(Circulation. 1995;92:2119-2126.)
© 1995 American Heart Association, Inc.
Articles |
Paracrine Coronary Endothelial Control of Left Ventricular Function in Humans
From the Cardiovascular Center, OLV Ziekenhuis, Aalst, Belgium, and the Department of Cardiology, University of Wales College of Medicine, Cardiff, UK (A.M.S.).
Correspondence to Dr Walter J. Paulus, MD, PhD, Cardiovascular Center, OLV Ziekenhuis, Moorselbaan 164, B9300 Aalst, Belgium, or to Dr Ajay M. Shah, MD, MRCP, Department of Cardiology, University of Wales, College of Medicine, Heath Park, Cardiff, CF4 4XN, UK.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Similar to endothelial modulation of vascular tone, myocardial contraction may be modulated by cardioactive agents released from the coronary endothelium. To investigate such modulation in humans, we performed invasive assessment of left ventricular (LV) function before, during, and after bicoronary infusion of substance P, which releases nitric oxide from the endothelium.
Methods and Results Eight healthy subjects were investigated during diagnostic coronary angiography and eight transplant recipients during annual catheterization. Tip-micromanometer LV pressure was recorded before, during, and after bicoronary (n=16) and right atrial (n=14) infusion of substance P (20 pmol/min). LV angiograms (n=11) were obtained before and at the end of the substance P infusion. At the end of the intracoronary substance P infusion, we observed (1) a fall in LV peak systolic pressure from 147±16 to 139±15 mm Hg (P<.01) in healthy subjects and from 147±25 to 141±22 mm Hg (P<.05) in transplant recipients; (2) a downward and rightward shift of the average LV end-systolic pressure-volume point consistent with depressed systolic performance; and (3) a rise in LV end-diastolic volume at comparable end-diastolic pressure, consistent with increased end-diastolic distensibility. Five minutes after the substance P infusion, LV peak systolic pressure was higher than at baseline in healthy subjects (154±18 mm Hg; P<.05). Right atrial infusion of substance P did not reproduce these changes.
Conclusions Bicoronary infusion of substance P modulates LV function in humans, probably through paracrine myocardial action of cardioactive agents released from the coronary endothelium.
Key Words: endothelium • diastole • contractility • myocardial contraction • endothelium-derived factors
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Endothelial regulation of vascular tone by the coordinated release of relaxing and contracting factors is well established.1 2 3 Recent experimental evidence suggests a similar modulation of myocardial contractile performance by endocardial4 5 and coronary vascular endothelium,6 7 which involves the paracrine release of cardioactive substances that induce negative or positive inotropic effects on underlying myocardium.5 6 8 9 10 11 In isolated ferret papillary muscles, stimulation of nitric oxide release from endocardial endothelium by substance P reduces isometric twitch force and hastens onset of isometric relaxation without affecting the rate of force development.5 This effect is associated with a rise in cGMP content and is mimicked by administration of the nitric oxide donor sodium nitroprusside or of cGMP analogues.5 12 In isolated ejecting guinea pig hearts, both substance P and bradykinin induce an enhancement of left ventricular relaxation, which is attributable to the paracrine release of nitric oxide.11 A similar action of exogenous nitric oxide and/or cGMP analogues has been demonstrated in isolated rat and guinea pig cardiomyocytes,13 14 in isolated ejecting guinea pig hearts,15 and recently in the human left ventricle during bicoronary infusion of the nitric oxide donor sodium nitroprusside.16 Other work suggests that nitric oxide production within cardiac myocytes themselves (eg, after cholinergic stimulation) may also influence contractile performance.17 In addition, both cultured endothelial cells8 and endothelial cells in situ10 18 appear to tonically release endothelin, which has positive inotropic activity on subjacent myocardium in isolated cardiac preparations. Other, as yet unidentified, cardioactive substances are also involved in these endothelial influences on the heart.5 6 9
