role of adrenoceptors and dopamine receptors in modulating ... · while dobutamin hae oftes th...

126

Role of Adrenoceptors and DopamineReceptors in Modulating Left Ventricular

Diastolic FunctionRoberto M. Lang, John D. Carroll, Shigeru Nakamura, Haruki Itoh, and Sol I. Rajfer

Although both dopamine and dobutamine are potent positive inotropic agents, multiplestudies indicate that dopamine may produce a rise in left ventricular (LV) filling pressure,while dobutamine often has the opposite effect. To ascertain the pharmacological andhemodynamic mechanisms responsible for the elevation in LV filling pressure observed withdopamine, we administered incremental infusions (2, 4, and 6 /tg/kg/min) of dopamine to 18open-chest, anesthetized dogs in the presence and absence of rauwolscine (selectivearadrenoceptor antagonist) (n = 7), terazosin (selective a,-antagonist) (n = 6), and domperi-done (selective dopamine2 antagonist) (n = 5), while measuring pressures in the LV and leftatrium and changes in dimension in the LV short-axis (with ultrasonic piezo crystals).Dobutamine (2, 4, and 6 /ig/kg/min) was infused in five additional dogs before and afteradministration of rauwolscine. The time constant of isovolumic pressure decay, peaklengthening rate (mm/sec), LV end-diastolic pressure, and diastolic pressure-dimensionrelation were computed. A significant elevation in LV end-diastolic pressure and a parallelincrease in LV end-diastolic chamber size was observed with dopamine, while a decline inLV end-diastolic pressure occurred with dobutamine. Yet both dopamine and dobutaminecaused a dose-related acceleration of pressure decay and augmentation of peak lengtheningrate. Furthermore, heart rate declined during the administration of dopamine but rosewith dobutamine. In the presence of either rauwolscine or terazosin, dopamine infusionresulted in a positive chronotropic effect and dose-dependent reductions in LV end-diastolicpressure and end-diastolic chamber dimension; arterial pressure fell only after terazosinadministration. The hemodynamic actions of dobutamine, however, were unchanged in thepresence of rauwolscine. Moreover, domperidone did not alter the hemodynamic responsesto dopamine. The results of the present study suggest that activation of prejunctionala2-adrenoceptors and postjunctional a,- and a2-adrenoceptors play an important role indetermining the hemodynamic responses to dopamine. The rise in LV filling pressureproduced by dopamine can be attributed to venoconstriction resulting from stimulation ofpostjunctional a,- and arreceptors. The decrease in heart rate observed with dopamine mayalso contribute toward the development of elevated LV filling pressures. (CirculationResearch 1988;63:126-134)

From the Section of Cardiology and Committee on ClinicalPharmacology, Departments of Medicine and Pharmacologicaland Physiological Sciences, The University of Chicago, Chicago,Illinois.

This manuscript from The University of Chicago was sent toJohn T. Shepard, Consulting Editor, for review by expertreferees, for editorial decision, and for final disposition.

Supported by National Institutes of Health National ResearchService award training grant HLO-7237 (R.M.L.) and by grantHL-35480 from the National Institutes of Health (S.I.R.). Thiswork was completed during Dr. Carroll's tenure as a MellonFoundation Fellow and an Amoco Foundation Scholar.

Address for reprints: John D. Carroll, MD, Cardiology Section(Box 124), The University of Chicago, 5841 South MarylandAvenue, Chicago, IL 60637.

Received July 13, 1987; accepted February 8, 1988.

Many clinical studies in congestive heart fail-ure have documented that dopamine fre-quently causes no reduction or an increase

in left ventricular (LV) filling pressure despite itspositive inotropic action.1-7 In contrast, the admin-istration of dobutamine may be associated with areduction in LV filling pressure.'-*-8-10 Dobutamineis a full agonist at the /3radrenoceptor site (positiveinotropic action) and possesses weak activity at theft-adrenoceptor (produces vasodilation) and ar

adrenoceptor sites (subserves vasoconstriction)11;thus, hemodynamic responses to dobutamine areessentially the result of its cardiotonic action medi-

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Lang et al Effects of Dopamlne and Dobutamine on Diastolic Function 127

