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Circulation. 1997;95:90-96

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(Circulation. 1997;95:90-96.)
© 1997 American Heart Association, Inc.

Articles

Dobutamine Enhances Cardiodepressant Effects of Receptor-Mediated Coronary Endothelial Stimulation

Jozef Bartunek, MD; Ajay M. Shah, MD, MRCP; Marc Vanderheyden, MD; Walter J. Paulus, MD, PhD

the Cardiovascular Center (J.B., M.V., W.J.P.), Aalst, Belgium, and Department of Cardiology (A.M.S.), University of Wales College of Medicine, Cardiff, United Kingdom.

Correspondence to Dr Walter J. Paulus, MD, PhD, Cardiovascular Center, O.L.V. Ziekenhuis, Moorselbaan 164, B9300 Aalst, Belgium (e-mail Walter.Paulus@ping.be) or to Dr Ajay M. Shah, MD, MRCP, Department of Cardiology, University of Wales, College of Medicine, Heath Park, Cardiff, CF4 4XN, UK (e-mail ShahAMZ@CF.AC.UK).


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
 down arrowDiscussion
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Background In humans, intracoronary infusion of substance P reduces left ventricular end-systolic pressure and left ventricular peak systolic pressure because of earlier onset of left ventricular relaxation induced by paracrine myocardial action of mediators released from the coronary endothelium. The present study investigated in humans the effects of ß-adrenergic stimulation, which also induces earlier left ventricular relaxation, on the left ventricular myocardial contractile response to intracoronary infusion of substance P.

Methods and Results Data were obtained in 13 patients after cardiac transplantation and in 3 patients with dilated nonischemic cardiomyopathy. Microtip left ventricular pressure recordings were obtained during a 5-minute intracoronary infusion of substance P (20 pmol/min) under control conditions and then repeated during concurrent intravenous administration of dobutamine. In the presence of dobutamine, intracoronary substance P caused a greater fall in left ventricular end-systolic pressure (transplantation control, -9±11 versus transplantation dobutamine, -20±18 mm Hg [P<.05]; cardiomyopathy control, -4±1 versus cardiomyopathy dobutamine, -10±3 mm Hg [P<.05]) and in left ventricular peak systolic pressure (transplantation control, -14±10 versus transplantation dobutamine, -30±22 mm Hg [P<.01]; cardiomyopathy control, -9±7 versus cardiomyopathy dobutamine, -15±6 mm Hg [P=.1]).

Conclusions Dobutamine enhances the cardiodepressant effect on myocardial contractile performance of receptor-mediated coronary endothelial stimulation in transplant recipients and in patients with dilated nonischemic cardiomyopathy. This enhancement could result from a potentiating interaction of the relaxation-hastening effect exerted by ß-adrenergic stimulation and by mediators released from the coronary endothelium, such as nitric oxide.


Key Words: endothelium • endothelium-derived factors • receptors, adrenergic, beta • myocardial contraction


*    Introduction
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 up arrowAbstract
 *Introduction
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 down arrowResults
 down arrowDiscussion
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In normal human subjects, bicoronary infusions of substance P induced a fall in LVPSP and LVESP with no change in LV dP/dtmax, an earlier onset of LV relaxation, and an increase in LV diastolic distensibility as evidenced by lower LV end-diastolic pressures at larger LV end-diastolic volumes and a downward displacement of individual diastolic LV pressure-volume relations.1 These effects were unrelated to peripheral vasodilatation because they were not reproduced by right atrial infusion of the same dose of substance P; they were also unrelated to autonomic nervous reflexes triggered by the intracoronary infusion of substance P, because they were also observed in transplant recipients1 with deficient afferent cardiac innervation.2 These effects were therefore attributed to substance P-induced coronary endothelial release and paracrine myocardial action of mediators such as NO. A similar cardiodepressant and LV relaxation–hastening effect was indeed previously observed during bicoronary infusion of the NO donor sodium nitroprusside.3