The present study investigates the myocardial effects of receptor-mediated coronary endothelial stimulation in humans by serial invasive assessment of left ventricular function before, during, and after bicoronary infusion of substance P. The latter is an 11–amino acid endogenous peptide and a potent endothelium-dependent vasodilator that is thought to act mainly by stimulating the release of nitric oxide,1 19 20 21 with little or no effect on underlying coronary vascular smooth muscle22 or myocardium.5 11 To examine the possible contribution, during the bicoronary infusion, of hemodynamic changes secondary to autonomic nervous reflexes or to peripheral vasodilation, left ventricular function was assessed both in healthy subjects and in transplant recipients with deficient cardiac innervation and also during right atrial infusion of a similar dose of substance P. The present results suggest a significant paracrine influence of endothelial cell factors on myocardial contractile function in humans.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Patients
Healthy Subjects
The healthy study group consisted of eight patients (seven women and one man; age range, 44 to 68 years; mean age, 57 years). All patients were referred for evaluation of chest pain and had no clinical or echocardiographic evidence of congenital, valvular, or cardiomyopathic heart disease. All medications were discontinued at least 24 hours before the study. Left ventricular angiography revealed normal left ventricular end-diastolic volume index (63±23 mL/m2) and normal left ventricular ejection fraction (71±11%) in all patients. Diagnostic coronary angiography, which preceded the actual study protocol, revealed absence of coronary artery disease and angiographically smooth coronary arteries. Because of the previously documented loss of endothelium-dependent vasodilation in patients with angiographically smooth coronary arteries and coronary risk factors,23 24 25 a review of risk factors was performed, with screening for hypercholesterolemia, hypertension, cigarette smoking, family history of coronary artery disease, and diabetes mellitus. Five patients had normal (<200 mg/100 mL) and three patients slightly elevated (<250 mg/100 mL) serum cholesterol. No patients had familial hyperlipidemia or were on cholesterol-lowering drugs. No patients were using antihypertensive medication or had elevated blood pressure off drugs the day preceding cardiac catheterization. Six patients had never smoked cigarettes, and one patient had stopped smoking 1 year earlier. Two patients had a positive family history for coronary artery disease (a parent or sibling with coronary artery disease at age <60 years). No patients had insulin-dependent or non–insulin-dependent diabetes mellitus.
Transplant Recipients
This group was
studied at the time of annual follow-up
catheterization and coronary angiography and
consisted of eight patients (two women and six men; age range, 30 to 63
years; mean age, 53 years) who had undergone orthotopic heart
transplantation. Four patients were studied 1 year after heart
transplantation, three patients 2 years after heart transplantation,
and one patient 3 years after heart transplantation. All patients were
on immunosuppressive therapy, which consisted of various combinations
of cyclosporine, prednisone, and azathioprine. No patient
was taking positive or negative inotropic drugs such as digitalis or
ß-blockers. For ethical reasons, treatment for
arterial hypertension was continued at the time of study
and consisted of calcium channel blockers in three patients and
angiotensin-converting enzyme inhibitors in
three patients. At the time of study, no patient had biopsy evidence of
rejection requiring adjustment of therapy. Four patients had
experienced previous (four or fewer) episodes of moderate to severe
allograft rejection. Left ventricular angiography revealed
normal left ventricular end-diastolic
volume index (72±22 mL/m2) in all patients and normal left
ventricular ejection fraction (65±10%) except in one
patient (48%). Coronary angiography, which preceded the study
protocol, revealed angiographically normal coronary arteries
without evidence of accelerated graft
atherosclerosis.26
Informed consent was obtained from all patients. The study protocol was approved by the local ethical committee, and there were no complications related to the procedure or study protocol.
Study Protocol
Left-right heart catheterization was
performed from the right and left femoral arteries and the right
femoral vein. Pressures were referenced to atmospheric pressure at the
level of the midchest, and left ventricular pressure was
measured with a high-fidelity
tip-micromanometer catheter calibrated
externally against a mercury reference and matched against luminal
pressure. The nonionic contrast agent iohexol was used in all
angiographic studies.