TABLE 1. Hemodynamic Responses to Dopamine Infusion Before and After Rauwolsdne

Dopamine

Control 2 figControl postrauwolscine

Dopamine + rauwolscine

101 ±6t

94±6

5.2+1

4.9 ±0.9

107±6t

91 ±5*

142±9*t 155:

96±22 100:

5.0±0.9 4.6±0.8*t 4.6:

4.7±0.8 4.2±0.8** 3.8:

Heart rate(beats/min) 88±4 83±6 72±5* 68±5*

Aortic meanpressure (mm Hg) 89±10 84±9* 92+12 104±14*

Left ventricularend-diastolicpressure (mm Hg) 4.8±0.8 5.6 + 0.9 6.9±1* 7.1 ±0.9*

Mean left atrialpressure (mm Hg) 4.6±0.9 4.9±0.9 5.7±1.2 6.1 ±0.8*

End-systolicdimension (cm) 2.82±0.34 2.77±0.34 2.76±0.35 2.59±0.4*

End-diastolicdimension (cm) 3.57±0.43 3.59±0.43 3.66±0.42* 3.61 ±0.5

Peak positive dP/dt(mmHg/sec) 3,031 ±210 3,127±224 4,267±63O* 6,007± 1,030* 3,299±151 4,062±648 5,883±765** 8,770

Peak lengtheningrate (mm/sec) 222 ±61 226 ±66 265 ±69* 300 ±70* 223 ±60 254 ±59* 265 ±57* 292

Time constant ofpressure decay(msec) 27±1.9 25.2±1.7 23±1.3 20.9±1.8* 26.3±2.1 23 ± 1.6* 18.3 =t 1.5** 14.6

2.82±0.35 2.76±0.35 2.66±0.32* 2.47:

3.58±0.43 3.53±0.44 3.47±0.42 3.30:

:9*t

14

1.1**

1.0**

0.35*

0.45**

1,100**

56*

±2.2**

All values are mean±SEM; n = l.*/?<0.017 for the differences from control values; tp<0.01 for the differences from the equivalent dose of dopamine, and *p<0.05.

ated by activation of /3,-adrenoceptors. Dopamineinfluences the cardiovascular system by actingdirectly on /3,-adrenoceptors, a-adrenoceptors, anddopamine receptors (produces vasodilation) and byacting indirectly by releasing norepinephrine fromsympathetic nerve endings.712-14 Activation of pre-junctional aradrenoceptors and doparnine^-receptorscan lead to a decrease in norepinephrine release fromsympathetic nerve terminals.13-16 The rise in LVfilling pressure occurring with dopamine has gener-ally been attributed to LV dilatation from an increasein LV afterload secondary to activation of postjunc-tional a-adrenoceptors on arterial vessels.1 How-ever, the relation between the elevation in LV fillingpressure and changes in the diastolic properties ofthe LV have not been assessed. In the present study,we examined the effects of dopamine and dobutamineon LV systolic and diastolic function and attempted todefine the pharmacological mechanisms responsiblefor differential responses to these two drugs.

Materials and MethodsSurgical Preparation and Instrumentation

Twenty-three adult mongrel dogs, weighing 21-32kg, were anesthetized with morphine, 5 mg/kg s.c,followed by administration of a-chloralose, 100mg/kg i.v. After endotracheal intubation, ventila-tion was maintained with a Harvard respirator (SouthNatick, Massachusetts). A median sternotomy wasperformed, and the heart was suspended in a peri-cardial cradle. Systemic arterial pressure was mea-sured with a fluid-filled catheter positioned in theleft femoral artery and with a Statham strain-gaugetransducer (model P23ID, Los Angeles, California).LV and left atrial pressures were measured with

high-fidelity micromanometer-tipped catheters(Millar Instruments, Houston, Texas) inserted ret-rogradely from the right femoral artery and ante-gradely from the pulmonary veins, respectively.Before insertion, both micromanometer-tipped cath-eters were calibrated at 37° C with a mercury manom-eter. Ultrasonic piezo crystals (2.5 mm diameter;Triton Technology, San Diego, California) weresutured against the endocardium through stab inci-sions and positioned perpendicular to the long axisof the LV, midway between the apex and the baseof the heart; they were used for continuous mea-surements of LV short-axis dimension. The electro-cardiogram, body temperature, and arterial oxygentension were monitored throughout the study.

