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Effects of epinephrine on distribution of blood flow in the pregnant ewe
Effects of epinephrine on distribution of blood flow in the pregnant ewe CHARLES R. ROSENFELD, M.D. M. DENNIS BARTON, M.D. GIACOMO MESCHIA, M.D. Denver, Colorado
Seven pregnant ewes ranging from 85 to 140 days of gestation were infused with systemic doses of epinephrine and uterine arterial flow dose-response curves were determined. With a constant systemic infusion of epinephrine at a mean rate of 0.29 ± 0.03 f.L/5/Kg. ·min., and the radionuclide labeled microsphere method to measure arterial blood flow, a 38.5 per cent decrease in total uterine arterial blood flow was demonstrated while systemic pressure was unaltered. At this dose the reduction in endometrial blood flow was significantly greater (-58. 7 per cent) than that in either the myometrium (- 36.9 per cent) or placental cotyledons ( -34.5 per cent) (p < 0.025 and < 0.005, respectively). There also occured a decrease in blood flow to the mammary gland and the pancreas, whereas increases in blood flow to the skeletal muscle, adipose tissue, and spleen were documented. It is evident from this study that during the pP.riod of ovine pregnancy investigated, the vascular beds of all tissues comprising the pregnant uterus, including the placental cotyledons, are sensitive to the vasoconstrictive effects of epinephrine.
THE RESPONSE of the uterine vascular bed to vasoactive agents is the subject of numerous studies. Previous studies 1- 6 have demonstrated that adrenergic drugs can influence the magnitude of uterine blood flow. The presence of both alpha- and beta-adrenergic drug receptor sites has been demonstrated in the uterine vascular bed. 4 Studies by Barton and associates 6 have also shuwn that similar concentrations of exogenous epinephrine and norepinephrine can cause similar reductions in uterine arterial flow when infused into the uterine artery. A 50 per cent reduction in uterine arterial flow occured with an intra-arterial concentration of exogenous epinephrine ranging from 2 to I 0 ng. per milliliter of arterial blood. This study raised two further questions. (I) Were some components of the uterine circulation spared from the action of
catecholamines? (2) If epinephrine caused significant vasoconstriction in the pregnant uterus at these low concentrations, what were the systemic effects of epinephrine in this same concentration range? In order to answer these questions, we employed a chronic unanesthetized sheep preparation with implanted uterine artery flow probes. Radioactively labeled microspheres \vere infused systemically before and during an intravenous epinephrine infusion in order to determine the effect of epinephrine on the placental, myometrial, and endometrial circulation, as well as other vascular beds.
Methods The study was performed in seven pregnant ewes ranging from 85 to I40 days of gestation and included three singleton and four twin pregnancies. The preparation was the same as that described by Rosenfeld and associates 7 • 8 consisting of pregnant animals with electromagnetic flow probes (Micron Instruments, Los Angeles, California) implanted around both uterine arteries and polyvinyl catheters (0.9 mm. inner diameter by 1.2 mm. outer diameter) in both femoral arteries passed to the trifurcation of the abdominal aorta and in a femoral vein passed to the high inferior vena cava. A radiopaque catheter ( 1.2 mm. inner
From the Division of Perinatal Medicine, Departments of Pediatrics, Physiolor;y, and Anesthesiolor;y. University of Colorado Medical Center. Supported by NIH grants HD 00781, HD 01866, and GRS 434. Received for publication November 29, 1974. Accepted January 9, 1975. Reprint requests: Dr. G. Meschia, 4200 E. 9th Ave., Denver, Colorado 80206.
156
Epinephrine on blood flow distribution
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Fig. 1. Continuous flowmeter recordings of right and left uterine arteries in an ewe of 130 days of gestation carrying a singleton pregnancy on the right. The time of infusion of isotope-labeled microspheres is noted. The systemic infusion of epinephrine at 0.25 ~Lg/min. ·Kg. produced a lower steady flow in both uterine arteries.