To achieve a homogeneous delivery of substance P throughout the left ventricle, a bicoronary infusion technique was used,16 except in five patients who had a left-dominant coronary system. To establish a bicoronary infusion, the arterial sheath in the right femoral artery was exchanged for a specially designed 8F arterial sheath that allowed passage of two 4F coronary catheters. In the patients with a left-dominant coronary artery system, the left coronary catheter was positioned in the left coronary ostium, whereas in all other patients, left and right 4F coronary catheters were placed in left and right coronary ostia, respectively.
Baseline left ventricular
pressure, left
ventricular dP/dt, right atrial pressure, and a bipolar
standard lead of the ECG were recorded on a Gould ES 1000
multichannel recorder (Fig 1
). In 11 patients (5
healthy subjects; 6 transplant recipients), left
ventricular cineangiography was performed in a 30° right
anterior oblique projection at 25 frames per second in held
inspiration with simultaneous fast-paper-speed
recordings (250 mm/s) of left ventricular pressure.
In these patients, a second left ventricular angiogram was
performed at the end of the global intracoronary substance
P infusion. To exclude confounding effects of repetitive left
ventricular angiograms on left ventricular
performance, no left ventricular angiography was
performed either before or at the end of the substance P infusion in 5
patients. In these patients, diagnostic left
ventricular angiography was performed at the end of the
study protocol. The intracoronary substance P infusion was
started after return of left ventricular pressures to
baseline value in those patients in whom a left ventricular
angiogram preceded the intracoronary infusion period.
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The dose of
substance P was divided between the two coronary
arteries in accordance with coronary
anatomy.16 In patients with a left-dominant
system, the entire dose was infused into the left coronary
catheter. In patients with a right-dominant system with a posterior
descending artery and a large posterolateral branch, one third of the
total dose was infused into the right coronary artery and two
thirds into the left coronary artery. In patients with a
right-dominant system with only a posterior descending artery, one
sixth of the total dose was infused into the right coronary
artery and the rest into the left coronary artery. These ratios
were used in a previous study on left ventricular effects
of the nitric oxide donor sodium nitroprusside16 and were
based on "myocardial jeopardy scores,"27 which
related coronary anatomy to magnitude of left
ventricular perfusion territory. The
intracoronary infusion of substance P was progressively
raised from a dose of 2.5 pmol/min to a dose of 20 pmol/min. The latter
dose was subsequently infused for a 5-minute period. A dose of 20
pmol/min has previously been used in studies investigating the effects
of substance P on coronary vasomotion.20 21
Substance P (Substance P acetate; Sigma Chemicals) was prepared for
human use as described previously20 and dissolved in 0.9%
saline, which was used as infusion vehicle. Maximal volume rate of
right coronary artery infusion varied from 0 to 0.7 mL/min and
of left coronary artery infusion from 1.3 to 2.0 mL/min.
Previous studies20 failed to detect effects on
coronary vasomotion or on systemic hemodynamics
of an intracoronary 0.9% saline infusion at similar volume
rates. During and for 5 minutes after the substance P infusion, left
ventricular pressure, left ventricular dP/dt,
right atrial pressure, and a bipolar standard lead of the ECG were
continuously recorded. Fast-paper-speed recordings
(250 mm/s) covering several respiratory cycles were obtained at
1-minute intervals. Hemodynamic data
(Table) were derived from the fast-speed
recordings and averaged over a complete respiratory cycle. At
the end of the 5-minute 20-pmol/min substance P infusion period, a
second left ventricular angiogram with
simultaneous left ventricular pressure
measurements was obtained in those patients in whom a baseline left
ventricular angiogram had been performed before the
substance P infusion.
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At least 15 minutes after the end of the intracoronary infusion, a similar infusion of substance P was performed in the right atrium in 14 patients. During and for 5 minutes after the right atrial infusion, left ventricular pressure, left ventricular dP/dt, right atrial pressure, and a bipolar standard lead of the ECG were continuously recorded, and fast-paper-speed recordings (250 mm/s) covering several respiratory cycles were obtained at 1-minute intervals. Hemodynamic data reported on the right atrial infusion were averaged over a complete respiratory cycle and derived from the fast-paper-speed recordings.