LV peak systolic and diastolic pressures, sys-temic arterial pressure, left atrial pressure, instan-taneous peak positive change in LV pressure withtime (dP/dt), and LV internal dimensions wererecorded with a Hewlett-Packard eight-channel ink-pen recorder (Waltham, Massachusetts) at 25, 50,and 100 mm/sec.

Drug ProtocolEighteen dogs received incremental infusions of

dopamine (2, 4, and 6 jig/kg/min) before and 30minutes after the intravenous administration of oneof the following antagonists: the selective a2-adrenoceptor antagonist rauwolscine (0.3 mg/kg,n = 7)17; the selective a,-adrenoceptor antagonistterazosin (0.3 mg/kg, n = 6)18; or the selectivedopamine2-antagonist domperidone (40 /xg/kg,n = 5).19 Five dogs received incremental infusions ofdobutamine (2, 4, and 6 /xg/kg/min) before and 30minutes after the intravenous administration of rau-



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128 Circulation Research Vol 63, No 1, July 1988

TABLE 2. Hemodynamk: Responses to Dopamlne Infusion Before and After Terazosin

Dopamine

ControlControl post

terazosin

Dopamine + terazosin

6/ig

Heart rate(beats/min) 97±I2 88 ± 11* 82 ± 11 * 75±9* 126± 13t 132 =t l i t 142±12*t 151±16*t

Aortic meanpressure (mm Hg) 89±7 84±7* 89±6 94±4* 83±5t 79±6*i 78 + 6*t 78±6*t

Left ventricularend-diastolicpressure (mm Hg) 4.7±0.7 5.0±0.5 5.9±0.7* 6.6±0.8* 4.9±0.5 4.4±0.6 4.l+0.6*t 3.5±0.5*t

Mean left atrialpressure (mm Hg) 2.3±0.5 2.3±0.4 2.6±0.4* 2.8±0.5* 1.9±0.3 1.8±0.4 1.8±0.3t 1.9±0.4t

End-systolicdimension (cm) 3.11 ±0.34 3.07±0.33 2.89±0.35* 2.79±0.29* 2.99 + 0.34* 2.95±0.33* 2.93 + 0.33* 2.89±0.34*

End-diastolicdimension (cm) 3.93±0.38 3.92±0.37 4.06±0.39* 4.10±0.38* 3.74 + 0.37 3.64±0.36* 3.59 + 0.37*t 3.56±0.38*+

Peak positive dP/dt(mm Hg/sec) 2,459±286 2,520 + 272 3,149±458* 3,979±515* 2,742±256 2,730±265 3,493 + 470* 4,776±305*

Peak lengtheningrate (mm/sec) 248±49 295±5I* 319±55* 469±53* 255±50 270±51 289 + 50* 307±56*

Time constant ofpressure decay(msec) 22.7 ±1.3 21.6±1.6 20.8±2 19.3±1.6* 21.4±1.6 19.6 + 0.6 16.9+1.1* 14.2 + 0.9*

All values are mean + SEM; n = 6.*p<0.017 for the differences from control values; tp<0.01 for the equivalent dose of dopamine; and tp<0.05.

wolscine (0.3 mg/kg). The doses used for rauwol-scine and terazosin have been determined previ-ously in our laboratory to provide selective a2- anda,-adrenoceptor antagonism, respectively.20 Thedose of domperidone almost eliminated the declinein arterial pressure induced by the selectivedopamine^-agonist A/,Af-di-n-propyldopamine,21 50fig/kg i.v. Before administration of any drugs, a30-minute control period was allotted to ensurehemodynamic stability. Baseline hemodynamic mea-surements were then obtained. Thereafter, a gradedinfusion of dopamine or dobutamine was adminis-tered at rates of 2, 4, and 6 /xg/kg/min. The infusionrate was increased at 15-minute intervals; hemody-namic measurements were obtained just before eachincrement in dosage and 15 minutes after the peakinfusion rate was achieved. After the drug infusionwas completed and hemodynamic parameters returnedto baseline (minimum of 15 minutes), the antagonistwas administered; 30 minutes later, the incrementalinfusion of dopamine or dobutamine was repeated.Persistent blockade by the antagonist for the durationof the experiment was documented by monitoring theresponse to the appropriate agonist after the finalinfusion of dopamine or dobutamine.

