental heart failure. Am
J Physiol. 1991;260:H1160–H1165.
9.
Kunze DL. Calcium and magnesium sensitivity of the
carotid baroreceptor reflex in cats. Circ Res. 1979;45:815–821.
10.
Kassis E, Amtorp O. Cardiovascular and
neurohumoral postural responses and baroreceptor abnormalities during a
course of adjunctive vasodilator therapy with felodipine for congestive
heart failure. Circulation. 1987;75:1204–1213.
11.
Andresen MC, Kunze DL. Ionic sensitivity of
baroreceptors. Circ Res. 1987;61(suppl I):I-66–I-71.
12.
Ichikawa M, Suzuki H, Kumagai K, Kumagai H, Ryuzaki M,
Nishizawa M, Saruta T. Differential modulation of baroreceptor
sensitivity by long-term antihypertensive treatment.
Hypertension. 1995;26:425–431.
13.
Warltier DC, Zyvoloski MG, Gross GJ, Brooks HL.
Comparative actions of dihydropyridine slow channel
calcium blocking agents in conscious dogs: alterations in baroreflex
sensitivity. J Pharmacol Exp Ther. 1984;230:376–382.
14.
Sato N, Uechi M, Asai K, Patrick T, Kudej RK, Vatner
SF. Effects of a novel inotropic agent, BAY y 5959, in conscious dogs:
comparison with dobutamine and milrinone. Am J
Physiol. 1997;272:H753–H759.
15.
Bechem M, Goldmann R, Gross R, Hallermann S, Hebisch S,
Hutter J, Rounding HP, Schramm M, Stoltefuss J, Straub A. A new type of
Ca-channel modulation by a novel class of 1,4-dihydropiridines.
Life Sci. 1997;60:107–118.[Medline]
[Order article via Infotrieve]
16.
Shen Y-T, Cowley AW Jr, Vatner SF. Relative roles of
cardiac and arterial baroreceptors in vasopressin
regulation during hemorrhage in conscious dogs. Circ
Res. 1991;68:1422–1436.
17.
Smyth HS, Sleight P, Pickering GW. Reflex regulation of
arterial pressure during sleep in man: a quantitative
method of assessing baroreflex sensitivity. Circ Res. 1969;24:109–121.
18.
Vatner SF, Higgins CB, Braunwald E. Sympathetic and
parasympathetic components of reflex tachycardia induced by
hypotension in conscious dogs with and without heart failure.
Cardiovasc Res. 1974;8:153–161.[Medline]
[Order article via Infotrieve]
19.
Higuchi S, Takeshita A, Ito N, Imaizumi T, Matsuguchi
H, Nakamura M. Arterial pressure and heart rate responses
to calcium channel blockers administered in the brainstem in rats.
Circ Res. 1985;57:244–251.
20.
Higuchi S, Takeshita A, Higashi H, Ito N, Imaizumi T,
Matsuguchi H, Nakamura M. Lowering calcium in the nucleus tractus
solitarius causes hypotension and bradycardia. Am J
Physiol. 1986;250:H226–H230.
21.
Lacolley P, Laurent S, Tsoucaris-Kupfer D, Legrand M,
Brisac AM, Schmitt H. Central modulation of baroreceptor reflex
response to phenylephrine by
dihydropyridines in rats. Hypertension. 1988;12:279–286.
22.
Laurent S, Girerd X, Tsoukaris-Kupfer D, Legrand M,
Huchet-Brisac AM, Schmitt H. Opposite central
cardiovascular effects of nifedipine and
BAY k 8644 in anesthetized rats. Hypertension. 1987;9:132–138.
© 1998 American Heart Association, Inc.
Basic Science Reports
Voltage-Dependent Calcium Channel Promoter Restores Baroreflex Sensitivity in Conscious Dogs With Heart Failure
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—The aim of this study was
to determine the mechanism by which the calcium channel promoter BAY y
5959 affects the control of heart rate and baroreflex sensitivity in
conscious dogs with pacing-induced heart failure (HF).
Key Words: dihydropyridine • nervous system • bradycardia
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Blunted baroreflex
sensitivity is characteristic of experimental1
and clinical2 heart failure. Because the blunted
baroreflex sensitivity and reduced heart rate variability in heart
failure correlate with mortality,3 4 preservation
of baroreflex sensitivity may be clinically important. The extent to
which blunted arterial baroreflex sensitivity is reversible
in heart failure remains controversial. Several studies have shown
partial recovery of arterial baroreflex function with
improved hemodynamics induced acutely by reduction in
preload and afterload5 or more chronically by
removal of the stimulus to heart failure.6 Other
studies have implicated alterations in ionic control of baroreceptors
as the mechanism for dysfunction in heart
failure.7 8 Although it is clear that calcium can
regulate baroreflex function, the extent to which calcium
activation9 or administration of calcium
antagonists affects baroreflex control in heart failure
also remains controversial.10 11 12 13
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Surgical Preparations
Eight adult mongrel dogs of either sex were anesthetized
with halothane (1.0 to 1.5 vol%) and ventilated with a Harvard
respirator after induction with thiopental (10 to 20 mg/kg IV). A left
thoracotomy was performed through the fifth intercostal space with a
sterile technique. Tygon catheters (Norton Elastic and Synthetic
Division) were placed into the descending thoracic aorta and left
atrial appendage. A solid-state miniature pressure transducer (P6,
Konigsberg Instruments) was implanted through the left
ventricular (LV) apex to measure LV pressure. A
screw-in–type pacing lead was attached to the right
ventricular free wall, and stainless steel pacing wires
were placed on the left atrium. The catheters and lead wires were
tunneled subcutaneously to the back of the neck, and the thoracotomy
was closed.