The present study investigates the effects of the ß-agonist dobutamine, which also hastens the onset of LV relaxation, on the LV contractile response to receptor-mediated coronary endothelial stimulation. High-fidelity tip-micromanometer LV pressures were recorded during intracoronary substance P infusion alone and during the concurrent administration of intravenous dobutamine. To minimize possible autonomic reflexes triggered by substance P acting on afferent nerve fibers of larger epicardial vessels, studies were performed in cardiac transplant recipients. To investigate the relevance of the present findings to LV dysfunction in heart failure, during which both adrenergic and NO synthase pathways are altered, studies were also performed in a limited group of patients with dilated nonischemic cardiomyopathy.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Patients
Transplant Recipients
Thirteen cardiac transplant recipients were studied at the time of annual follow-up catheterization and coronary angiography (5 women and 8 men; age range, 49 to 70 years; mean age, 59 years). Three patients were studied 2 years after transplantation, 5 patients 3 years after transplantation, 3 patients 4 years after transplantation, and 2 patients 6 years after transplantation. All patients were taking immunosuppressive therapy, which consisted of various combinations of cyclosporine, prednisolone, and azathioprine. Immunosuppressive and antihypertensive treatments were continued at the time of study. Antihypertensive treatment consisted of calcium channel blockers in 7 patients and angiotensin-converting enzyme inhibitors in 10 patients. Eleven patients had experienced previous (four or fewer) episodes of moderate to severe allograft rejection. LV angiography, which was performed after the study protocol in 12 patients, revealed normal LV end-diastolic volume index (60±16 mL/m2) and normal LVEF (75±10%) in all patients. Coronary angiography, which was performed before the study protocol, revealed angiographically normal coronary arteries without angiographic evidence of accelerated graft atherosclerosis.4

Patients With Dilated Cardiomyopathy
Three patients were studied at the time of diagnostic catheterization of the left and right sides of the heart and coronary angiography (one woman and two men; age range, 45 to 60 years; mean age, 52 years). Only diuretic therapy was continued at the time of study. LV angiography, which was performed after the study protocol, revealed LV end-diastolic volume index of 156±18 mL/m2 and LVEF of 28±12%, and coronary angiography revealed angiographically normal coronary arteries.

Study Protocol
Catheterization of the left and right sides of the heart was performed from the left and right femoral arteries and the right femoral vein. LV pressure was measured by use of a high-fidelity tip-micromanometer catheter inserted from the right femoral artery, calibrated externally against a mercury reference, and matched against luminal pressure. Right atrial pressure was measured by use of a Swan-Ganz catheter. All pressures were referenced to atmospheric pressure at the level of the midchest. Intracoronary infusion of substance P was performed with the use of a 4F left coronary catheter inserted from the left femoral artery and positioned in the left coronary ostium. Left coronary artery infusion resulted in homogenous delivery of substance P to the LV in 6 of the 13 transplant recipients and in 2 of the 3 dilated cardiomyopathy patients because of the presence of a left dominant coronary system.

The protocol is illustrated in Fig 1Down. The intracoronary infusion of substance P was progressively raised from a dose of 2.5 pmol/min to a dose of 20 pmol/min over a 1-minute period. A dose of 20 pmol/min1 5 6 was subsequently infused for a 5-minute period. Ten minutes after completion of the first intracoronary substance P infusion period, an intravenous infusion of dobutamine was started at a dose of 1 µg·kg-1·min-1 and progressively titrated upward to increase resting heart rate by 20 bpm. Once the target heart rate was attained, the infusion rate of dobutamine was maintained constant (transplant recipients, 4±2 µg·kg-1·min-1; dilated cardiomyopathy patients, 8±2 µg·kg-1·min-1) for a 5-minute period, at the end of which new baseline recordings were obtained. In one transplant recipient, two LV angiograms were obtained during intravenous dobutamine infusion (one before and one at the time of maximal effect of intracoronary substance P). The angiogram obtained at the time of maximal effect of intracoronary substance P influenced subsequent hemodynamic changes. The data obtained in this patient were therefore excluded from the data analysis of the TableDown and were only used to construct the LV pressure-volume loops shown in Fig 2Down.



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  		Figure 1. Outline of study protocol showing timing of intracoronary substance P infusions (SP-IC) and timing of intravenous dobutamine administration. LVP indicates LV pressure; RAP, right atrial pressure.