Data AnalysisThe electrocardiogram, LV systolic and end-

diastolic pressures, systemic arterial pressure, meanleft atrial pressure, instantaneous peak positivedP/dt, and LV end-diastolic and end-systolic cham-ber dimensions were measured directly from thetracings. The time constant of LV isovolumic pres-sure decay was computed as the negative reciprocalof the slope of the linear regression line describing

the relation between the natural logarithm of LVpressure and time.22-23 Peak LV diastolic lengthen-ing rate was calculated as the maximal rate ofchange in dimension measured by the endocardialpiezo crystals during diastole.

At each dose of dopamine and dobutamine, adiastolic pressure-dimension relation was con-structed from simultaneous pressure and dimensioncoordinates determined at 5-msec intervals fromtracings recorded at a paper speed of 100 mm/sec.

Statistical AnalysisAll values are expressed as mean ± SEM. Statis-

tical analyses involving comparisons of control withposttreatment data were performed with the Stu-dent's t test for paired samples and then by usingthe Bonferroni correction for multiple comparisons.Statistically significant differences were accepted ata p value less than 0.05/K, where K = number ofcomparisons. Comparisons of data obtained afterthe administration of rauwolscine and terazosinwere performed with the t test for unpaired sam-ples, and statistical significance was accepted at apvalue less than 0.05.

ResultsHemodynamic Responses to Dopamine

The hemodynamic data obtained before and afterincremental infusions of dopamine are depicted inTables 1 and 2. The infusion of dopamine resulted ina significant dose-related negative chronotropic effect(Figure 1). This was accompanied by a small butsignificant decrease in mean aortic pressure at aninfusion rate of 2 /ig/kg/min; as the infusion rate



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Lang et al Effects of Dopamine and Dobutamine on Diastolic Function 129

HEART RATE PEAK dP/dtp<0.01

oo

uio

Uloa.u0.

701

60-

50-

40-

30-

20-

10-

-10-

-20-

-30 J

Ifr p<0.017 vs CTR

# p<0.05 vs DAp<0 05

it*

u

X

DA2 DA4 ? A O

FIGURE 1. Bar graph depicting percent change in heartrate during dopamine infusion before and after rauwol-scine and terazosin. Dopamine infusion resulted in adose-dependent negative chronotropic effect. In the pres-ence of rauwolscine or terazosin, dopamine produced adose-related increase in heart rate. This augmentation inheart rate was greater after rauwolscine than terazosin.CTR, control; DA, dopamine; R, rauwolscine; T, terazo-sin; DA2, 4, and 6, dopamine at 2, 4, and 6 fig/kg/min,respectively.

was increased further, mean aortic pressure rosegradually and was elevated above control values atthe 6 pig/kg/min rate.

Dopamine augmented overall LV systolic per-formance as evidenced by a progressive increase inpeak positive dP/dt (Figure 2). It also produced anelevation in LV end-diastolic chamber dimension,which occurred in parallel with a rise in LV end-diastolic pressure. The increase in LV end-diastolicpressure and mean left atrial pressure occurreddespite accelerated pressure decay and a reductionin end-systolic chamber dimension. In Figure 3A,the LV diastolic pressure-dimension relation beforeand after dopamine (6 /Ag/kg/min) is shown for arepresentative experiment. In early diastole, dopa-mine caused a leftward and downward shift becauseof reduced end-systolic chamber size and reducedLV pressure relative to chamber dimension. In latediastole, the administration of dopamine resulted inan increase in LV end-diastolic dimension accompa-nied by an elevation in LV end-diastolic pressure.

Effects of Rauwolscine and Terazosin onHemodynamic Responses to Dopamine

The effects of rauwolscine and terazosin on thehemodynamic responses to dopamine are depictedin Tables 1 and 2 and Figures 1, 2, 4, and 5.