diameter by 2.2 mm. outer diameter) was also passed via the ieft common carotid artery into the ieft ventricle. 7 The flow probes and inguinal catheters were carried out to the flank through a subcutaneous tunnel and were maintained in a canvas pouch fastened to the ewe's skin with steel pins. The !eft ventricular catheter was kept in a separate pouch attached to the neck. All catheters were flushed daily with heparinized saline (1,000 U. per milliliter). Following surgery the ewes were maintained in stalls in the laboratory and studied after they had recovered from surgical trauma, generally within 4 days. Systemic arterial and venous pressures were monitored by pressure transducers connnected to a Gould amplifier (model N-4307-04, Cleveland, Ohio) and a twochannel Brush recorder (Model 220, Gould Inc., Cleveland, Ohio). Uterine blood flow was monitored with Micron Instruments electromagnetic flowmeters (Mode! RC 1000, Los Angeles, California) and recorded on another two-channel Brush recorder. The flow probes employed have a linear response to flows in the range studied and are provided with flow signal and zero flow calibrations. The response of uterine arterial blood flow to systemic doses of epinephrine was investigated as follows. Epinephrine solutions were freshly made by adding 4 mi. of 1: 1000 epinephrine chloride (Adrenalin, Parke Davis) to 996 mi. of 5 per cent dextrose in isotonic saline, giving a concentration of 4 ;.Lg per milliliter of base, and used for no more than 4 hours at a time. This solution was infused with a Harvard infusion pump at varying rates through the inferior vena cava catheter. The period of infusion was 5 minutes for each rate examined, followed by a rest
period of 10 to 15 minutes, permitting flows to return to preinfusion ieveis. No more than six infusions were performed per day. Simultaneous blood pressure, pulse rate, and uterine arterial blood flow measurements were obtained and electronically integrated. The speeds of the infusions were randomly chosen and dose-response curves constructed. A rate of epinephrine infusion was identified for each animal that caused a 30 to 40 per cent reduction of uterine blood flow. One to 2 days after determining the doseresponse curve to systemic epinephrine infusion, the procedure was repeated, using the predetermined dose of epinephrine with the objective of infusing isotope-labeled microspheres into the left ventricle of the ewe before and during the constant epinephrine infusion (Fig. 1). The method for the infusion and analysis of microspheres has been described in detail elsewhere and is summarized here. Radioactive carbonized microspheres (Minnesota Mining and Manufacturing Co.) with 141 Ce and 51 Cr labels, a specific activity of 1OmCi. per gram, and a mean diameter of 25 l.t ± 5 S.D. were employed. The exact amount of microspheres in the infused suspension was determined by adding the microspheres, 8 to 10 mi. of sterile isotonic saline, and 1 drop of Tween 20 to a preweighed counting vial containing a magnetic stirring rod and reweighing the vials. The suspension was mixed on a magnetic stirer for 45 minutes and four 0.1 mi. samples of the suspension \Vere removed in pre,veighed lengths of polyvinyl tubing while the mixing continued. These catheters were placed in preweighed counting vials, weighed, and counted. The mean counts per minute (c. p.m.) per gram of suspension were calculated. The suspension, whose weight and radioactivity per gram
158 Rosenfeld, Barton, and Meschia
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Table I. Mean total counts per minute and number of microspheres infused into the study animals Isotope
Counts per minute
No.
16.71 X 106 7.37 X 106 7
0.904 X 106 0.178 X 106 7
12.52 X 106 3.24 X 106 7
1.826 X 106 0.368 X 106 7
t41Ce:
Mean ± S.E.M.
N. 51Cr: Mean ±S.E.M.
N.
was known, was infused by air desplacement through the left ventricular catheter while the microspheres were kept in suspension with a stirring warming unit. The suspension was infused over 30 to 40 seconds and the ventricular catheter flushed with 10 mi. of isotonic saline. Afterward the entire administration unit was reweighed and the total counts per minute and number of microspheres infused were determined (see Table 1). In the experiments reported here, the microspheres were infused before the epinephrine infusion and again during the epinephrine infusion. The latter microsphere infusion was not begun until the uterine blood flow, monitored by the implanted flowprobes, had reached a lower, steady rate of flow. Starting just prior to the microsphere infusion, arterial reference samples were withdrawn into counting vials under oil from both femoral artery catheters at a rate of 3.66 mi. per minute for 3 minutes with a Harvard pump. This method allows the calculation of cardiac output as well as individual organ flows. Individual organ blood flows were calculated with the arterial samples by solution of the following equation: Organ flow (mi./min.) = Total c.p.m. for organ Withdrawal sreed Mean c. p.m. in arterial sample x (mi./min.
(1)
Cardiac output (CO) was obtained by the solution of the following equation: CO (mi./min.) = Total microspheres infused Mean microspheres in arterial sample
X
Withdrawal sred (mi./min.