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  		Table 1. Effects of Intravenous Dobutamine on LV Function and on Changes in LV Function During and After Intracoronary Infusion of Substance P in Transplant Recipients



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  		Figure 2. LV pressure (LVP)-volume (LVV) loops obtained during intravenous dobutamine infusion before ({blacksquare}) and during ({square}) intracoronary substance P infusion in one transplant recipient.

Informed consent was obtained from all patients. The study was approved by the local ethics committee, and there were no complications related to procedure or study protocol.

Data Analysis
LV volumes and LVEF were derived from single-plane LV angiograms by use of the area-length method and a regression equation.7 LV pressure-volume relations (Fig 2Up) were constructed by matching corresponding points of LV pressure and volume by use of a cine frame marker. The time constant of LV pressure decay ({tau}) was calculated from the digitized pressure data points of isovolumic LV relaxation with the use of an exponential curve fit with zero asymptote pressure.8 With the use of spontaneous beat-by-beat alterations in LVESP, the slope (R) of a {tau} versus LVESP relation9 was calculated in baseline conditions, at the time of maximal effect of intracoronary substance P, during intravenous dobutamine at the time of new baseline recordings, and during intravenous dobutamine at the time of maximal effect of intracoronary substance P. The duration of LVEST, which indicated the time to onset of LV relaxation, was measured as the interval from the Q wave on the ECG to the moment of LV dP/dtmin. Data were analyzed by use of a repeated measures ANOVA followed by a multiple comparison test (Student-Newman-Keuls test).


*    Results
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 up arrowMethods
 *Results
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Effects of Intracoronary Substance P Infusion on LV Hemodynamics
The TableUp shows changes in LV hemodynamics during and after the control intracoronary substance P infusion in the transplant recipient group (n=12). Figs 3 through 6DownDownDownDown show changes in LVPSP, LVESP, LV dP/dtmin, and LVEST, respectively, in the transplant recipient group at the time of maximal effect (which occurred after 2.2±0.6 minutes), at the end of the 5-minute intracoronary substance P infusion, and 5 minutes after cessation of the intracoronary substance P infusion. At the time of maximal effect, there was no significant change in R (control, -0.1±0.3 ms/mm Hg; substance P, 0.0±0.4 ms/mm Hg). In the dilated cardiomyopathy group (n=3), intracoronary substance P resulted in falls in heart rate (-5±5 bpm; P=NS), LVPSP (-9±7 mm Hg; P=NS), LVESP (-4±1 mm Hg; P<.05), LVEST (-3±18 ms; P=NS), and {tau} (-4±1 ms; P<.05) at the time of maximal effect (after 2.4±0.2 minutes of infusion).



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  		Figure 3. Changes observed in the transplant recipient group in LVPSP ({Delta}LVPSP) (mean±95% CI) during intracoronary substance P infusion (IC SP Inf) at the time of maximal effect, at the end of the 5-minute intracoronary infusion period, and 5 minutes after cessation of the intracoronary infusion in control conditions (Control) and after intravenous pretreatment with dobutamine (IV Dob Inf). *P<.05 IV Dob Inf vs Control; {dagger}P<.01 IV Dob Inf vs Control.



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  		Figure 4. Changes observed in the transplant recipient group in LVESP ({Delta}LVESP) (mean±95% CI) during intracoronary substance P infusion (IC SP Inf) at the time of maximal effect, at the end of the 5-minute intracoronary infusion period, and 5 minutes after cessation of the intracoronary infusion in control conditions (Control) and after intravenous pretreatment with dobutamine (IV Dob Inf). *P<.05 IV Dob Inf vs Control.



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  		Figure 5. Changes observed in the transplant recipient group in LV dP/dtmin ({Delta}LVdP/dt min) (mean±95% CI) during intracoronary substance P infusion (IC SP Inf) at the time of maximal effect, at the end of the 5-minute intracoronary infusion period, and 5 minutes after cessation of the intracoronary infusion in control conditions (Control) and after intravenous pretreatment with dobutamine (IV Dob Inf). {ddagger}P<.001 IV Dob Inf vs Control.