DA2 DA6

FIGURE 2. Bar graph depicting percent change in peakpositive dPIdt during dopamine infusion before and afterrauwolscine and terazosin. Dopamine infusion resulted ina dose-dependent augmentation of peak positive dPIdt.Terazosin did not alter the augmentation in peak positivedPIdt evoked by dopamine. In contrast, the increase inpeak positive dPIdt elicited by dopamine was significantlygreater in the presence of rauwolscine. DA, dopamine; R,rauwolscine; T, terazosin; CTR, control; and DA2, 4, and6, dopamine at 2, 4, and 6 pg/kg/min, respectively.

Before the infusion of dopamine, the administra-tion of rauwolscine elicited an increase in heart ratefrom 88±4 to 10l±6 beats/min (/?<0.01); otherhemodynamic variables did not change signifi-cantly. In the presence of rauwolscine, dopamineproduced a further increase in heart rate and agreater augmentation in peak positive dP/dt. Meanaortic pressure fell slightly at an infusion rate of 2/ig/kg/min but exhibited no significant change fromcontrol values at higher infusion rates. In contrastto measurements obtained before the administra-tion of rauwolscine, LV end-diastolic and left atrialpressures declined with dopamine. The increase inpeak lengthening rates and reduction in the timeconstant of pressure decay induced by dopaminepersisted after rauwolscine administration, thechange in the latter parameter actually being moreexaggerated.

Before the infusion of dopamine, the administra-tion of terazosin evoked an increase in heart rate(from 97±l2 to I26±13 beats/min, p<0.0l), adecline in mean arterial pressure (from 89 ±7 to83 ±5 mm Hg, /?<0.05), and a reduction in LVend-systolic dimension (from 3.11 ±0.34 to2.99±0.34 cm, p<0.05). In the presence of terazo-sin, a significant positive chronotropic effect of



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4 -

3 -

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1 -

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D CONTROL• DA 6

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MEAN LEFT ATRIAL PRESSURE

2.7 2.9 3.1 3.3MINOR AXIS (cm)

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B7 -

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3 -

2 -

1 -

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•

Q CONTROL. BDOSO

2.8 3.0 3.2 3.4MINOR AXIS (cm)

3.6

FIGURE 3. Graph depicting left ventricular diastolicpressure-dimension relation is shown for a representativeexperiment before and after administration of dopamine(Panel A) and dobutamine (Panel B) at a rate of 6 ^glkglmin. In early diastole, dobutamine and dopamine causeda leftward shift because of reduced end-systolic chambersize and reduced pressures relative to chamber diameter.In late diastole, infusion of dopamine resulted in anincrease in left ventricular end-diastolic dimension accom-panied by an elevation in left ventricular end-diastolicpressure. With dobutamine, after the initial diastolicpressure nadir, no significant shift in left ventricularpressure-dimension relation was noted. DA 6, dopamineat 6 fig/kg/min. DOB 6, dobutamine at 6 uglkglmin.

dopamine was observed and was accompanied by adecline in mean aortic, LV end-diastolic and meanleft atrial pressures. The increase in peak positivedP/dt and peak lengthening rates and the reductionin time constant of pressure decay observed withdopamine persisted in the presence of terazosin.

Comparisons of the hemodynamic responses todopamine in the presence of rauwolscine and tera-zosin revealed a greater increase in heart rate afterrauwolscine than terazosin (p<0.05) (Figure 1).The augmentation in heart rate after rauwolscineoccurred when no alteration in arterial pressureoccurred, while a decline in arterial pressure wasdocumented after terazosin. The elevation in peakpositive dP/dt evoked by dopamine was also greaterafter rauwolscine than terazosin (p<0.01) (Figure2). Both rauwolscine and terazosin prevented theincrease in LV end-diastolic pressure, LV end-diastolic dimension, and mean left atrial pressureproduced by dopamine (Figure 4). The augmenta-

x-,

20-

10-

-10-

-20-

DA

DA+R

^

^

Tp<0 017 vsCTR

p<0.05 vs DA

DA2 OA4 DA6

FIGURE 4. Bar graph depicting percent change in meanleft atrial pressure during dopamine infusion before andafter rauwolscine and terazosin. Dopamine infusionresulted in an increase in mean left atrial pressure. In thepresence of rauwolscine or terazosin, dopamine elicited adose-dependent decrease in left atrial pressure; decline inpressure was greater after rauwolscine when comparedwith terazosin. DA, dopamine; R, rauwolscine; T, tera-zosin; CTR, control; DA2, 4, and 6, dopamine at 2,4, and6 /ig/kg/min.

tion in peak lengthening rate and decrease in end-systolic chamber dimension induced by dopaminewas maintained after rauwolscine and terazosin;however, the acceleration in LV pressure decayevoked by dopamine was greater after rauwolscinewhen compared with values obtained in the pres-ence of terazosin (p<0.01) (Figure 5).