(2)
Samples for arterial blood gases were drawn from the femoral artery before each epinephrine infusion during construction of dose-response curves and also before and after each isotope-labeled microsphere infusion. The ewes were killed within 24 hours after the second microsphere infusion and dissected for tissue preparation. The uterus, vagina, and cervix were
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Obstet. Gynecol.
removed en bloc and the cervix and vagina then dissected from the uterus. The endometrium and myometrium were separated by sharp and blunt dissection. The efficacy of this method has previuosly been confirmed by histologic examination. 7 The three components of the uterus (cotyledons, endometrium. and myometrium) were then weighed. The following organs were also removed and weighed: brain, mammary gland, lungs, heart, liver, spleen, pancreas. kidneys. ovaries, Fallopian tubes, thyroid gland, and adrenal glands. Representative samples of foreleg skin. mammary gland skin, hindleg muscle, chest wall muscle. and small bowel were also removed and placed directly into counting vials. Samples were counted in a Nuclear-Chicago automatic dual-channel gamma counter with a 3 inch crystal detector and a wide well. The 51 Cr was counted as an emission peak of 0.321 Kev. (window range. 0.271 to 0.371 Kev.) and the 141 Ce was counted at a peak of 0.145 Kev. (window range, 0.127 to 0.162 Kev.). L'nder these conditions 4.5 t.o 5.5 per cent of the 51 Cr counts appeared in the 141 Ce window and 0.3 to 0.7 per cent of the 141 Ce counts appeared in the 51 Cr window. The true counts per minute f(n· each isotope were calculated by the solution of the appropriate simultaneous equation. Control flows before epinephrine infusion and experimental flows during epinephrine infusion for each organ or tissue studied were calculated. The paired t test was used to determine degrees of significance between control and experimental flows. All mean values are presented as ±I standard error of the mean (S.E.M.).
Results Fig. 2 demonstrates the dose-response curves of mean systemic arterial pressure and uterine blood flow to the intravenous infusion of epinephrine. The curves depicting the changes in mean arterial pressure and uterine blood flow are similar in each of the animals studied. There is no significant change in the systemic pressure as the infused dose of epinephrine increases until there occurs a decrease in uterine arterial blood How of greater than 40 to 50 per cent. With the use of these dose-response curves, an infusion rate of epinephrine which would lead to the largest decrease in uterine blood flow without alteration in the systemic pressure was chosen for use in the subsequent microsphere studies. The dose employed in these studies ranged from 0.192 to 0.410 t-tg/min. ·kg. with a mean of 0.287 t-tg/min. ·kg. ± 0.034. At this rate of infusion there was a significant change in heart rate, increasing from 102 ± 9.1 to 122 ± 13.4 beats
Epinephrine on blood flow distribution 159
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per minute (p < 0.05) but no significant alteration in the mean systemic pressure (control of 92.0 mm. Hg ± 3. 7 and experimental of 92.3 mm. Hg ± 6.0). A typical response of uterine blood flow to the epi· nephrine infusion is demonstrated in Fig. 1. After studying the first two animals and calculating the uterine arterial blood flow from the microsphere data, a discrepancy between this data and the simultaneously observed flowmeter data was noted. This had not been our experience in the past8 and led to the discovery of a malfunctioning component in the gamma counter. From previous experiments, which permitted the comparison of 61 simultaneous determinations of uterine blood flow by the microsphere and flow probe methods, we were able to construct an
equati~n8 which related the two measurements: Microsphere flow (mi./min.) = Flowmeter flow (ml./min.)- 36 mi./min.
(3)
0.86 The uterine arterial flows for the first two animals studied were corrected with the use of Equation (3). As the per cent distribution of the microspheres was known and not affected by the gamma counter malfunction, it was possible to determine the arterial blood flow to each of the uterine tissues. Once the gamma counter was repaired this descrepancy did not recur. In a third animal we were unable to place the microspherc infusion catheter into the left ventricle.
Januaq 15, 1976
160 Rosenfeld, Barton, and Meschia Ano.
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Table II. The effect of a systemic infusion of epinephrine on total uterine blood flow and blood flow rate to the separate uterine tissues as measured with the microspherc method
Total uterine flow, without cervix (ml./min.): Control 566.7 720.6 Experimental 429.8 390.8 Per cent change -24.2 -45.8
l007.0 656.0 -34.9
748.8 391.7 -47.7
1818.0 508.6 -55.5
541.6 419.6 -22.5
793.7 478.5 -38.6
-38.5 ± 4.6*
CotyledoMry flcrw (ml.lmin.): Control 379.1 Experimental 299.6 -21.0 Per cent change
578.3 339.3 -41.3
848.9 589.7 -34.9
535.4 299.3 -47.7
1543.0 739.4 -52.1
443.1 368.1 -22.5
614.5 395.8 -35.6
-34.5
Myometrial flow ( ml./min.): Control 23.8 20.2 Experimental Per cent change 15.3
19.2 9.7 -49.7
45.7 26.0 -43.2
48.4 27.0 -44.1
53.5 21.3 -60.1
21.7 17.7 -16.3
27.7 19.5 -29.5
-36.9 ± 6.4*
Endometrial flow (ml. !min.): Control 163.8 IlO.O Experimental Per cent change -32.8
123.1 41.8 -66.0
112.8 40.0 -64.5
165.5 65.4 -60.5
221.6 47.9 -78.4
77.4 33.9 -56.3
151.5 72.2 -52.3
-58.7 ± 5.3*
t
t
Percentage cardiac output to the uterus: Control 7.94 Experimental 3.42
9.35 4.29
20.6 7.38
*
14.5 6.75
4.8*
13.1 ± 2.8 5.46 ± 1.9**
*p < 0.025. **The decrease is significant at p < 0.05. tCardiac output not available, see text. tCardiac output not available, no left ventricular catheter. See text.
