Increased pulmonary vascular capacitance with P-adrenergic receptor stimulation: an experimental study of the effect of isoproterenol on the pulmonary vascular

volume-pressure relationship 0. A. SMESETM' AND N. w. SCOTT-DOUGLAS

Deparlment of Medical Phjisiology, Universltpt of Calgary, C~1gai-y~ Alta., Canada

Department of Medicine, Ui-miversi~g! of Calgary and Cardbova.sc~lslar Laboratories, Foothills Prsvinc-dal Hospita!, Calgary, Alta., Canada

Departmeref c$Medicab Physiology, University of Calgary, Calgary, Alta., Clinada

Department of Medicine, Univer.sitb, of Caigap and Cardiovascu/ar Laborcrtories, Foothills Provincial Hospitczl, Calgary, A lta ., Canada

AND

Departments of Medicine and Medical Phy.~iskogy, Vniversif;)' oj. Csrlghpaty , Calgay, Alta . , Canada

Received November 20, 1886

SMISETH, 0. A * , ~ c ~ T T - ~ ~ B u G E . ~ ~ , N. W., MANYARI, D., KINGMA, I., SMITH, E. R., and TYBERG, J. V. 1988. Increased pulmonary vascular capacitance with @-adrenergic receptor stimulation: an experimental study of the effect of isoproterenol on the pulmonary vascular volume-pressure relationship. Can. J. Physiol. Pharmaco1. 66: 85-89.

The present study is an investigation of the effect of P-adrenergic receptor stimu%atisn by isoproterenol on pulmonary vascular capacitance. The experiments were done in six intact-chest, anaesthetiaed dogs in which pulmonary and cardiac blood volumes were assessed by blood pool scintigraphy. Hsoproterenol(O.158 pg-kg-' -min-') significantly ( p < 0.005) lowered pulmonary capillary wedge pressure (PpcW) and pulmonary artery pressure (PpA) but did not significantly change pulmonary blood volume (PBV). Left ventricular end-diastolic pressure and total cardiac volume both significantly (p < 0.005) decreased. Pulmonary vascular volume - pressure (V-B) relationships before and during isoproterenol were described by means of blood transfusions and hemorrhage. In individual dogs the PBV-Ppcw and the PBV-(Ppcw + PPA)/2 relationships were significantly shifted upward by isoproterenol ( p < 0.05 or less); slope changes were variable. Pooled data from all dogs also showed a significant ( p < 0.001) upwad shift in the pulmonary vascular V-P relationship regardless of which measure of distending pressure was used. These results suggest that P-receptor stimulation by isoproterenol increases pulmonary vascular capacitance by increasing the unstressed volume.

S u a s e ~ ~ , 0. A . , S C ~ T T - D ~ U G L A S , N. W., MANYAKPI, D., KINGMA, I., SMITH, E. W . , et TYBERG, J . V. 1988. Hncrcased pulmonary vascular capacitance with p-adrenergic receptor stimulation: an experimental study of the effect of isoproterenol on the pulmonary vascular volume-pressure relationship. Can. J. Physiol . Pharrnacol . 66 : 85-89.

La prksente ttbmde examine l'effet de la stimulation des rkcepteurs fkidr6nergiques par l'isoprotCr6no% sur la capacitk vaseulaire pulmonaire. Les expkriences ont 6tC effectuCes sur six chiens anesth6siCs dont les volumes sanguins pulmonaires et cardiaques ont e d Cvduds par scintigraphie de pools sanguins. L'isoprotCrCnol (0,158 pg-kg-' -min-') a diminuC signifi- cativement ( p < 0,W5) la pression capilkire pulmsnaire (PCP) et la pression artkrielle pulnzonaire (PAP)? mais n'a pas modifiC significativement le volume sanguin pulmonaire (VSP). La pression tClCdiastolique ventriculaire gauche et le volume cudiaque total ont diminu6 significativement ( p < 0,005). Les relations volume - pression (V-B) vasculaires pulmonaires avant et durant I'adrninistration d'isoproterCno1 ont 6tk etablies par des transfusions sanguines et des hCmonagies. Chez des chiens, les relations VSP-PCP et VSP-(Pep + P ~ p ) / 2 ont kt6 significativement dCcal6es vers lc haut par I'isoprot6rCnol ( p < 0,05 ou moins); les profils des pentes vxiaient. Les donnkes recueillies chez taus les chiens ant aussi montrd un dCcdage vers %e haut significatif de Ia relation V-P vasculaire pulmonaire peu importe la mesure de pression utilis6e. Ces rdsultats sugg$rent que la stimulation de rkcepteurs-P par l'isoprottrknol augmente %a capacitk vasculaire pulmonaire en augmentant le volume au ~ p s s .