Data Analysis
Left ventricular volumes and ejection fractions
were
derived from single-plane left ventricular angiograms
by use of the area-length method and a regression
equation.28 Left ventricular
pressure-volume relations were constructed by matching
corresponding points of left ventricular pressure and
volume by use of a cine frame marker. The time constant of left
ventricular pressure decay was calculated from the
digitized pressure data points of isovolumic left
ventricular relaxation with an exponential curve fit with
zero-asymptote pressure.29 Pressure data
points were digitized at 3-ms intervals from the moment of left
ventricular dP/dtmin to a time at which
left ventricular pressure equaled left
ventricular end-diastolic pressure plus 5
mm Hg. To avoid erroneous changes in time constant induced by a shift
of the starting point or of the end point of the time constant
analysis, the values of time constant for each patient before,
at the end of, and 5 minutes after the intracoronary
substance P infusion were derived from curve fits with identical
starting point (the lowest pressure at which left
ventricular dP/dtmin occurred) and end
point (the pressure that equaled the highest left
ventricular end-diastolic pressure plus 5
mm Hg).30 31 32 The duration of left
ventricular electromechanical systole (Table
, LVEST), which
indicated the time to onset of left ventricular relaxation,
was measured as the interval from the Q wave on the ECG to the moment
of left ventricular dP/dtmin.
Single comparison data were analyzed with Student's t test for paired data. Multiple-comparison data were analyzed with a repeated-measures ANOVA followed by a multiple-comparison test (Student-Newman-Keuls). Statistical significance was set at a two-tailed probability level of P<.05.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Effects of Intracoronary Substance P Infusion on Left Ventricular Hemodynamics
A representative set of recordings of single-lead ECG, left ventricular dP/dt, left ventricular tip-micromanometer pressure, and right atrial pressure in control conditions, at the end of the intracoronary substance P infusion, and 5 minutes after cessation of the intracoronary substance P infusion are shown in Fig 1
. The Table shows the effects
of a
bicoronary substance P infusion on left
ventricular hemodynamics in healthy
subjects and in transplant recipients.
In healthy subjects, significant
reductions of left
ventricular peak systolic pressure, left
ventricular end-systolic pressure, and left
ventricular dP/dtmin were observed at
the end of the intracoronary substance P infusion. Five
minutes after cessation of the intracoronary substance P
infusion, left ventricular peak systolic pressure and left
ventricular end-systolic pressure were significantly
higher than at baseline or at the end of the intracoronary
infusion period, and left ventricular
end-diastolic pressure was significantly higher than at
the end of the intracoronary infusion period. Fig 2 shows
individual patient data of left
ventricular peak systolic and end-diastolic
pressures before, at the end of, and after cessation of
intracoronary substance P infusion in healthy subjects.
Heart rate and left ventricular dP/dtmax
remained unchanged throughout and after the intracoronary
substance P infusion period.
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) data of
left ventricular peak systolic (left) and
end-diastolic (right) pressures (LVPSP and LVEDP,
respectively) before (Pre), at the end of (SP), and after cessation of
(Post SP) bicoronary infusion of substance P in healthy
subjects. 
P<.01 SP vs Pre; #P<.001 Post SP vs
SP; §P<.05 Post SP vs Pre; ¥P<.05 Post SP vs
SP.
In transplant recipients, a significant
reduction in left
ventricular peak systolic pressure was observed at the end
of the intracoronary substance P infusion. Five minutes
after the intracoronary substance P infusion, left
ventricular peak systolic pressure, left
ventricular end-systolic pressure, and left
ventricular end-diastolic pressure were
significantly higher than at the end of the intracoronary
infusion. Fig 3 shows individual patient data of left
ventricular peak systolic and end-diastolic
pressures before, at the end of, and after cessation of
intracoronary substance P infusion in transplant
recipients. Heart rate, left ventricular
dP/dtmax, and dP/dtmin
were unaltered during and after intracoronary substance P
infusion.