Table III. Tissues and organs demonstrating a significant change in arterial blood flow during an epinephrine infusion Tissue or organ
Skeletal muscle Intra-abdominal fat Spleen Pancreas Mammary gland skin Total uterus
Per cent change*
p
+434.6 ± 112.4
0.025 <0.05 <0.01 <0.025 <0.05 <0.025
+ 180.0 ± 41.5 + 138.9 ± 29.2 -27.8 ± -44.2 ± -38.5 ±
7.6
10.1 4.6
*Mean ± S.E.M.
The catheter was left in the ascending portion of the thoracic aorta. Because of this, cardiac output and blood flow to those organs served by the ascending aorta were not calculated. Thus, we were able to analyze blood flow to all organs in only four animals, and flows to organs served by the descending aorta for an additional animal. Uterine blood flow data are available for all seven animals studied. Cardiac output was available in four animals. The mean cardiac output was 7,279 mi. per minute in the control period and 8,937 ml. per minute during the epinephrine infusion. The cardiac output increased 18 to 76 per cent in three animals and decreased 10.5 per cent in the fourth.
Table II shows the effect of epinephrine on myometrial, endometrial, and placental blood flows. When the separate uterine tissues are compared it can be seen that the endometrium exhibited a significantly greater decrease in blood flow (-58.7 per cent± 5.3) than either the myometrium (-36.9 per cent± 6.4, p < 0.025) or the placental cotyledons ( -34.5 per cent± 4.7 p < 0.005). There was no significant difference between the responses seen in the myometrium and placental cotyledons (p > 0.50). In the three ewes carrying singleton pregnancies, the responses to epinephrine in the pregnant and nonpregnant horns of the uterus were compared and no difference was observed. Cervical blood flow was also examined and found to decrease from 6.03 ± 1.06 to 3.94 ± 0.91 ml. per minute but these changes were not statistically significant. No significant changes were seen in ovarian and Fallopian tube flows. Because of the nature of the animal preparation and the method for measuring blood flow with the isotope-labeled microspheres, it was possible to compare blood flow changes within the uterus with changes of blood flow to other organs and tissues. The results of this comparison are presented in Tables III and IV and Fig. 3. Skeletal muscle obtained from the hindlimb and the chest wall, pooled samples from peritoneal and
Epinephrine on blood flow distribution 161
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omental fat, and the spleen demonstrated significant increases in flow, whereas the uterine tissues, skin overlying the mammary gland, and the pancreas showed significant decreases in flow. There was a slight increase in flow to the hind leg skin that was not statistically significant. The data for organ blood flows in the four ewes in which cardiac output was determined were analyzed in order to determine the change in the distribution of cardiac output that occured during the infusion of epinephrine (Table IV). It should be noted that there was a significant decrease in the percentage of cardiac output going to the kidneys. The blood flow to the ovine mammary gland was noted to increase with gestational age of the animals in these experiments. Our data demonstrated control mammary blood flow of 15.9 ml. per minute at 85 days of gestation and 228 ml. per minute at 140 days of gestation. In each of the animals studied the infusion of epinephrine consistently caused a decrease in mammary blood flow ranging from 13 to 70 per cent but, because of the large variation in the control flows, the decrease demonstrated was not statistically significant (0.1 0 > p > 0.05). No significant changes were seen in arterial pH or Paco 2 during the studies. Values were consistent with those previously recorded. 9
Comment The vascular effects of catecholamines have been widely studied with systemic and individual organ infusions in both man and laboratory animals. 10 The new features of the present study are ( 1) the demonstration of epinephrine-induced vasoconstriction in
Table IV. Organs demonstrating a significant change in the percentage of cardiac ouput received, as determined in four ewes Per cent cardiac output* Organ
Control
Right kidney Left kidney Combined kidneys Spleen Pancreas Total uterus without cervix
5.3 ± 0.3 5.2 :t 0.5 10.5 :t 0.5 3.8 :t 0.4 2.1±0.4 13.1 :t 2.8
I Experimental 4.14 4.13 8.27 6.6 1.3 5.5
± 0.2 ± 0.5 :t
0.5
± 0.1 ± 0.3 ± 1.9
pt <0.05 N.S. 0.05 0.005 <0.025 <0.05
*Mean ± S.E.M. tPaired analysis, Student's t test.
