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Circulation. 1995;92:2119-2126

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(Circulation. 1995;92:2119-2126.)
© 1995 American Heart Association, Inc.

Articles

Paracrine Coronary Endothelial Control of Left Ventricular Function in Humans

Walter J. Paulus, MD, PhD; Pascal J. Vantrimpont, MD; Ajay M. Shah, MD, MRCP

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.


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
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


*    Introduction
up arrowTop
 up arrowAbstract
 *Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
down arrowReferences
 
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.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
down arrowDiscussion
down arrowReferences
 
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 1Down). 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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  		Figure 1. Representative set of recordings in a healthy subject of single-lead ECG, left ventricular (LV) dP/dt, LV tip-micromanometer pressure (LVP), and right atrial pressure (RAP) in control conditions, at the end of the 20-pmol/min substance P infusion period (Substance P), and 5 minutes after cessation of the substance P infusion (Post Substance P). At the end of the substance P infusion, there was a reduction in left ventricular peak systolic pressure. Five minutes after the substance P infusion, left ventricular peak systolic pressure was higher than at baseline or at the end of the substance P infusion.

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 (TableDown) 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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  		Table 1. Effects of Intracoronary Substance P on Left Ventricular Hemodynamic and Relaxation Indexes

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 (TableUp, 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.


*    Results
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
*Results
down arrowDiscussion
down arrowReferences
 
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 1Up. The TableUp 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 2Down 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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  		Figure 2. Graphs showing individual and mean ({circ}) 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. {dagger}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 3Down 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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  		Figure 3. Individual and mean ({circ}) 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 transplant recipients. *P<.05 SP vs Pre; °P<.01 Post SP vs SP; ¥P<.05 Post SP vs SP.

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 4Down (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 4Down (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 4Down (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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  		Figure 4. Left, Left ventricular pressure (LVP)–volume (LVV) loops obtained before ({blacksquare}) and at the end ({bullet}) 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 ({blacksquare}) and at the end of ({bullet}) the intracoronary substance P infusion. Right bottom, Average value (n=9) of left ventricular dP/dtmax–end-diastolic volume (LVEDV) points before ({blacksquare}) and at the end of ({bullet}) the intracoronary substance P infusion.

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 4Up, left).

The effects of intracoronary substance P on left ventricular relaxation indexes are shown in the TableUp. 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 5Down 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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  		Figure 5. Graphs showing mean 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 ({circ}) and right atrial (RA) {square} infusion of substance P. *P<.05 vs RA; {dagger}P<.01 vs RA.


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
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.