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In nine patients (four healthy subjects; five transplant
recipients),
adequate left ventricular angiograms could be obtained
before and at the end of the intracoronary substance P
infusion. In these patients, intracoronary substance P
infusion resulted in a significant increase in left
ventricular end-diastolic volume, from
122±47 to 128±52 mL (P<.05). Left ventricular
ejection fractions and end-systolic volumes were comparable before
(66±11%; 46±23 mL) and at the end of (67±9%; 48±27
mL) the
intracoronary substance P infusion. Fig 4
(left) shows a representative example of left
ventricular pressure-volume loops obtained before and
at the end of the intracoronary substance P infusion. At
the end of the intracoronary substance P infusion, the left
ventricular pressure-volume loop shifted to the right.
Fig 4 (right top) shows the average values (n=9) of the
end-systolic pressure-volume points before and at the end of
the intracoronary substance P infusion. The
intracoronary substance P infusion induced a significant
fall (P<.02) in end-systolic left
ventricular pressure at comparable left
ventricular end-systolic volume and a downward and
slightly rightward shift of the average end-systolic
pressure-volume point, consistent with reduced systolic
pump performance.33 To account for the preload
dependence of left ventricular
dP/dtmax,34 left
ventricular dP/dtmax was plotted as a
function of left ventricular end-diastolic
volume in Fig 4 (right bottom). On this plot, reduced systolic
pump
performance at the end of the intracoronary
substance P infusion was evident from the rightward and slightly
downward shift of the relation between left ventricular
dP/dtmax and left ventricular
end-diastolic volume. This shift resulted from a
comparable left ventricular dP/dtmax
value at significantly larger left ventricular
end-diastolic volume.
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) and at the end
(
) of the intracoronary substance P infusion in a
representative patient. Right top, Average value (n=9)
of left ventricular end-systolic pressure
(LVESP)–volume (LVESV) points before (To exclude confounding effects of repetitive left ventricular angiograms on left ventricular performance after cessation of the substance P infusion, no left ventricular angiograms were obtained before or at the end of the substance P infusion in five patients. In these patients, left ventricular peak systolic pressure after cessation of the substance P infusion (155±18 mm Hg) was also higher than at baseline (150±22 mm Hg; P<.05) or at the end of the substance P infusion (144±21 mm Hg; P<.01), thereby excluding an effect of repetitive left ventricular angiography on left ventricular hemodynamics in the postinfusion period.
Effects of Intracoronary Substance P Infusion on Left
Ventricular Diastolic Function
The increase in left ventricular
end-diastolic volume and the trend for lower left
ventricular end-diastolic pressures
(before, 14±4 mm Hg; end of substance P infusion, 12±5 mm Hg;
P=.07) are consistent with increased left
ventricular end-diastolic distensibility at
the end of the intracoronary substance P infusion.
Increased left ventricular diastolic
distensibility at the end of the intracoronary substance P
infusion was also evident from the downward and rightward shift of
individual diastolic left ventricular
pressure-volume relations (Fig 4, left).
The effects of
intracoronary substance P on left
ventricular relaxation indexes are shown in the Table. In
both healthy subjects and transplant recipients,
intracoronary substance P infusion failed to influence the
time constant of left ventricular pressure decay. In
healthy subjects, left ventricular
dP/dtmin at the end of the intracoronary
substance P infusion was significantly lower than at baseline or after
cessation of the substance P infusion. Left ventricular
electromechanical systole time was significantly shorter at the end of
the intracoronary substance P infusion in the study group
as a whole (P<.005) and in transplant recipients. The
latter finding is consistent with earlier onset of left
ventricular isovolumic relaxation at the end of
intracoronary substance P infusion.
Comparative Effects of Intracoronary and Right Atrial
Substance P Infusion
In 14 patients, a similar infusion of substance P
was performed in
the right atrium after the intracoronary infusion. Fig 5 shows
mean values of left ventricular peak
systolic and left ventricular end-diastolic
pressures before, at the end of, and 5 minutes after cessation of
intracoronary and right atrial substance P infusions. At
the end of and 5 minutes after cessation of intracoronary
substance P infusion, left ventricular peak systolic
pressure was significantly different from left ventricular
peak systolic pressure at corresponding times during right atrial
infusion. Five minutes after intracoronary substance P
infusion, left ventricular end-diastolic
pressure was significantly higher than after right atrial infusion.