Effects of Domperidone on HemodynamicResponses to Dopamine

The hemodynamic responses to dopamine werenot altered in the presence of domperidone (datanot shown).

Hemodynamic Responses to DobutamineThe hemodynamic data obtained before and after

the administration of rauwolscine are depicted inTable 3.

The infusion of dobutamine resulted in an increasein heart rate and mean arterial pressure. LV end-diastolic pressure was decreased marginally at aninfusion rate of 6 /xg/kg/min, while mean left atrialpressure remained unchanged. LV systolic perform-ance improved as evidenced by an increase in peak



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T1ME CONSTANT OF PRESSURE DECAY

• DA

• DA+R

TII1

t

p<0.017 vs CTR

0«0.05 vs DA p<0.01

DA2 DA4 DA6

FIGURE 5. Bar graph depicting percent change in pres-sure decay during dopamine infusion before and afterrauwolscine and terazosin. Dopamine produced an accel-eration in left ventricular pressure decay. After rauwol-scine, dopamine elicited an even greater acceleration inleft ventricular pressure decay that did not occur in thepresence of terazosin. DA, dopamine; R, rauwolscine; T,terazosin; CTR, control; and DA2, 4, and 6, dopamine at2, 4, and 6 fig/kg/min.

positive dP/dt and a decrease in end-systolic cham-ber size. These alterations were associated with anacceleration of pressure decay and augmentation ofpeak LV lengthening rate.

In Figure 3B, the LV diastolic pressure-dimension relation before and after dobutamine (6/xg/kg/min) is shown for a representative experi-ment. In early diastole, dobutamine caused a left-ward and downward shift because of reduced end-systolic chamber dimension and reduced LVpressure relative to chamber dimension. With dobu-tamine, after the initial diastolic pressure nadir, nosignificant shift in the ventricular pressure-dimension relation was noted.

No significant changes in the hemodynamic re-sponses to dobutamine were noted after rauwolscine.

DiscussionTo analyze the specific pharmacological actions

of dopamine and dobutamine that influence LVdiastolic function, we examined the hemodynamicresponses to dopamine in the presence and absenceof selective dopamine^, a,- and a2-adrenoceptorantagonists, and dobutamine in the presence andabsence of a selective a2-antagonist. Our findingsdemonstrate the importance of a-receptor activa-tion in modulating the effects of dopamine on dias-tolic and systolic performance.

Heart RatePrevious studies have demonstrated that the

administration of dopamine, a /3,-adrenoceptor ago-nist, is frequently not accompanied by an increasein heart rate.1-3-5-8-13-14 We have also recentlyobserved no significant change in heart rate duringthe administration of dopamine to patients withdilated cardiomyopathy.24 In the present study, theinfusion of dopamine resulted in a dose-dependentnegative chronotropic effect. This cannot be attrib-uted solely to a baroreflex-mediated response to arise in arterial pressure since a decline in heart ratewas noted at infusion rates when no alteration inarterial pressure had occurred. Since no significantchanges in the hemodynamic responses to dopa-mine were observed after the administration ofdomperidone, activation of prejunctional dopaminezreceptors (stimulation of dopamine^ receptors leadsto a reduction in the release of norepinephrine fromsympathetic nerve endings1516) did not appear to beresponsible for the decrease in heart rate seen withdopamine. However, in the presence of rauwol-scine, the administration of dopamine resulted in adose-related increase in heart rate that occurredeven when mean arterial pressure was rising. Tera-zosin also reversed the negative chronotropic effectof dopamine, but the increase in heart rate occurredin conjunction with a reduction in arterial pressure.In contrast, dobutamine produced an augmentationin heart rate that was unaffected by rauwolscine.These observations suggest that blockade of pre-junctional a2-adrenoceptors, the activation of whichinhibits neuronal release of norepinephrine,16