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  		Figure 6. Changes observed in the transplant recipient group in LVEST (time to onset of LV relaxation) ({Delta}LVEST) (mean±95% CI) during intracoronary substance P infusion (IC SP Inf) at the time of maximal effect, at the end of the 5-minute intracoronary infusion period, and 5 minutes after cessation of the intracoronary infusion in control conditions (Control) and after intravenous pretreatment with dobutamine (IV Dob Inf).

Effects of Intravenous Dobutamine on LV Hemodynamics
The effects of intravenous dobutamine on LV hemodynamics in the transplant recipients are shown in the TableUp. R (0.0±0.3 ms/mm Hg) remained unaltered during intravenous dobutamine. In the cardiomyopathy group, intravenous dobutamine caused rises in LV dP/dtmax (from 1217±535 to 1597±764 mm Hg/s; P<.05) and LV dP/dtmin (from 1127±465 to 1453±531 mm Hg/s; P<.05) and falls in LVEDP (from 22±10 to 13±8 mm Hg; P<.05) and {tau} (from 69±14 to 50±15 ms; p<.01).

Effects of Intracoronary Substance P Infusion on LV Hemodynamics During Intravenous Dobutamine Infusion
The TableUp and Figs 3 through 6UpUpUpUp show changes in LV hemodynamics during and after the intracoronary substance P infusions under control conditions and in the presence of intravenous dobutamine in the transplant recipients. During concurrent intravenous dobutamine, intracoronary infusion of substance P caused maximal effects after 2.5±1.0 minutes. At the time of maximal effects, there was no change in R (0.1±0.6 ms/mm Hg). The maximal changes in LVPSP and LV dP/dtmin observed with intracoronary substance P after intravenous pretreatment with dobutamine were significantly larger than the maximal changes of the same hemodynamic variables observed during intracoronary substance P alone. Fig 2Up shows LV pressure-volume loops obtained in one patient during intravenous dobutamine before and at the time of maximal effect of intracoronary substance P. Intracoronary substance P during intravenous dobutamine resulted in a downward displacement of the LV end-systolic pressure-volume point, consistent with reduced LV systolic performance,10 and a rightward shift of the diastolic LV pressure-volume relation, consistent with increased LV diastolic distensibility. The changes observed at the end of the 5-minute intracoronary substance P infusion in LVPSP, LVESP, and LV dP/dtmin were significantly larger after pretreatment with intravenous dobutamine than in the control run. Five minutes after cessation of intracoronary substance P subsequent to pretreatment with dobutamine, LVPSP and LVESP were still significantly lower than baseline values. These reductions in LVPSP and LVESP were significantly different from the small rise observed in the same hemodynamic variables 5 minutes after cessation of the intracoronary substance P infusion in the control run. In the dilated cardiomyopathy group, intracoronary substance P in the presence of intravenous dobutamine resulted in significant (P<.05) falls in LVPSP (-15±6 mm Hg), LVESP (-10±3 mm Hg), and LVEDP (-5±2 mm Hg) at the time of maximal effect (after 2.4±0.2 minutes of infusion). Compared with the control intracoronary substance P infusion, intracoronary substance P in the presence of intravenous dobutamine resulted in larger falls in LVESP (P<.05), LVPSP (P=.10), and LVEST (-15±13 ms; P<.05).


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
Myocardial Contractile Response to Coronary Endothelial Stimulation
The main finding of the present study is that ß-adrenoceptor stimulation potentiates the cardiodepressant effect of substance P–induced coronary endothelial stimulation in human cardiac transplant recipients and in dilated cardiomyopathy patients. On the basis of the data from a previous study,1 which showed significant changes in LV function only during intracoronary but not during right atrial infusion of the dose of substance P used in the present study, the changes in LV function observed in the current study are consistent with direct myocardial effects of coronary endothelial stimulation, probably mediated by an interaction between the ß-adrenergic system, and substances released from the endothelium. Because of previous experimental studies, which observed similar changes in LV contractile performance during intracoronary infusion of substance P and reversal of these changes after inhibition of NO activity,11 the LV contractile response observed in the present study during the intracoronary substance P infusion could be attributed to a direct myocardial effect of NO released by substance P from the coronary endothelium.