[Traduit par la revue]

Introduction While the effects of P-adxenergic receptor stimulation on

cardiac function and on arteriolar vasomotor tone are well established, it is still unclear how vascular capacitance is affected. (Capacitance is used here as a general term relating the total contained volume of the vasculature to the distending pressure ((Rothe 1983).) Experimental studies on isolated veins seem to show consistently that p-adrenergic stimulation pro- duces vasodilation (Abbshad et al. 1965; Altura 1978). How- ever, in vivo studies have shown decreased systemic vascular

' ~ u t h o r to whom reprint requests may be sent at the following address: Johm Castbergsv. 9,0673 Oslo 6, Noway.

capacity with the @-stimulatsr, isoproterensl (Green 1977; Greenway and Hwnes 198 1; Rutlen et al. 1981 a; Bennett et al. 1984). (Capacity in this paper is used in the sense of contained blood volume (Rothe H 983) .) Similarly, studies of isolated pulmonary vessels and .isolated lung lobe preparations (Brody and Stemrnler 1968) also show @-receptor-mediated vassdila- tion, but the role sf P-adrenergic receptors in the regulation of pulmonary vascular capacitance in the in situ lung has not been well defined. Some authors repofled that isoproterenol produced a marked increase in pulmonary blood volume (PBV) (Feeley et d. 1963), while other investigators (Thowaldsen et al. 1984) reported no significant change. PBV may change as a result of changes in vascular tone as well as passive mechanisms

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86 CAN. J . PHYSIQL. PHAWMACQL. VOL. 66, I988

secondary to changes in inflow or outflow pressure. Other factors that may affect PBV include airway pressure and interstitial pressure, both of which may determine the effective capillary distending pressure. Changes in PBV due to passive mechanisms should cause no change in the position of the pulmonq vascular volume - pressure (V-P) rekitionship, whereas changes in vascular tone or changes in PBV secondary to extravascular factors would be accompanied by a shift in the V-P relationship. The present study was designed to investigate the effect of P-adrenergic receptor stimulation by isoproterenol 081 p u l r n o n ~ vascular capacitmce by determining the effect on the pulmonary vascular V-P relationship.

Experimental preparation Experiments were cmied out in six mongrel dogs weighing

14-22 kg. One week prior to the study the dogs were sglenectomized. Without this procedure, release of blood from the spleen could change the hematocrit and this might have complicated the determination of blocad volume by equilibrium blood pool scintigraphy. Furthermore, isoproterenol is known to produce splenic contraction. On the day of the experiment the dogs were maesthetized with an i.v. bolus of sodium pentobarbital (25 rng/kg) followed by a continuous infusion of 3.5 mg.kg-'-la-' (Hotvedt et al. 1982). The dogs were placed in the supine position and were ventilated by a constant volume respirator (model 607, Marvard Apparatus Co., Inc., Millis, MA). An electrscar- diogram was monitored from a limb Bead, and body temperature was monitored and maintained by a warming blanket and lamp. Left ventricular pressure was measured with an 8F micromanometer-tipped catheter with a reference lumen (model PC-488, Millar Instruments, Houston, TX) which was introduced via a femoral artery. Aortic and central venous pressures were recorded through catheters introduced via a femoral artery and vein, respectively. Pulmonary artery (PpA) and pulmonary wedge pressures (PEW) were recorded by a triple lumen Westation catheter with a themlistor. The fluid-filled catheters were connected to transducers (model B23Ib, Statham-Gould, Oxnard, CA) . Catheters for infusions and blood sampling were introduced into the jugular and femoral veins. Pressures and ECG were recorded on a multichannel recorder (model VW 16, Electronics for Medicine/Hon- eywell, White Plains, NY). Lead makers were sutured on the skin to be used as reference points during analysis of blood pool scintigraphy.