*    References
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*References
 

  1. Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev. 1991;43:109-142. [Medline] [Order article via Infotrieve]
  2. Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature. 1988;332:411-415. [Medline] [Order article via Infotrieve]
  3. Vane JR, Anggard EE, Botting RM. Regulatory functions of the vascular endothelium. N Engl J Med. 1990;323:27-36. [Medline] [Order article via Infotrieve]
  4. Brutsaert DL, Meulemans AL, Sipido KR, Sys SU. Effects of damaging the endocardial surface on the mechanical performance of isolated cardiac muscle. Circ Res. 1988;62:358-366. [Abstract/Free Full Text]
  5. Smith JA, Shah AM, Lewis MJ. Factors released from endocardium of the ferret and pig modulate myocardial contraction. J Physiol (Lond). 1991;439:1-14. [Abstract/Free Full Text]
  6. McClellan G, Weisberg A, Kato NS, Ramaciotti C, Sharkey A, Winegrad S. Contractile proteins in myocardial cells are regulated by factor(s) released by blood vessels. Circ Res. 1992;70:787-803. [Abstract/Free Full Text]
  7. Li K, Rouleau JL, Andries L, Brutsaert DL. Effect of dysfunctional vascular endothelium on myocardial performance in isolated papillary muscles. Circ Res. 1993;72:768-777. [Abstract/Free Full Text]
  8. Mebazaa A, Mayoux E, Maeda K, Martin L, Lakatta EG, Robotham JL, Shah AM. Paracrine effects of endocardial endothelial cells on myocyte contraction mediated via endothelin. Am J Physiol. 1993;265:H1841-H1846. [Abstract/Free Full Text]
  9. Shah AM, Mebazaa A, Wetzel RC, Lakatta EG. Novel cardiac myofilament desensitizing factor released by endocardial and vascular endothelial cells. Circulation. 1994;89:2492-2497. [Abstract/Free Full Text]
  10. McClellan G, Weisberg A, Rose D, Winegrad S. Endothelial cell storage and release of endothelin as a cardioregulatory mechanism. Circ Res. 1994;75:85-96. [Abstract/Free Full Text]
  11. Grocott-Mason R, Anning P, Evans H, Lewis MJ, Shah AM. Modulation of left ventricular relaxation in the isolated ejecting heart by endogenous nitric oxide. Am J Physiol. 1994;267:H1804-H1813. [Abstract/Free Full Text]
  12. Shah AM, Lewis MJ, Henderson AH. Effects of 8-bromo-cyclic GMP on contraction and on inotropic response of ferret cardiac muscle. J Mol Cell Cardiol. 1991;23:55-64. [Medline] [Order article via Infotrieve]
  13. Brady AJB, Warren JB, Poole-Wilson PA, Williams TJ, Harding SE. Nitric oxide attenuates cardiac myocyte contraction. Am J Physiol. 1993;265:H176-H182. [Abstract/Free Full Text]
  14. Shah AM, Spurgeon HA, Sollott SJ, Talo A, Lakatta EG. 8-Bromo-cGMP reduces the myofilament response to Ca2+ in intact cardiac myocytes. Circ Res. 1994;74:970-978. [Abstract/Free Full Text]
  15. Grocott-Mason R, Fort S, Lewis MJ, Shah AM. Myocardial relaxant effect of exogenous nitric oxide in the isolated ejecting heart. Am J Physiol. 1994;266:H1699-H1705. [Abstract/Free Full Text]
  16. Paulus WJ, Vantrimpont P, Shah AM. Acute effects of nitric oxide on left ventricular relaxation and diastolic distensibility in humans. Circulation. 1994;89:2070-2078. [Abstract/Free Full Text]
  17. Balligand JL, Kelly RA, Marsden PA, Smith TW, Michel T. Control of cardiac muscle function by an endogenous nitric oxide signaling system. Proc Natl Acad Sci U S A. 1993;90:347-351. [Abstract/Free Full Text]
  18. Evans HG, Lewis MJ, Shah AM. Modulation of myocardial relaxation by basal release of endothelin from endocardial endothelium. Cardiovasc Res. 1994;28:1694-1699. [Medline] [Order article via Infotrieve]
  19. Furchgott RF. Role of endothelium in responses of vascular smooth muscle. Circ Res. 1983;53:557-573. [Free Full Text]
  20. Kushawa SS, Crossman DC, Bustami M, Davies GJ, Mitchell AG, Maseri A, Yacoub MH. Substance P for evaluation of coronary endothelial function after cardiac transplantation. J Am Coll Cardiol. 1991;17:1537-1544. [Abstract]
  21. Mügge A, Heublein B, Kuhn M, Nolte C, Haverich A, Warnecke J, Forssmann WG, Lichtlen PR. Impaired coronary dilator responses to substance P and impaired flow-dependent dilator responses in heart transplant patients with graft vasculopathy. J Am Coll Cardiol. 1993;21:163-170. [Abstract]
  22. Bossaller C, Habib GB, Yamamoto H, Williams C, Wells S, Henry PD. Impaired muscarinic endothelium-dependent relaxation and cyclic guanosine 5' monophosphate formation in atherosclerotic human coronary artery and rabbit aorta. J Clin Invest. 1987;79:170-174.
  23. Vita JA, Treasure CB, Nabel EG, McLenachan JM, Fish RD, Yeung AC, Vekshtein VI, Selwyn AP, Ganz P. Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. Circulation. 1990;81:491-497. [Abstract/Free Full Text]
  24. Seiler C, Hess OM, Buechi M, Suter TM, Krayenbuehl HP. Influence of serum cholesterol and other coronary risk factors on vasomotion of angiographically normal coronary arteries. Circulation. 1993;88:2139-2148. [Abstract/Free Full Text]
  25. Egashira K, Inou T, Hirooka Y, Yamada A, Maruoka Y, Kai H, Sugimachi M, Suzuki S, Takeshita A. Impaired coronary blood flow response to acetylcholine in patients with coronary risk factors and proximal atherosclerotic lesions. J Clin Invest. 1993;91:29-37.
  26. Gao SZ, Alderman EL, Schroeder JS, Silverman JF, Hunt SA. Accelerated coronary vascular disease in the heart transplant patient: coronary arteriographic findings. J Am Coll Cardiol. 1988;12:334-340. [Abstract]