The direct effects of NO on myocardial contractile function and their subcellular mechanism have been the subject of intense recent investigation in different species, in different experimental preparations, and in the presence or absence of ß-adrenergic stimulation.12 In general, the studies can be divided into those that have investigated (1) the effects of endothelium-derived NO, NO donors, or cGMP analogues on basal cardiac function and (2) the interactions between NO/cGMP and the ß-adrenergic pathway.

Under basal conditions, studies in several different species and preparations indicate that endothelium-derived NO, NO donors, or cGMP analogues induce an earlier onset of myocardial relaxation with a reduction of peak performance and no change in isometric dF/dtmax or LV dP/dtmax.12 This "relaxant" effect has been observed in isolated rat cardiac myocytes,13 in ferret14 15 and cat16 papillary muscles, in isolated ejecting guinea pig hearts,11 17 and in human subjects undergoing cardiac catheterization.1 3 On the basis of studies in isolated single cardiomyocytes13 and skinned porcine18 and human19 cardiac fibers, this relaxant effect has been attributed to a reduction in myofilament responsiveness to calcium secondary to an NO-induced elevation of myocardial cGMP and activation of cGMP-dependent protein kinase. Other studies in hamster papillary muscles20 and isolated rat myocytes21 did not specifically look at the relaxation or relengthening phase but reported a similar reduction in frequency-dependent potentiation of contractile performance by basal NO production, which was reversed after administration of NO synthase inhibitors.

Studies by Balligand et al22 23 indicate that NO produced within isolated adult rat cardiac myocytes modulates the inotropic response to ß-adrenergic stimulation. Blockade of myocardial constitutive NO synthase by N{omega}-nitro-L-arginine potentiated the positive inotropic response to the ß-agonist isoproterenol. In the same preparation, induction of inducible NO synthase by specific inflammatory cytokines also resulted in a depressed positive inotropic response to isoproterenol.24 The mechanism of this effect has been considered to be a cGMP-mediated stimulation of phosphodiesterase with a consequent reduction in cAMP levels. Exogenous NO donors have also been reported to reduce cAMP-stimulated sarcolemmal calcium influx in guinea pig25 and frog26 cardiomyocytes. Other studies suggest the potential for positive inotropic actions of NO, probably mediated by a cGMP-induced inhibition of phosphodiesterase with a consequent increase in cAMP levels. In human atrial cardiomyocytes,27 low doses of an NO donor increased basal calcium current. In cat papillary muscles16 and isolated rat ventricular myocytes,28 low doses of NO donor had a positive inotropic action whereas high doses had a cardiodepressant and relaxant16 action similar to that described above. This concentration-dependent transition from a positive to a negative inotropic effect of the NO donor in cat papillary muscles was influenced by concurrent administration of isoproterenol in that the presence of isoproterenol caused this transition to occur at a lower concentration of the NO donor.16 On the other hand, no positive inotropic actions were observed with low doses of exogenous NO donors or endothelium-derived NO in isolated guinea pig hearts11 17 or with the exogenous NO donor sodium nitroprusside in normal human subjects.3 Inhibition of basal NO activity by NO synthase inhibitors in isolated rat cardiomyocytes,22 23 in dogs in vivo,29 and in human subjects with LV dysfunction30 also failed to reveal negative inotropic effects, as would be expected if NO had a basal positive inotropic action in these settings.

In the present study, the LV cardiodepressant effect of substance P was markedly potentiated by concurrent ß-adrenergic stimulation. The underlying subcellular mechanism remains speculative. Possible mechanisms include either an enhanced negative inotropic action of NO or a reduced positive inotropic action of NO. The greater cardiodepression during dobutamine could have resulted from a greater reduction in myofilament responsiveness to calcium secondary to the combination of cGMP-dependent protein kinase action and cAMP-induced phosphorylation of troponin I and C proteins.31 Consistent with such a mechanism, the pattern of response to intracoronary substance P, characterized by reduced LVPSP and LVESP and earlier onset of LV relaxation, was similar both in the presence and absence of dobutamine. Alternatively, a reduced positive inotropic action could have resulted from a cGMP-induced decrease in dobutamine-stimulated cAMP level secondary to changes in phosphodiesterase activity and a consequent decrease in cytosolic calcium transients. With such a mechanism, the overall pattern of effect of substance P would be expected to change, which was not observed. Additional possibilities include other cGMP-mediated actions of NO12 or non–cGMP-mediated, non–cAMP-mediated actions of NO on excitation-contraction coupling processes32 or on energetic pathways.33