Wadionucdide studies B l o d voBum changes were assessed by equilibrium blood pool

radionuclide angiography (Rutlen et al. B 98 1 b; Clements et al. 198 1 ; Robinson et al. 1985). Briefly, after in vivo labelling of the red blood cells (intravenous injection of stannous gyrophosphate followed by 20 mGi of technetium-99m pertechnetate) (1 Ci = 37 GBq), static 60-s scintigrirns of the entire chest were recorded with a gamma camera (model DYNA-MO 4 equipped with a diverging collimator, Picker, Northford, CT) interfaced to a mobile computer (model BPS-2800, ADAC Laboratories, %an Jose, CA). To minimize the amount of circulating free technetium-99m, scintigrarns were recorded at least 45 rnin after initial labelling. Since the position of the camera in relation to the dog was unchanged in successive recordings. regions of interest were only defined on the first scintigrarn. The correct positions of the regions selected were confirmed in subsequent images using the analog pictures and the Bead markers. The exact recording time of each scintigrarn was noted, and for each measurement a 10-mL blood sample was drawn for determination of blood specific radioactivity.

Relative changes in regional blood volume were quantitated using the change in count rate corrected for biological decay and dilution. By labelling the erythrocytes with technetium-99m, the radioactivity emitted from any region of interest will be proportional to the blood volume of that region providing the hematocrit remains constant. However, changes in hematocrit will alter the radioactivity emitted from a given volume of blood. In the present study this was adjusted for by dividing the radioactivity recorded from any region by the

radioactivity per fmnillilitre of a simultaneous reference blood sample (i,e., blood specific radioactivity). The following regions were studied: the entire chest, the entire heart, and a region located in the mid-chest including the large naediastinal vessels. The BBV was given by the count rate in the entire chest minus the count rate in the heart and the mid-chest regions. The contribution of the chest wall to the activity of the thoracic visera has been shown to be constant (Lindsey and Guyton 1959); the background was considered to remain constant in successive scintigrms.

Experimental protocol The following variables were recorded: pressures in the left

ventricle, the aorta, the inferior vema cava and the pulmonary artery (including pulmonary wedge pressure), blood volumes of the lungs and the heart, and a limb lead electrocardiogram.

To define pulmonary vascular V-P curves, blood volume was altered by incremental blood transfusions and hemorrhage. Blood for transfusion was obtained from a donor dog and the dogs were transfused in several steps. After each transfusion or bleeding, a 3-min period was allowed for stabilization before recordings were obtained. To obtain control V-P curves, an average voBume of 400 mL was given. Four of the dogs were then bled an average volume of 250 m&. Hsoproterenol was then infused i .v. at a rate of 0.150 pg .kg-' *min- with recordings repeated 1 BB min after beginning the infusion. Recor- dings were taken again after stepwise transfusions of an average volume of 300 mL. The isoproterenol infusion was discontinued, 300 d of blood was withdrawn, and recordings were obtained 15 rnin later. In five of the dogs cardiac outputs were determined by themodilution . Statistics

Values before and during isoproterenol were compared statistically using Student's t-test for paired samples (two-tailed). Values are given as mean t SEM. For each dog the pulmonary vascular V-P relations before and during isoproterenol were fitted to linear regressions. A small sample test for parallelism (Kleinbaum and Kupper 1978) demonstrated no significant difference in the slope before and during isoproterenol. Therefore, for each dog the p u l m o n q vascular V-P relations before and during isoproterenol were compared by analysis of covariance.

Since the slopes of the linear regressions were somewhat variable and since the total number of experiments was not large, we used an additional approach to quantitate the shift in the pulmonary V-P relationship. The PBV at a distending pressure of 7 m M g (Vp7) (1 m H g = 133.3 Pa) was determined for each dog and a Student's t-test was performed on these values. In all analyses a probability of less than 0.05 was considered to indicate significance.

Table 1 shows the immediate effects of isoproterenol on hernodynamic variables and blood volumes. As expected, there was an increase in heart rate ( p < 0.001) and a decrease in mean aortic blood pressure ( p < 0.001). Left ventricular end-diastolic pressure decreased by 6.5 mmHg ( p < 0.005) and the mean total cardiac blood volume decreased by 30% ( p < 0.085). Cardiac output increased moderately ( p < 0.0 I), while mean pulmonary artery pressure and pulmonq vascular resistance both decreased ( p < 0.05 and p < 0.05, respectively). Mean pulmonary capillary wedge pressure decreased by 3 mmHg ( p < 0.005), but there was no statistically significant change in PBV.