each component of the vascular bed of the pregnant uterus and (2) the greater sensitivity of the reproductive tissues to the vasoconstrictive properties of epinephrine than the other organs or tissues of the body. The effect of catecholamines on uterine blood flow was first studied in detail by Robson and Schild. 11 Writing in 1938, they found that epinephrine produced uterine arterial vasoconstriction in both pregnant cats and spayed cats treated with estrone or with estrone and progesterone. The contractile response of the myometrium to catecholamines is known to depend on the hormonal state of the animal. 12 Their results indicated that the response of the uterine vasculature to epinephrine was free of female hormonal influence. In subsequent studies by Ahlquist and Woodbmf in pregnant dogs and by Adams and associates 1 in pregnant sheep, the vasoconstrictive effects of epineph-
162
Rosenfeld, Barton, and Meschia .\m.
rine on uterine blood flow were confirmed. Studies on the effect of systemic catecholamine infusions on blood flow to the gravid ovine uterus have been reported by Greiss. 3 In these studies, he reported a 50 per cent reduction in uterine vascular conductance following systemic infusions of greater than 0.5 ,ug/Kg./min. of epinephrine or norepinephrine. There was no significant difference in response over the period of gestation studied, 112 to 147 days. Our study. which demonstrates in ewes from 85 to 140 days of gestation a 39 per cent reduction in uterine arterial flows during systemic infusions of epinephrine ranging from 0.2 to 0.4 ,ug/Kg./min., is in good agreement with Greiss' data. The present study documents that, at the dose levels that were employed, the vasculature of all three uterine tissues (endometrium, myometrium. and placental cotyledons) are sensitive to the vasoconstrictive effects of epinephrine. It was further demonstrated that the response of the endometrial vasculature to epinephrine (a 59 per cent reduction in blood flow) was greater than that noted in either the placental cotyledons (a 35 per cent reduction) or the myometrium (a 37 per cent reduction), whereas the responses in these two tissues were similar. This documentation of a vascular response by all of the uterine tissues to epinephrine suggests the presence of alpha receptors in the arterioles of each of the uterine tissues and presents evidence that these receptor sites remain sensitive to the vasoconstrictive effects of epinephrine during pregnancy. Arterial blood flow to the mammary gland and to the skin overlying the mammary gland was decreased by the epinephrine infusion (see data). Mammary gland arterial blood flow has been shown to decrease in response to epinephrine. 13 · 14 In contrast to the mammary gland skin, skin from the ventral surface of the hind leg did not demonstrate a significant reduction in blood flow. Skin vasculature may vary in its reactivity to systemic catecholamine infusions according to its location. In the dose range of epinephrine studied here, 0.2 to 0.4 ,ug/Kg./min .. skeletal muscle, intra-abdominal fat, and splenic blood flows were all increased significantly, whereas blood flows to the pancreas were decreased. The vasodilatory effect of epinephrine on skeletal muscle has been attributed to beta/receptor stimulation. Low doses of epinephrine given intra-arterially into the forearm muscle of man produce a transient sharp rise in the arterial flow of greater than 100 per cent of control, followed by a lower, sustained flow that is greater than 50 per cent of control. 15 These results are supported by data from the present study which
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Januarv L'i. 19711 Obstet. GynewL
demonstrate a striking increase in blood flow to chest wall and hindlimb muscle(> 400 per cent of control) in the face of unaltered mean systemic pressure. Epinephrine has been domonstrated to cause an increase in blood flow to adipose tissue in this study. The phenomenom has been demonstrated in canine subcutaneous adipose tissue infused with epinephrine at a concentration of 0.0 I ,ug per milliliter. 