Study Limitations
The LV contractile response observed in the present study during the intracoronary substance P infusion was attributed mainly to a direct myocardial effect of NO released by substance P from the coronary endothelium because of previous experimental studies, which observed similar changes during intracoronary infusion of substance P and reversal of these changes after inhibition of NO activity.11 Definitive proof that NO mediated the LV contractile response to substance P in the present study would have necessitated the concomitant intracoronary infusion of a NO synthase inhibitor. Therefore, the potential contribution to the observed changes in LV contractile performance by endothelially released cardioactive factors other than NO cannot be excluded.

Substance P and other vasoactive neuropeptides have been identified previously in afferent nerve fibers supplying the cardiovascular system,34 and both substance P and NO have been shown to modulate afferent activity of arterial baroreceptors.34 35 Apart from interfering with the afferent arm of vagal reflexes, NO also mediates efferent vagal coronary vasodilation resulting from both cardiac sensory receptors (Bezold-Jarisch reflex) and carotid chemoreflexes.36 To avoid changes in LV performance secondary to autonomic reflexes induced by the intracoronary infusion of substance P, the present observations were performed in cardiac allograft recipients. A recent study2 that specifically looked at the Bezold-Jarisch reflex in transplant recipients failed to demonstrate reinnervation of ventricular chemosensory endings subserved by vagal afferents up to 74 months after transplantation. The use of transplant recipients as a model of deficient cardiac innervation is, however, subject to criticism because of numerous reports that demonstrate time-dependent sympathetic37 38 39 40 and even sensory41 reinnervation after cardiac transplantation. In the present study, the rise in heart rate observed in the transplant recipients during the intracoronary substance P infusion could have resulted from partial sympathetic reinnervation and a baroreceptor reflex triggered by the fall in aortic pressure during the intracoronary substance P infusion.

Caution should be exercised in extrapolating the results of the present study performed in cardiac allograft recipients to normal subjects. Significant alterations of sarcolemmal receptors and signal transduction pathways have been reported after cardiac transplantation, eg, upregulation of ß2- but not of ß1-receptors.42 In isolated human cardiomyocytes, the positive inotropic response to ß2-adrenergic stimulation is apparently not mediated by increases in cAMP or in cAMP-dependent phosphorylation of phospholamban.43 Because of the high content of ß2-receptors in transplanted myocardium, dobutamine could have exerted part of its positive inotropic effect through non–cAMP-dependent mechanisms, and this specific mode of action could have interfered with the results of the present study. Apart from alterations in the myocardium, the cardiac allograft is also affected by coronary endothelial dysfunction, resulting in a reduced response to receptor-mediated stimulation.44 In our previous study on the LV myocardial contractile response to intracoronary substance P,1 the hemodynamic changes observed were similar in normal subjects and transplant recipients free of rejection or graft vasculopathy, although the numbers studied were not large enough to exclude with certainty small differences between groups.

In 6 of 13 transplant recipients and in 2 of 3 dilated cardiomyopathy patients, left coronary infusion of substance P probably resulted in a homogeneous delivery of the drug throughout the LV myocardium because of the presence of a left-dominant coronary system. In the other patients, who had right-dominant coronary systems, left coronary infusion of substance P failed to affect portions of the LV perfused by the right coronary artery, and this could have resulted in nonuniform effects on LV function. However, we observed similar effects in both groups of patients; furthermore, any nonuniform effect of intracoronary substance P would have influenced LV performance similarly with or without intravenous dobutamine.