Experiments were conducted in the control state, before pacing,
and after heart failure had developed. Dogs were studied in the
conscious state while lying quietly on their right side. All
hemodynamic measurements were recorded in sinus
rhythm, after a 20- to 30-minute stabilization period after the
pacemaker was turned off. The aortic and left atrial catheters were
connected to strain-gauge manometers (Statham Instruments) for
measurements of arterial and left atrial pressures. LV
pressure and its first derivative (dP/dt) were measured with the
miniaturized pressure gauge, and the ECG was recorded. All
hemodynamic measurement data were recorded on a
multichannel tape recorder (Honeywell) and played back on a
direct-writing oscillograph (Gould-Brush). Heart failure, characterized
by ascites and exercise intolerance, was induced by right
ventricular pacing at 240 bpm for 3 to 5 weeks with a
programmable pacemaker (model EV4543, Pace Medical) that was worn
externally in a vest.
All data are expressed as mean±SEM. Because the same animals
were used to compare the effects of the 2 agents in the absence and
presence of ganglionic blockade, a repeated-measures ANOVA procedure of
Super ANOVA (Abacus Concepts) was used to determine statistical
significance of the differences between the groups. If the ANOVA
demonstrated overall significant differences, individual comparisons
between baseline and the response to each drug were made by contrast
analysis. A regression analysis was used to determine
the statistical significance of the slope of baroreflex sensitivity. A
value of P<0.05 was taken as the minimal level of
significance.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Baseline Hemodynamics
Heart failure was induced after 3 to 5 weeks of pacing:
heart rate and LV end-diastolic pressure were significantly
greater (P<0.01), and LV systolic pressure, LV
dP/dt, and mean arterial pressure were significantly
depressed (P<0.05) (Table 1
).
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Table 1. Baseline Hemodynamics in Control State and With
Heart Failure
Norepinephrine reduced heart rate in control (-23±2
bpm) and less so, P<0.05, with heart failure (-12±3 bpm)
Table 2). The
norepinephrine-induced bradycardia was autonomically
mediated, because in the presence of ganglionic blockade, heart rate
rose in response to norepinephrine in control (+18±5 bpm)
and less so, P<0.05, with heart failure (+6±1 bpm). In
control, mean arterial pressure rose in response to
norepinephrine to a lesser extent in the absence of
ganglionic blockade (+23±3 mm Hg) than in the presence of
ganglionic blockade (+73±13 mm Hg). With heart failure, mean
arterial pressure rose less, P<0.05, in
response to norepinephrine in both the absence (+15±4
mm Hg) and presence (+37±10 mm Hg) of ganglionic blockade
compared with values in control. In the control state,
norepinephrine increased LV dP/dt by 40±10% and 160±30%
in the absence and presence of ganglionic blockade, respectively. With
heart failure, the increase in LV dP/dt in response to
norepinephrine was significantly attenuated
(P<0.05) in both the absence (+20±5%) and presence
(+61±19%) of ganglionic blockade compared with values in the control
state. The greater increases in pressures and LV dP/dt were predictable
after ganglionic blockade because of the loss of reflex buffering.
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Table 2. LV Effects of NE (0.2
µg · kg-1 · min-1) in Control
State and With Heart Failure With and Without Ganglionic Blockade
(n=7)
BAY y 5959 reduced heart rate by 30±3 bpm in the control state
and similarly (-40±6 bpm) with heart failure (Table 3). In the presence of
ganglionic blockade, BAY y 5959 failed to alter heart rate either in
control or with heart failure. In the control state, mean
arterial pressure did not change in the absence of
ganglionic blockade (+3±3 mm Hg), but it rose in the presence of
ganglionic blockade (+25±4 mm Hg). With heart failure, mean
arterial pressure rose more, P<0.05, in
response to BAY y 5959 in the absence (+10±3 mm Hg) and presence
(+33±5 mm Hg) of ganglionic blockade compared with values in the
control state. BAY y 5959 increased LV dP/dt in the absence (+68±9%)
and in the presence (+138±4%) of ganglionic blockade in control. With
heart failure, the percent increase in LV dP/dt in response to BAY y
5959 was not diminished either in the absence (+91±9%) or in the
presence (+131±9%) of ganglionic blockade.