unmasks the positive chronotropic activity of dopa-mine; stimulation of /3radrenoceptors is probablyresponsible for the increase in heart rate. Theaugmentation in heart rate occurring after terazosinprobably represents a baroreflex-mediated responseto the decrease in arterial pressure resulting frompostjunctional a,-adrenoceptor blockade. Our find-ings are consistent with the data of Heyndrickx etal25 who demonstrated that prejunctional a2-adrenoceptors played an important role in modulat-ing the heart rate and myocardial contractileresponse to exercise. These investigators reportedthat the administration of phentolamine (nonselec-tive a-adrenoceptor antagonist) or yohimbine (selec-tive a2-antagonist) resulted in the potentiation of theheart rate and peak positive dP/dt responses toexercise because of the exaggerated release of nor-epinephrine from sympathetic nerves.

Myocardial ContractilityPeak positive dP/dt increased in a dose-

dependent manner during the infusion of dopamineand dobutamine. Neither terazosin nor domperi-done altered the augmentation in peak positivedP/dt evoked by dopamine. In contrast, the increasein peak positive dP/dt elicited by dopamine wassignificantly greater in the presence of rauwolscine



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TABLE 3. Hemodynamic Responses to Dobotamine Infusion Before and After Rauwolsdne

Heart rate(beats/min)

Aortic meanpressure (mm Hg)

Left ventricularend-diastolicpressure (mm Hg)

Mean left atrialpressure (mm Hg)

End-systolicdimension (cm)

End-diastolicdimension (cm)

Peak positive dP/dt(mm Hg/sec)

Peak lengtheningrate (mm/sec)

Time constant ofpressure decay(msec)

Control

99±I2

82±4

3.3±l.2

3.3±1.3

2.97 + 2.8

3.92+1.8

2,141 ±156

357 ±19

23 ±1

2/tg

107±17

88±4*

3.5+1.7

3.5±l.6

2.88±2.9

3.92+1.8

2,674 ±240*

383 ±36

21±1*

Dobutamine

4 fig

111±17

91±4*

3.1 =t 1.4

3.8±1.9

2.77±3.3*

3.89±2.88

3,582 ±303*

437 ±48*

18.5±1*

115±23*

94±5*

2.9±1.3*

3.6±1.7

2.71 ±3.4*

3.96±l.8

4,340 ±483*

489 ±45*

I6±l*

Control postrauwolscine

98+15

81+4

3.4+1.3

3.5 + 1.6

3.00±2.7

3.94+1.8

1,947 + 205

350 + 58

21±2

Dobutamine + rauwolscine

2/ig

112±15

87±4

3 . 3 + 1 . 4

3.36±1.4

2.82±3.7

3.%±2

2,673 ±406*

388 ±57

19±l*

4/ig

110+15

90 + 4*

3.2±l.4

3.44±1.4

2.76±3.7

3.%±1.9

3,246 ±534*

425±51*

16±2*

6^g

125±15*

90±4*

3.4±l.4

3.40+1.5

2.73±3.6*

3.91 ±1.9

3,433 ±455*

423 ±50*

I3±2*

All values are mean±SEM; n = 5.*p<0.017 for the differences from control values.

and occurred in conjunction with a decrease in LVdiastolic chamber dimension. Augmented release ofnorepinephnne from sympathetic nerve endings isprobably responsible for the changes in peak posi-tive dP/dt observed with dopamine in the presenceof rauwolscine. Consistent with this interpretationis the absence of any significant alterations in thehemodynamic responses to dobutamine (possessesno a2-agonist activity) after the administration ofrauwolscine.26

In the present study, the administration of rau-wolscine alone was not associated with an increasein peak positive dP/dt. A lack of change in restingpeak positive dP/dt after infusion of the nonselec-tive a-adrenoceptor antagonist phenoxybenzaminewas reported by Yamaguchi et al27 in anesthetizeddogs. On the other hand, these investigatorsobserved a significant decline in peak positive dP/dtwith the administration of the selective a2-adrenoceptor agonist clonidine. They suggested thatsignificant activation of prejunctional a2-adrenocep-tors did not occur under basal conditions in theiranesthetized dog model. Our results are consistentwith these data. Further support for our findings hasbeen reported in humans by Jie et al.28 They dem-onstrated that basal norepinephnne spillover in theforearm was not altered after a2-adrenoceptor block-ade, but the enhanced norepinephnne spilloverinduced by tyramine was further augmented in thepresence of a selective a2-adrenoceptor antagonist.Thus, it appears that extensive activation of pre-junctional a2-adrenoceptors may not occur underbasal conditions. However, the potent a2-adrenoceptor agonist activity of dopamine, which

may blunt expression of its full cardiotonic effect, isunmasked in the presence of rauwolscine.