Compared with baseline, right atrial substance P infusion failed to
significantly alter left ventricular peak systolic and
end-diastolic pressures. At the end of the
intracoronary substance P infusion, mean right atrial
pressure (3.9±2.2 mm Hg) was significantly lower than at baseline
(4.5±2.4 mm Hg; P<.05) or after cessation of the
intracoronary infusion (4.7±2.3 mm Hg;
P<.05). Right atrial infusion of substance P failed to
influence mean right atrial pressure (baseline, 4.4±2.7 mm Hg; end of
infusion, 4.4±3.3 mm Hg; after cessation of infusion, 4.8±3.2
mm Hg).
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infusion of substance P. *P<.05 vs RA;
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The present study is the first to demonstrate paracrine coronary endothelial control of left ventricular myocardial contractile performance in humans. A selective bicoronary substance P infusion in healthy subjects elicited a biphasic response of left ventricular peak systolic pressure. This biphasic response consisted of a significant drop in left ventricular peak systolic pressure at the end of the 5-minute infusion period followed by a significant overshoot of left ventricular peak systolic pressure 5 minutes after cessation of the intracoronary infusion. These findings appeared unrelated to autonomic nervous reflexes because a similar response pattern was also observed in cardiac transplant recipients with deficient cardiac innervation. The changes in left ventricular peak systolic pressure observed during and after intracoronary infusion of substance P were unlikely to be due to peripheral vasodilation, since they were not reproduced by infusion of the same dose of substance P in the right atrium.
Endothelial Modulation of Myocardial Contraction:
Experimental and Clinical Evidence
The paracrine effects of
endothelial cells on
myocardial contraction have been demonstrated by use of
receptor-mediated stimulation, although flow-induced shear
stress perhaps constitutes a more
physiologically relevant
stimulus.35 In isolated ferret papillary muscle
preparations, substance P reduced twitch amplitude through a
relaxation-hastening effect in the presence of an intact
endocardium but failed to do so after removal of the endocardium or in
the presence of hemoglobin, which inactivates nitric
oxide.5 A similar specificity for
endothelial cells of substance P was previously
reported in human coronary artery smooth muscle, which failed
to react to substance P in the absence of coronary
endothelium.22 In isolated ejecting guinea
pig hearts, both substance P and bradykinin induced earlier and faster
left ventricular pressure decay without affecting left
ventricular pressure rise.11 These effects
were significantly attenuated by hemoglobin and could be mimicked in
the same preparation after administration of the exogenous nitric oxide
donor sodium nitroprusside.15 Neither substance P nor
bradykinin had any effect on endothelium-denuded
guinea pig papillary muscles.11
In the present study, receptor-mediated coronary endothelial stimulation through selective bicoronary infusion of substance P resulted in a biphasic left ventricular response with different effects on left ventricular performance during and after cessation of the bicoronary infusion period. At the end of the intracoronary infusion period of substance P, a significant drop in left ventricular peak systolic pressure was observed in both healthy subjects and transplant recipients. In a subgroup in whom adequate sequential left ventricular angiograms were obtained, reduced systolic pump performance was evident at the end of the intracoronary substance P infusion from the downward and slightly rightward shift of the left ventricular end-systolic pressure-volume point and from the unaltered left ventricular dP/dtmax value despite larger left ventricular end-diastolic volume. Increased left ventricular diastolic distensibility was evident at the end of the intracoronary substance P infusion from the larger left ventricular end-diastolic volumes at comparable left ventricular end-diastolic pressures and from the downward shift of individual diastolic left ventricular pressure-volume relations. This increase in left ventricular diastolic distensibility cannot be explained by a substance P–induced rise in coronary blood flow or in coronary vascular engorgement, which would affect left ventricular diastolic distensibility in an opposite way.16 In the entire study group, there was earlier onset of left ventricular isovolumic relaxation because of the significant reduction in left ventricular electromechanical systole time. Reduced left ventricular pressure development, increased left ventricular diastolic distensibility, and a left ventricular relaxation–hastening effect have recently been described during bicoronary sodium nitroprusside infusion in humans and have been attributed to a direct myocardial effect of exogenous nitric oxide through activation of guanylyl cyclase to increase cGMP.16 A similar pattern of contractile change has also been observed in the in vitro studies of nitric oxide and of cGMP.13 14 15 The initial left ventricular response observed in the present study at the end of the bicoronary substance P infusion could therefore be consistent with a direct myocardial effect of nitric oxide released by substance P from the endothelium of the coronary vasculature. Definitive proof of nitric oxide mediation of the left ventricular response to substance P would require concomitant infusion of a nitric oxide synthase inhibitor. At present, therefore, a possible contribution of endothelial cardioactive factors other than nitric oxide is not excluded.