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Table 3. LV Effects of BAY y 5959 (20
µg · kg-1 · min-1) in Control
State and Heart Failure With and Without Ganglionic Blockade
(n=8)
Atropine blocked the decreases in heart rate entirely with BAY y
5959 in the control state, but with heart failure, BAY y 5959 still
reduced heart rate by 11±4 bpm after atropine (P<0.05
versus before heart failure). In the presence of
propranolol, BAY y 5959 reduced heart rate by 27±4 bpm in
control and tended to reduce heart rate less, by 18±3 bpm, with heart
failure.
In conscious SAD dogs, nitroglycerin decreased
mean arterial pressure by 40±3 mm Hg but did not
change heart rate. Phenylephrine increased mean
arterial pressure by 47±5 mm Hg but did not change
heart rate. These experiments confirmed the adequacy of SAD dogs.
However, BAY y 5959 at a dose of 20
µg · kg-1 · min-1
decreased heart rate (-23±4 bpm) in SAD dogs, whereas mean
arterial pressure increased by 23±8 mm Hg (Figure 1).
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Figure 1. Percent changes in heart rate, mean
arterial pressure, and LV dP/dt in response to BAY y 5959
(5, 10, and 20 µg · kg-1 ·
min-1) are compared in intact conscious dogs without heart
failure (n=8) ( 
) and in conscious dogs with arterial
baroreceptor denervation (SAD) without heart failure (n=6) (
).
Values are mean±SEM. *P<0.05. Baseline values are
shown at top of each panel.
The PI/SAP slope constructed in response to blood pressure changes
induced by phenylephrine and nitroglycerin
was decreased with heart failure (4.8±0.9 ms/mm Hg, n=5) compared
with control (11.5±1.3 ms/mm Hg, n=5) (Figure 2). In the presence of BAY y 5959, the
PI/SAP slope was significantly increased in control (33.6±9.9
ms/mm Hg, P<0.05) and with heart failure (24.1±5.2
ms/mm Hg, P<0.05).
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Figure 2. Top, Individual data; bottom, mean±SEM data.
PI/SAP slopes after alterations in arterial pressure
induced by IV nitroglycerin and
phenylephrine are shown in control ( , open bar), with
heart failure (
, light shaded bar), and after BAY y 5959 was
administered in control (, dark shaded bar) and with heart failure
(
, solid bar). Baroreflex sensitivity was blunted significantly
(P<0.05) in heart failure vs control and enhanced
significantly (P<0.05) after BAY y 5959 infusion, even
above pre–heart failure levels.
Heart rate fell by 15±6 bpm in response to intra–carotid artery
BAY y 5959 infusion. However, heart rate
was not changed while the same dose of BAY y 5959 was infused
systemically. Mean arterial pressure and LV dP/dt were not
affected by either intra-carotid artery or IV BAY y 5959 infusion at
this low dose. The PI/SAP slope was similar during IV BAY y 5959
infusion at this low dose (5.0±0.4 ms/mm Hg) and in heart failure in
the absence of drug infusion (4.8±0.5 ms/mm Hg) (Figure 3). However,
intra-carotid artery low-dose BAY y 5959 infusion increased the PI/SAP
slope significantly (12.7±2.8 ms/mm Hg, n=4, P<0.05)
compared with the slope in heart failure in the absence of BAY y 5959
infusion (4.8±0.5 ms/mm Hg).
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Figure 3. Top, Examples of individual data; bottom,
mean±SEM data. Depressed PI/SAP slope after IV
nitroglycerin and phenylephrine is shown in
heart failure ( , open bar). Slope was enhanced with intra–carotid
artery infusion of BAY y 5959 (, solid bar). However, when same dose
of BAY y 5959 was administered systemically (
, shaded bar) in heart
failure, slope was not affected, because dose was too low to be
effective systemically.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
Decreased baroreflex sensitivity is a hallmark of heart failure
and has been associated with increased
mortality.3 Decreased baroreflex sensitivity in
heart failure was confirmed in the present study in the model of
chronic rapid pacing by observation of blunted reflex bradycardia in
response to norepinephrine-induced hypertension on the one
hand and depressed PI/SAP slopes in response to pharmacological
alterations in arterial pressure on the other hand.
Acknowledgments
This study was supported in part by US Public Health Service
grants HL-59139, HL-33107, HL-37404, and AG-14121; a gift from Bayer
Pharmaceutical Co; and a Fellowship from Merck & Co, Inc.
Footnotes
1 Drs Uechi and Asai contributed equally to this article. 
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
1.
Higgins CB, Vatner SF, Eckberg DL, Braunwald E.
Alterations in the baroreceptor reflex in conscious dogs with heart
failure. J Clin Invest. 1972;51:715–724.
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