16 In the same study isoproterenol was noted to increase fat blood flow, suggesting that beta-receptor stimulation can lead to vasodilation in adipose tissue. The splenic vasculature has been widely studied and found to respond to infused catecholaminesY· 18 Beta-adrenergic stimulation led to increases in splenic blood flow, whereas alpha stimulation decreased flow. Epinephrine was demonstrated in the cat to increase splenic blood flow from 60 to I 60 per cent of control flows 17 • ts following doses from 0. I to 1.0 ,ug per kilogram. In the pregnant sheep studied here splenic blood flow also increased without a 'ystemic blood pressure increase. It is possible that with the use of higher doses of exogenous epinephrine. splenic vasoconstriction might have occurred. The arterial bed of the pancreas has been shown by other investigators to possess both alpha and beta receptors, 19 but the response of this organ to catecholamines is by no means settled. We were able to demonstrate a significant reduction in pancreatic blood flow of approximately 28 per cent, occurring 2 to 3 minutes after the initiation of the epinephrine infusion, and not associated with an alteration in systemic arterial pressure. Arterial blood flow to tissues such as heart, brain, kidney. liver, and bowel has been found to be altered by catecholamines in Yarious studies, but did not demonstrate a significant change following the 0.2 to 0.4 ,ug/Kg. ·min. epinephrine infusion employed here in pregnant sheep. Though no significant change in blood flow to the kidneys was documented during the epinephrine infusion, the per cent cardiac output reaching them was significantly reduced. As the skeletal muscle makes up a large part of the body mass in these animals. it is conceivable that the increase in flow to this tissue (>400 per cent) accounts for both the increase and redistribution of cardiac output. Epinephrine is of use in various clinical situations in obstetrics, such as an adjuvant for local anesthetic solutions. If epinephrine were inadvertently given in sufficient quantity into the vascular system during a local anesthetic injection, it might have a deleterious effect on uterine blood flow in the pregnant human. Slow intravenous or subcutaneous epinephrine in the human subject has little effect on mean blood pressure,
Epinephrine on blood flow distribution 163
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but does significantly decrease peripheral resistance and increase both cardiac output and heart rate. 10 In the experiments reported here, a dose of epinephrine that produced no significant change in mean systemic blood pressure did significantly increase muscle blood flow, did significantly increase heart rate, and in three
of four instances did increase cardiac output. The same dose also led to a 38 per cent reduction in total uterine blood flow in the pregnant ewe. On the basis of these findings, it can be suggested that deleterious effects might occur in a pregnant woman exposed to relatively low arterial concentrations of epinephrine.
REFERENCES 1. Adams, F. M., Assali, N., Cushman, M., and Westersten, A.: Interrelationships of maternal and fetal circulations, Pediatrics 27: 627, 1961. 2. Ahlquist, R. P., and Woodbury, R. A.: Influence of drugs and uterine activity upon uterine blood flow, Fed. Proc. 6: 305, 1947. 3. Greiss, F. C., Jr.: The uterine vascular bed: Effect of adrenergic stimulation, Obstet. Gynecol. 21: 295, 1963. 4. Greiss, F. C., Jr.: Differential reactivity of the myoendometrial and placental vasculatures: Adrenergic responses, AM.]. 0BSTET. GYNECOL. 112: 20, 1972. 5. Ladner, C., Brinkman, C. R., Weston, P., and Assali, N. S.: Dynamics of uterine circulation in pregnant and non-pregnant sheep, Am.]. Physiol. 218: 257, 1970. 6. Barton, M. D., Killam, A. P., and Meschia, G.: Response of ovine uterine blood flow to epinephrine and norepinephrine, Proc. Soc. Exp. Bioi. Med. 145: 966, 1974. 7. Rosenfeld, C. R., Killam, A. P., Battaglia, F. C., Makowski, E. L., and Meschia, G.: Effeect of estradiol-17-beta on the magnitude and distribution of uterine blood flow in nonpregnant, oophorectomized ewes, Pediatr. Res. 7: 139, 1973. 8. Rosenfeld, C. R., Morriss, F. H., Makowski, E. L., Meschia, G., and Battaglia, F. C.: Circulatory changes in the reproductive tissues of ewes during pregnancy, Gynecol. Invest. 5: 252, 1974. 9. Battaglia, F. C., Behrman, R. E., de Lannoy, C. W., Hathaway, W., Makowski, E., Meschia, G., and Seed, A. E.. Exposure to high altitude of sheep with different haemoglobins, Q.]. Exp. Bioi. 54: 423, 1969. 10. Innes, I. R., and Nickerson, M.: Drugs acting on postganglionic adrenergic nerve endings and structures
11. 12. 13.
14.
15. 16.
17.