Five minutes after cessation of the intracoronary substance P infusion, left ventricular peak and end-systolic pressures were significantly higher than at baseline in the healthy subjects. A similar trend was observed in the transplant recipients. The mechanisms underlying this overshoot of left ventricular pressure development were not elucidated in the present study and could relate to arterial baroreceptor reflexes triggered by the fall in arterial pressure during the intracoronary infusion period or to direct myocardial effects from positive inotropic factors such as endothelin,8 10 either in response to substance P or as a consequence of the changes in nitric oxide activity. In the latter case, the actions of such factors could have been initially masked by the simultaneous activity of nitric oxide. Alternatively, the overshoot in left ventricular pressure could be a manifestation of multiple subcellular actions of nitric oxide–induced cGMP elevations, such that a "negative inotropic" effect was more easily reversible than a "positive inotropic" effect. In this regard, it is relevant to note that elevation of cGMP may induce both negative inotropic and positive inotropic effects, probably depending on the relative activation of cGMP-dependent protein kinases, various cGMP-dependent phosphodiesterases, and cGMP-dependent phosphatases.14 A third possibility is that the rise in left ventricular pressure may represent a "rebound" increase in myocardial contractile response after washout of nitric oxide, for example, as is often the case upon reversal of acidosis.
Systemic Vasodilation and Autonomic Reflexes
To examine the
possible contribution of systemic vasodilator
effects of substance P during the bicoronary infusion, the
same dose was infused in the right atrium in 14 patients after the
intracoronary infusion after return of left
ventricular pressure to baseline values. At the end of the
right atrial infusion and 5 minutes after cessation of right atrial
infusion, no significant changes in left ventricular
pressures were observed compared with baseline. Both the left
ventricular pressures observed at the end of the
intracoronary infusion and 5 minutes after cessation of
intracoronary infusion were significantly different from
the left ventricular pressures observed at corresponding
times during and after the right atrial infusion. Hence, even if during
the intracoronary infusion all of the substance P would
pass through the coronary vascular bed into the right atrium
and affect left ventricular performance by a
pulmonary or systemic vasodilator action, this mechanism could
not explain the observed changes in left ventricular peak
systolic pressure during intracoronary infusion. This
result confirms a previous study,36 which failed to
observe significant changes in systolic blood pressure in healthy
humans during intravenous administration of substance P up
to doses of 200 pmol/min, or 10 times the maximal dose used in the
present study. In the present study, a small reduction in mean
right atrial pressure was observed during bicoronary
infusion of substance P. Because right atrial infusion of substance P
failed to influence right atrial pressure, this drop in right atrial
pressure more likely resulted from right ventricular
unloading because of improved left ventricular
distensibility16 than from pulmonary vasodilation
because of right atrial spillover.