  27. Dash H, Johnson RA, Dinsmore RE, Harthorne JW. Cardiomyopathic syndrome due to coronary artery disease. Br Heart J. 1977;39:733-739. [Free Full Text]
  28. Fifer MA, Grossman W. Measurement of ventricular volumes, ejection fraction, mass and wall stress. In: Grossman W, Baim DS, eds. Cardiac Catheterization, Angiography, and Intervention. 4th ed. Philadelphia, Pa: Lea & Febiger; 1991:300-318.
  29. Paulus WJ, Vantrimpont PJ, Rousseau MF. Diastolic function of the nonfilling human left ventricle. J Am Coll Cardiol. 1992;20:1524-1532. [Abstract]
  30. Martin G, Gimeno JV, Cosin J, Guillem MI. Time constant of isovolumic pressure fall: new numerical approaches and significance. Am J Physiol. 1984;247:H283-H294.
  31. Paulus WJ, Heyndrickx GR, Buyl P, Goethals MA, Andries E. Wide range load shifts of combined aortic valvuloplasty-arterial vasodilation slow isovolumic relaxation of the hypertrophied left ventricle. Circulation. 1990;81:886-898. [Abstract/Free Full Text]
  32. Paulus WJ, Bronzwaer JGF, Felice H, Kishan N, Wellens F. Deficient acceleration of left ventricular relaxation during exercise after heart transplantation. Circulation. 1992;86:1175-1185. [Abstract/Free Full Text]
  33. Kass DA, Maughan WL. From `Emax' to pressure-volume relations: a broader view. Circulation. 1988;77:1203-1212. [Free Full Text]
  34. Little WC, Park RC, Freeman GL. Effects of regional ischemia and ventricular pacing on LV dP/dtmax-end-diastolic volume relation. Am J Physiol. 1987;252:H933-H940. [Abstract/Free Full Text]
  35. Lamontagne D, Pohl U, Busse R. Mechanical deformation of vessel wall and shear stress determine the basal release of endothelium-derived relaxing factor in the intact rabbit coronary vascular bed. Circ Res. 1992;70:123-130. [Abstract/Free Full Text]
  36. Fuller RW, Maxwell DL, Dixon CMS, McGregor GP, Barnes VF, Bloom SR, Barnes PJ. Effect of substance P on cardiovascular and respiratory function in subjects. J Appl Physiol. 1987;62:1473-1479. [Abstract/Free Full Text]
  37. Pernow B. Substance P. Pharmacol Rev. 1983;35:86-141.
  38. Lundberg JM, Hokfelt T, Fahrenkrug J, Nilsson G, Terenius L. Peptides in the cat carotid body (glomus caroticum): VIP-, enkephalin-, and substance P-like immunoreactivity. Acta Physiol Scand. 1979;107:279-281. [Medline] [Order article via Infotrieve]
  39. Burke MN, McGinn AL, Homans DC, Christensen BV, Kubo SH, Wilson RF. Evidence for functional sympathetic reinnervation of left ventricle and coronary arteries after orthotopic cardiac transplantation in humans. Circulation. 1995;91:72-78. [Abstract/Free Full Text]
  40. Stark RP, McGinn AL, Wilson RF. Chest pain in cardiac-transplant recipients: evidence of sensory reinnervation after cardiac transplantation. N Engl J Med. 1991;324:1791-1794. [Medline] [Order article via Infotrieve]
  41. Fish RD, Nabel EG, Selwyn AP, Ludmer PL, Mudge GH, Kirshenbaum JM, Schoen FJ, Alexander RW, Ganz P. Responses of coronary arteries of cardiac transplant patients to acetylcholine. J Clin Invest. 1988;81:21-31.
  42. Dzau VJ, Gibbons GH, Cooke JP, Omoigui N. Vascular biology and medicine in the 1990s: scope, concepts, potentials and perspectives. Circulation. 1993;87:705-719. [Free Full Text]
  43. Wang J, Wolin MS, Hintze TH. Chronic exercise enhances endothelium-mediated dilation of epicardial coronary artery in conscious dogs. Circ Res. 1993;73:829-838. [Abstract/Free Full Text]
  44. Hintze TH, Wang J, Omar HA, Wolin MS. Enhanced large coronary artery dilation in conscious dogs and relaxation in vitro after chronic pacing induced increased coronary blood flow velocity. Circulation. 1989;80(suppl II):II-279. Abstract.
  45. Shapiro LM. Morphologic consequences of systematic training. In: Maron BJ, ed. The Athlete's Heart. Cardiology Clinics. Philadelphia, Pa: WB Saunders; 1992;10:219-226.
  46. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction. Circulation. 1990;81:1161-1172. [Abstract/Free Full Text]
  47. Ross J Jr. Afterload mismatch in aortic and mitral valve disease: implications for surgical therapy. J Am Coll Cardiol. 1985;5:811-826. [Abstract]
  48. Drexler H, Lu W. Endothelial dysfunction of hindquarter resistance vessels in experimental heart failure. Am J Physiol. 1992;262:H1640-H1645. [Abstract/Free Full Text]
  49. Teerlink JR, Gray GA, Clozel M, Clozel JP. Increased vascular responsiveness to norepinephrine in rats with heart failure is endothelium dependent. Circulation. 1994;89:393-401. [Abstract/Free Full Text]
  50. Drexler H, Hayoz D, Munzel D, Hornig B, Just H, Brunner HR, Zelis R. Endothelial function in chronic congestive heart failure. Am J Cardiol. 1992;69:1596-1601. [Medline] [Order article via Infotrieve]
  51. Rakusan K, Moravec J, Hatt PY. Regional capillary supply in the normal and hypertrophied rat heart. Microvasc Res. 1980;20:319-326. [Medline] [Order article via Infotrieve]
  52. Lorell BH. Left ventricular hypertrophy: the consequences for diastole. In: Gaasch WH, LeWinter MM, eds. Left Ventricular Diastolic Dysfunction and Heart Failure. Malvern, Pa: Lea & Febiger; 1994:345-353.
  53. De Bruyne B, Bronzwaer JGF, Heyndrickx GR, Paulus WJ. Comparative effects of ischemia and hypoxemia on left ventricular systolic and diastolic function in humans. Circulation. 1993;88:461-471.[Abstract/Free Full Text]



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