18. 19.
innervated by them, in Goodman, L. S., and Gilman, A., editors: The Pharmacologic Basis of Therapeutics, New York, 1970, pp. 478-523. Robson,]. M., and Schlid, H. 0., Effect of drugs on the blood flow and activity of the uterus, ]. Physiol. 92: 9, 1938. Robson,]. M., and Schild, H. 0.: Response of eat's uterus to hormones of the posterior pituitary lobe, J. Physiol. 92: I, 1938. Hebb, C. 0., and Linzell,]. L.: Some conditions affecting the blood flow through the perfused mammary gland, with special reference to the action of adrenalin, Q. J. Exp Physiol. 36: 159, 1951. Houvenaghel, A.: Action of catecholamines on blood flow through the mammary gland in unanesthetized lactating small ruminants, Arch. Int. Pharmacodyn. 186: 190, 1970. Whelan, R. F., and de Ia Lande, I. S.: Action of adrenalin on limb blood vessels, Br. Med.]. 19: 125, 1963. Ballard, K., Cobb, C. A., and Rosell, S.,: Vascular and lipolytic responses in canine subcutaneous adipose tissue following infusion of catecholamines, Acta Physiol. Scand. 81:246,1971. Greenway, C. V., and Stark, R. D.: The vascular responses of the spleen to intravenous infusion of catecholamines, angiotensin, and vasopressin in the anesthetized cat, Br.]. Pharmacal. 38: 583, 1970. Ross, G.: Effects of catecholamines on splenic blood flow in the cat, Am.]. Physiol. 218: 1079, 1967. Barlow, T. E., Greenwell, ]. R., Harper, A. A., and Scratcherd, T.: The effect of adrenalin and noradrenalin on the blood flow, electrical conductance, and external secretion of the pancreas,]. Physiol. 217: 665, 1971.
Seven pregnant ewes ranging from 85 to 140 days of gestation were infused with systemic doses of epinephrine and uterine arterial flow dose-response curves were determined. With a constant systemic infusion of epinephrine at a mean rate of 0.29 ± 0.03 f.L/5/Kg. ·min., and the radionuclide labeled microsphere method to measure arterial blood flow, a 38.5 per cent decrease in total uterine arterial blood flow was demonstrated while systemic pressure was unaltered. At this dose the reduction in endometrial blood flow was significantly greater (-58. 7 per cent) than that in either the myometrium (- 36.9 per cent) or placental cotyledons ( -34.5 per cent) (p < 0.025 and < 0.005, respectively). There also occured a decrease in blood flow to the mammary gland and the pancreas, whereas increases in blood flow to the skeletal muscle, adipose tissue, and spleen were documented. It is evident from this study that during the pP.riod of ovine pregnancy investigated, the vascular beds of all tissues comprising the pregnant uterus, including the placental cotyledons, are sensitive to the vasoconstrictive effects of epinephrine.
THE RESPONSE of the uterine vascular bed to vasoactive agents is the subject of numerous studies. Previous studies 1- 6 have demonstrated that adrenergic drugs can influence the magnitude of uterine blood flow. The presence of both alpha- and beta-adrenergic drug receptor sites has been demonstrated in the uterine vascular bed. 4 Studies by Barton and associates 6 have also shuwn that similar concentrations of exogenous epinephrine and norepinephrine can cause similar reductions in uterine arterial flow when infused into the uterine artery. A 50 per cent reduction in uterine arterial flow occured with an intra-arterial concentration of exogenous epinephrine ranging from 2 to I 0 ng. per milliliter of arterial blood. This study raised two further questions. (I) Were some components of the uterine circulation spared from the action of
catecholamines? (2) If epinephrine caused significant vasoconstriction in the pregnant uterus at these low concentrations, what were the systemic effects of epinephrine in this same concentration range? In order to answer these questions, we employed a chronic unanesthetized sheep preparation with implanted uterine artery flow probes. Radioactively labeled microspheres \vere infused systemically before and during an intravenous epinephrine infusion in order to determine the effect of epinephrine on the placental, myometrial, and endometrial circulation, as well as other vascular beds.
Methods The study was performed in seven pregnant ewes ranging from 85 to I40 days of gestation and included three singleton and four twin pregnancies. The preparation was the same as that described by Rosenfeld and associates 7 • 8 consisting of pregnant animals with electromagnetic flow probes (Micron Instruments, Los Angeles, California) implanted around both uterine arteries and polyvinyl catheters (0.9 mm. inner diameter by 1.2 mm. outer diameter) in both femoral arteries passed to the trifurcation of the abdominal aorta and in a femoral vein passed to the high inferior vena cava. A radiopaque catheter ( 1.2 mm. inner
From the Division of Perinatal Medicine, Departments of Pediatrics, Physiolor;y, and Anesthesiolor;y. University of Colorado Medical Center. Supported by NIH grants HD 00781, HD 01866, and GRS 434. Received for publication November 29, 1974. Accepted January 9, 1975. Reprint requests: Dr. G. Meschia, 4200 E. 9th Ave., Denver, Colorado 80206.