Figures 1A and 1B illustrate the individual transfusion - hemorrhage-defined pu lmonq vascular V-P relationships with PEW and (PpCW 9 PpA)/2, respectively, as measures of the distending pressure. In each dog, regardless of the measure of distending pressure, during isoproterenol infusion the relation shifted upward, which indicates that the lungs accommodated a larger blood volume for any given distending pressure. After

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TABLE 1. Immediate effects of isoproterenol on pressures and blood volumes

Control Hsoproterenol

PPA ( d g ) 12.8_+ 1.6 10.8_+ 1.4 (p<CB.005)

Pcv ( m d g ) 0.9-+0.7 0.02 0.6 (p<0.010)

HR (min- I ) 130+8 190k6 (p<O.OOl)

CO (~ -min - I ) 1.6 20.2 2.020.2 (p<0,01)

Lung val. (96) 100 93+2 (ns)

Heart vol. (96) 100 69 + 2 (p<Q.005)

PVR ( r n ~ n ~ ~ ~ ~ - ' . m i n - ' ) 5.2k0.5 4.3 50 .3 (p<0.05)

NOTE: PAO, mean aortic pressure; PI veo, left ventricular end-diastolic pressure; PKW, mean pu8mona1-y capillary wedge pressure; PpA, mean pulmonary artery pressure; Pcv, mean central venous pressure: HR, heart rate; CO, cardiac output; PVR, pulmolaary vascula~ resistance. Values are means 9 %EM.

TABLE 2A. PpCW vs. pulmonary blood volume

S lop Intercept

Dog Control Isoproterenol Control Isoproterenol p

TABLE 2B. (Pxw + PpA)/2 vs. pulmonary blood volume

Slope Intercept

Dog Control Isoproterenol Control Isoproterenol p

- - - - - -

NOTE: PKw, pulmonary capillary wedge pressure; PpA, pulmonary artery pressure. p , significance of analysis of covaiarace.

isoproterenol had been discontinued, a single recording (open square) in each dog returned to the control V-P relationship.

The slope, intercept, and significance of the analysis of cova.riarace of the pulmonary V-P relationships before and during isoproterenol are listed in Tables 219 and 2B for PPCW and

FIG. 1. (A) The effect of isoproterenol on puhnonay blood volume - pulmonary capillary wedge pressure (Pww) relations in individual dogs, Blood volumes are given as percentage of the first control recording. Regression lines before (open circles) and during (solid circles) isoproterenol infusion are indicated. A single recording after isoproterenol is indicated (open squares). Isoprote~nol shifted the volume-pressure relation upwards and to the left. (B) Issproterensl and pulmonary blood volume - vascular pressure relations. The mean pulmonary vascular distending pressure is represented by the average of mean pulmonary artery pressure (PpA) and mean pulmonary capil- lary wedge pressure (PEW). Blood volumes are given as percentage of the first control recording. Regression lines before (open circles) and during (solid circles) isoproterenol infusion are indicated. A single recording after isoproterenol is indicated (open squares). Isoproteren~l shifted the volume-pressure relation upwards and to the left.

for (PpCW + PPA)/2, respectively. Each individual dog showed a significant shift of the pulmonary V-P relationship ( p < 0.05 or less). An analysis of covariance with all the dogs grouped together (problematic because of unequal sample size between dogs) also indicates a significant upward shift ( p < 0.001) in the pulmonary V-P relationship due to isoproterenol for either measure of the pulmonary vascular distending pressure.

To quantitate the shift in the pulmonary V-P relationship due to isoproterenol infusion, the change in volume at a distending pressure of '8 mmHg (Vp7, which was near the middle of the pressure ranges) was calculated for each dog and averaged. Vp7 using Ppew as the distending pressure was 134 2 1'8% for control and 173 k 82% during isoproterenol. This relative increase in blood volume of 29% was statisticaily significant ( p < 0.05). When the mean of PpA and BKw was used, Vp7 was 104 5 and 119 9 5% for control and isoproterenol,

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88 CAN. J. PHYSIOL. PHARMACOL. VOL. 66, 1988

respectively. This 14% relative increase in blood volume was also significant ( p < 0.00 1) .

Discussion In the present study, P-adrenergic stimulation with isoproter-

enol was associated with decreased pulmonary vascular resis- tance and pulmonary vascular pressures but unchanged PBV . When the relationship was defined more fully by volume loading and hemorrhage, there was an upward shift in the pulmonary vascular V-P relationship. The values of Vp7 in this study are similar to those reported by Feeley et al. (1963) who showed a 30% increase in pulmonary blood volume as a result of a 2 pg a min- . kg- ' infusion of isoproterenol .