Myocardial Relaxation and Diastolic PropertiesThe administration of dopamine and dobutamine

resulted in an acceleration of LV pressure decay.Isolated muscle studies have demonstrated thatisoproterenol, a /3-adrenoceptor agonist, also ac-celerates tension decay.29-32 Activation of /3,-adrenoceptors leads to an increase in intracellularcyclic adenosine monophosphate. This messengeraccelerates the rate of calcium reuptake by thesarcoplasmic reticulum, thereby enhancing ventric-ular relaxation.33 A reduction in end-systolic dimen-sion may be an additional factor favoring morerapid pressure decay by augmenting elastic recoilfrom a smaller chamber size.34-36 The infusion ofdopamine after rauwolscine resulted in an evengreater acceleration of pressure decay presumablyas a result of greater activation of/3,-adrenoceptorsbecause of increased neuronal release of norepi-nephrine.

The filling dynamics of the LV are mainly deter-mined by the atrioventricular pressure gradient.This pressure gradient determines the inflow fillingpattern in early diastole.37 Both dopamine and dobu-tamine accelerated pressure decay, thereby increas-ing the left atrial-LV pressure gradient in earlydiastole and as a result, an augmentation of peakLV lengthening rate occurred. This more rapid andcomplete tension decay is reflected in the leftwardand early downward shift of the LV pressure-dimension relation in early diastole. Thus, the risein filling pressures observed with dopamine cannot



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be attributed to a primary effect on myocardialrelaxation.

Vascular EffectsArterial vasoconstriction due to a-adrenoceptor

activation has been postulated to be the mecha-nism responsible for the increased LV filling pres-sures observed with dopamine.1 A secondaryincrease in LV end-diastolic dimension in responseto the increase in vascular load would mediate thisrise in end-diastolic pressure. In the present study,dopamine increased end-diastolic dimension andpressure even before mean arterial pressure rose.The rise in LV filling pressure observed during theinfusion of dopamine was abolished by rauwol-scine and terazosin. The absence of venoconstric-tion and a reversal of heart rate slowing couldaccount for the effects of the a-adrenoceptor antag-onists on the responses to dopamine. While thepresent study did not directly demonstrate thatdopamine produced venoconstriction, previouswork from our laboratory and others' has demon-strated this hemodynamic effect of dopamine that ismediated through activation of postjunctional a,- anda2-adrenoceptors.38-39 Vasoconstriction in arterial ves-sels resulting from stimulation of these receptors willbe counterbalanced by dopaminermediatedvasodilation,1415 which has not been described in thevenous system.1415 Accordingly, a rise in LV end-diastolic pressure may be observed at concentrationsof dopamine that are not associated with an elevationin arterial pressure.

ConclusionThe infusion of dopamine resulted in heart rate

slowing, augmentation of peak positive dP/dt,enhanced LV pressure decay, and an elevation inLV filling pressure. The rise in LV end-diastolicpressure observed with dopamine is probably relatedto both venoconstriction and heart rate slowing.The greater positive chronotropic and inotropiceffects of dopamine in the presence of rauwolscinecan be attributed to enhanced release of norepineph-rine from sympathetic nerve endings due to block-ade of prejunctional a2-adrenoceptors.

AcknowledgmentsWe wish to thank David James, Dorothy J. Doug-

las, Pam Tolocka, and Glenn Hallam for expertassistance in preparing this manuscript, and PetritAlibali for technical assistance.

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KEY WORDS • dopamine • dobutaminefunction • a-adrenoceptor

diastolic



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R M Lang, J D Carroll, S Nakamura, H Itoh and S I Rajferfunction.

Role of adrenoceptors and dopamine receptors in modulating left ventricular diastolic

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