Substance P and other vasoactive neuropeptides have previously been identified in afferent nerve fibers supplying the mammalian cardiovascular system37 and shown to modulate afferent activity of arterial baroreceptors.38 To evaluate the possible contribution of autonomic reflexes induced by the intracoronary administration of substance P, data from healthy subjects were compared with those from transplant recipients with deficient cardiac innervation. The results in both study groups were similar, and the left ventricular effects of the intracoronary substance P infusion are therefore unlikely to be related to autonomic reflexes triggered by the intracoronary administration of substance P. The use of transplant recipients as a model of deficient cardiac innervation is, however, subject to criticism because of recent evidence of time-dependent sympathetic39 and sensory40 reinnervation after cardiac transplantation. Stimulation of arterial baroreceptors by the fall in arterial pressure during the intracoronary infusion period could have contributed to the rebound rise in left ventricular peak systolic and end-diastolic pressures after cessation of the infusion. Despite the evidence from previous studies that the cardiac allograft develops coronary endothelial dysfunction,21 41 42 the present study failed to detect an obvious difference in paracrine coronary endothelial control of left ventricular function between healthy subjects and transplant recipients. However, in view of the relatively small numbers of patients studied, we cannot exclude the possibility of subtle, minor alteration in endothelial function in the transplant group.
Relevance to Left Ventricular Function and
Dysfunction
Both physiological and pathological
alterations of coronary endothelial function
could alter the release of paracrine factors and affect left
ventricular performance. Provided that the
myocardial effects of flow-induced nitric oxide
release35 are similar to those observed in the present
study with substance P stimulation, they may serve to facilitate acute
physiological matching of ventricular
contractile function to coronary flow: during increases in
heart rate, increased coronary flow would stimulate nitric
oxide release, which would hasten the onset of left
ventricular relaxation, lower left ventricular
end-diastolic pressures, and thereby facilitate
ventricular filling and subendocardial coronary
perfusion.
Chronic changes in coronary endothelial function may also modify ventricular function. In conscious dogs, chronic exercise43 or pacing stress44 enhances nitric oxide release from the endothelium of the epicardial coronary arteries. A similar increase in the effects of nitric oxide on the myocardium could explain the increased left ventricular volumes and distensibility observed in athlete's heart45 or under conditions of elevated left ventricular wall stress, such as occurs in the remodeling process after myocardial infarction46 or during left ventricular volume or pressure overload.47 In circumstances such as cardiac failure, hypertrophy, or hypoxia, the balance of endothelial release of paracrine factors could shift toward positive inotropic substances. In both experimental48 49 and clinical50 heart failure, muscarinergic receptor stimulation induces a blunted arterial vasodilator response because of reduced endothelial release of nitric oxide. In hypertrophy, cardiac muscle hyperplasia increases the diffusion distance from coronary microvasculature to cardiomyocytes,51 and as evident from the original work of Yanagisawa et al,2 hypoxia is a potent stimulus for the release of endothelin from vascular endothelial cells. These effects could contribute to the reduction of left ventricular diastolic distensibility observed in the hypertrophied left ventricle52 or during episodes of hypoxic perfusion at the time of angioplasty balloon coronary occlusion.53
Conclusions
In the present study, bicoronary infusion of
substance P resulted in a significant drop in left
ventricular peak systolic pressure and an increase in left
ventricular end-diastolic distensibility.
These effects were comparable to previously reported left
ventricular effects of nitric oxide16 and
could possibly be explained by a substance P–mediated paracrine
endothelial release of nitric oxide by the
coronary vasculature. These changes in left
ventricular performance as a result of
receptor-mediated paracrine coronary
endothelial stimulation appeared to be unrelated to
systemic vasodilation or to autonomic reflexes. Similar changes
occurring during flow-induced nitric oxide release may serve as an
acute and chronic adaptive mechanism in conditions such as
tachycardia and athlete's heart, while abnormal
endothelial function may contribute to left
ventricular dysfunction in conditions such as cardiac
overload or failure.
|
Acknowledgments |
|---|
Dr Shah is the recipient of a Senior Clinical Fellowship of the UK Medical Research Council and is also supported by the British Heart Foundation. We thank the Pharmacy Department of the University Hospital of Wales (Cardiff) for preparation of substance P for human use and the nursing staff of the cardiac catheterization laboratory of the Cardiovascular Center (Aalst) for their technical assistance.
Received October 25, 1994; revision received April 3, 1995; accepted May 10, 1995.
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