Pulmonary and cardiac blood volumes were determined by equilibrium blood pool radionuclide angiography, a technique that previously has been used successfully to record changes in regional blood volume (Okada et al. 1979; Rutlen et al. 1981 b; Tubau et al. 1983; Clements et al. 198 1). It is not obvious which pressure should be used to represent the pulmonary vascular distending pressure* Since 65-9596 of the pulmonary vascular capacity is located in the capillaries and veins (Landis and Hodenstine 1950; Green 1950; Engelberg and DuBois 19%9), it could seem justified to use pulmonary capillary wedge pressure. However, since the pulmonary arteries contribute significantly to pulmonary vascular compliance (Cars and Safhan 3 9651, others have taken this into account by using the average of pulmonary artery (inflow pressure) and left atrial pressure (outflow pressure) as an approximation of pulmonary vascular distending pressure (Milnos et al, 1968; Yu 1969). In the present study both measures of the distending pressure were used and the results were not qualitatively different. Ideally, pulmonary vascular distending pressure should be calculated as intravas- culx minus interstitial pressure. In the present study it is unlikely that a change in extravascular lung water md a subse- quent change in interstitial h ydros tatic pressure contributed to the effect of isoprsterenol on the pulmonary vascular V-P curve, since the first recording was taken only 10 min after the start of the isoproterenol infusion, and furthermore, since the transfusion allowed comparison at similar intravascular pres- sure. Alveolar pressure and pleural pressure, which both may affect pulmonary vascular pressure, were not recorded. How- ever, a constant-volume respirator was used md end-expiratory pressure was maintained constant (atmospheric) throughout the experiment. It is also unlikely that the increase in pulmonary blood volume is attributable to an increase in pulrnonary epithelial permeability. If the increase in blood voHume was a result of extravascular movement of labelled red blood cells, then the recording after isoprotereno1 was discontinued would have remained shifted upward from the control curve. Since in each dog the post-isoproterenol recording had returned to the control V-P relation, a change in pulmonary epithelial per- meability probably is not a problem.

Maseri et al. (1972) pointed out the importance of recmitment of previously unpePfbased vascular channels as a major deter- minant of changes in PBV. Recruitment and derecmitment are fundamentally related to critical closing pressure, which in turn is a function of vessel size and wall tension (Nichol et al. 1951). .An increase in inflow pressure or a decrease in smooth muscle tone both could lead to recruitment of additional vessels and therefore to augmentation of PBV. Isoproterenol, however, slightly decreased mean pulmonary artery pressure. Although the possibility that isoproterenol may have caused recmitment secondary to decreased vasomotor tone cannot be excluded, the

finding that the pulmonary V-P curves before and during isoproterenol tended to diverge with increasing pulmonary vascular pressures suggests that recruitment did not play a major role' If recruitment was a major determinant of the change in pulmonary blood volume, the two curves should have comver- ged at higher pulmonary vascular pressures when recruitment should be maximal with or without isoprsterensl.

Isoproterenol caused no substantial change in total thoracic (central) blood volume. There was a small decrease in the ungated total cardiac blood volume that might reflect changes in end-systolic as well as end-diastolic volume. However, this volume change is small relative to the total central blood volume, and isoproterenol caused no important shift of blood between the chest and the peripheral circulation. This is in contrast with epinephrine, which causes a combination of cardiac stimulation and systemic venoconstriction. This leads to a shift of blood from the peripheral to the central circulation, which tends to increase preload and thereby further increases cardiac output (Greenway 1983). However, the effect of isoproterenol on systemic vascular capacity might depend on the Ievel of transhepatic vascular resistance. It has been shown by Green (1979) and by Rutlen et al. (1981w, 1981 b) in dogs with markedly elevated portal venous pressure that isopro- terenol reduces splanchnic vascular volume, at Beast in part, by lowering transhepatic resistance.

Hn conclusion, the dogs in this preparation responded the P-adrenergic receptor stimulation with isoproterenol by shifting the pulmonary vascular V-P relationship upwards, thus indica- ting an increase in the unstressed volume. This increase in unstressed volume is probably mediated through vasodilation rather than recruitment of new vascular channels.

Acbowledgments We thank Gerald Groves. Colleen Kondo, and Cheryl Pawl&

for skillful technical assistance and Gregory Douglas for typing the manuscript. 8. A. Smiseth and I. Kingma were Research Fellows, N. W. Scott-Douglas holds a Studentship and 3. V. Tyberg is a Medical Scientist of the Alberta Heritage Founda- tion for Medical Research which supported the study through an Establishment Grant. The study was also supported by a grant-in-aid from the Alberta Heart and Strobe Foundation.

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