In the transplant recipient group of the present and previous1 studies, we observed during intracoronary infusion of substance P an earlier onset of LV relaxation, no change in LV pressure decay rate as evidenced by the constancy of {tau}, and increased LV diastolic distensibility. An earlier onset of LV relaxation, which probably resulted from a cGMP-induced reduction of myofilamentary calcium sensitivity, qualifies as a positive relaxant or lusitropic effect because it prolongs diastole and facilitates LV filling. The constancy of {tau} in the transplant recipients could have resulted from balancing effects of reduced LVESP and altered myofilamentary calcium sensitivity. In the normal heart, LV pressure decay rate is insensitive to LVESP and the slope (R) of the LVESP-{tau} relation therefore equals zero.45 In the cardiac allograft, LV end-systolic load reduction as a result of arterial vasodilation prolongs {tau}.46 This finding is consistent with the slightly negative baseline value of R observed in the present study and could explain the constancy of {tau} during intracoronary infusion of substance P by balancing the effects of LV end-systolic load reduction and altered myofilamentary calcium sensitivity. This explanation could be further validated through investigation of LVESP-{tau} relations before and during intracoronary infusion of substance P by use of balloon occlusions of the inferior vena cava to widen the range of LVESP. In the failing heart, lower LVESP accelerates LV pressure decay, and this results in a positive value of R.9 45 In the dilated cardiomyopathy group of patients in the present study, intracoronary infusion of substance P caused a significant reduction in {tau}, probably as a result of this altered load sensitivity of the failing LV. The increase in LV diastolic distensibility observed during intracoronary infusion of substance P in the present and previous studies1 could be explained by cGMP-induced reduction in myofilament response to calcium, which reduces resting or diastolic tone.3 12 13

Clinical Relevance
The larger cardiodepressant effect of endogenous NO during ß-adrenergic stimulation could be relevant to LV dysfunction in heart failure because of recent demonstration of inducible NO synthase activity in endomyocardial biopsy samples of patients with dilated cardiomyopathy47 and because of the presence of both elevated plasma nitrate48 49 and plasma catecholamine50 levels in higher symptomatic classes of heart failure. Whether the beneficial effect of ß-adrenergic blockers in patients with dilated cardiomyopathy and heart failure51 might in part involve the NO pathway (eg, a reduced cardiodepressant effect) is an intriguing question that could be addressed in future studies. Although the present study confirms the observations made in the transplant recipients in a smaller group of dilated nonischemic cardiomyopathy patients, extrapolation of the present results to heart failure warrants caution because of alterations in myocardial and endothelial functions, which have been recognized to occur in failing myocardium. cAMP production is impaired despite elevated levels of circulating catecholamines,52 and abnormalities have been found at several levels of the ß-adrenoceptor signal transduction pathway.53 Sarcoplasmic reticulum calcium handling is also impaired, resulting in a flattened myocardial force-frequency relation54 and a blunted adrenergic amplification of this relation.55 Moreover, the phenotype of intramyocardial endothelial cells in failing hearts is also altered.56

Conclusions
In the present study on cardiac transplant recipients and dilated cardiomyopathy patients, concurrent treatment with intravenous dobutamine markedly potentiated the cardiodepressant effect on LV contractile function of receptor-mediated coronary endothelial stimulation by substance P. This larger cardiodepressant effect during intracoronary substance P infusion was evidenced by a larger fall in LVPSP and LVESP, which probably resulted from a potentiating interaction of the relaxation-hastening effect exerted by ß-adrenergic stimulation and by mediators released from the coronary endothelium, such as NO.


*    Selected Abbreviations and Acronyms
 
{tau} = time constant of left ventricular pressure decay
LV = left ventricular, left ventricle
LVEF = left ventricular ejection fraction
LVESP = left ventricular end-systolic pressure
LVEST = left ventricular electromechanical systole time (time to onset of left ventricular relaxation)
LVPSP = left ventricular peak systolic pressure
NO = nitric oxide
R = slope of {tau} versus left ventricular end-systolic pressure relation


*    Acknowledgments
 
Dr Shah is supported by a UK Medical Research Council Senior Clinical Fellowship.

Received April 25, 1996; revision received July 26, 1996; accepted August 19, 1996.


*    References
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 up arrowDiscussion
 *References
 

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