156
Epinephrine on blood flow distribution
Volume 124 Number 2
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Fig. 1. Continuous flowmeter recordings of right and left uterine arteries in an ewe of 130 days of gestation carrying a singleton pregnancy on the right. The time of infusion of isotope-labeled microspheres is noted. The systemic infusion of epinephrine at 0.25 ~Lg/min. ·Kg. produced a lower steady flow in both uterine arteries.
diameter by 2.2 mm. outer diameter) was also passed via the ieft common carotid artery into the ieft ventricle. 7 The flow probes and inguinal catheters were carried out to the flank through a subcutaneous tunnel and were maintained in a canvas pouch fastened to the ewe's skin with steel pins. The !eft ventricular catheter was kept in a separate pouch attached to the neck. All catheters were flushed daily with heparinized saline (1,000 U. per milliliter). Following surgery the ewes were maintained in stalls in the laboratory and studied after they had recovered from surgical trauma, generally within 4 days. Systemic arterial and venous pressures were monitored by pressure transducers connnected to a Gould amplifier (model N-4307-04, Cleveland, Ohio) and a twochannel Brush recorder (Model 220, Gould Inc., Cleveland, Ohio). Uterine blood flow was monitored with Micron Instruments electromagnetic flowmeters (Mode! RC 1000, Los Angeles, California) and recorded on another two-channel Brush recorder. The flow probes employed have a linear response to flows in the range studied and are provided with flow signal and zero flow calibrations. The response of uterine arterial blood flow to systemic doses of epinephrine was investigated as follows. Epinephrine solutions were freshly made by adding 4 mi. of 1: 1000 epinephrine chloride (Adrenalin, Parke Davis) to 996 mi. of 5 per cent dextrose in isotonic saline, giving a concentration of 4 ;.Lg per milliliter of base, and used for no more than 4 hours at a time. This solution was infused with a Harvard infusion pump at varying rates through the inferior vena cava catheter. The period of infusion was 5 minutes for each rate examined, followed by a rest
period of 10 to 15 minutes, permitting flows to return to preinfusion ieveis. No more than six infusions were performed per day. Simultaneous blood pressure, pulse rate, and uterine arterial blood flow measurements were obtained and electronically integrated. The speeds of the infusions were randomly chosen and dose-response curves constructed. A rate of epinephrine infusion was identified for each animal that caused a 30 to 40 per cent reduction of uterine blood flow. One to 2 days after determining the doseresponse curve to systemic epinephrine infusion, the procedure was repeated, using the predetermined dose of epinephrine with the objective of infusing isotope-labeled microspheres into the left ventricle of the ewe before and during the constant epinephrine infusion (Fig. 1). The method for the infusion and analysis of microspheres has been described in detail elsewhere and is summarized here. Radioactive carbonized microspheres (Minnesota Mining and Manufacturing Co.) with 141 Ce and 51 Cr labels, a specific activity of 1OmCi. per gram, and a mean diameter of 25 l.t ± 5 S.D. were employed. The exact amount of microspheres in the infused suspension was determined by adding the microspheres, 8 to 10 mi. of sterile isotonic saline, and 1 drop of Tween 20 to a preweighed counting vial containing a magnetic stirring rod and reweighing the vials. The suspension was mixed on a magnetic stirer for 45 minutes and four 0.1 mi. samples of the suspension \Vere removed in pre,veighed lengths of polyvinyl tubing while the mixing continued. These catheters were placed in preweighed counting vials, weighed, and counted. The mean counts per minute (c. p.m.) per gram of suspension were calculated. The suspension, whose weight and radioactivity per gram
158 Rosenfeld, Barton, and Meschia
Januaq 15. 1!17!i
Am
Table I. Mean total counts per minute and number of microspheres infused into the study animals Isotope
Counts per minute
No.
16.71 X 106 7.37 X 106 7
0.904 X 106 0.178 X 106 7
12.52 X 106 3.24 X 106 7
1.826 X 106 0.368 X 106 7
t41Ce:
Mean ± S.E.M.
N. 51Cr: Mean ±S.E.M.
N.
was known, was infused by air desplacement through the left ventricular catheter while the microspheres were kept in suspension with a stirring warming unit. The suspension was infused over 30 to 40 seconds and the ventricular catheter flushed with 10 mi. of isotonic saline. Afterward the entire administration unit was reweighed and the total counts per minute and number of microspheres infused were determined (see Table 1). In the experiments reported here, the microspheres were infused before the epinephrine infusion and again during the epinephrine infusion. The latter microsphere infusion was not begun until the uterine blood flow, monitored by the implanted flowprobes, had reached a lower, steady rate of flow. Starting just prior to the microsphere infusion, arterial reference samples were withdrawn into counting vials under oil from both femoral artery catheters at a rate of 3.66 mi. per minute for 3 minutes with a Harvard pump. This method allows the calculation of cardiac output as well as individual organ flows. Individual organ blood flows were calculated with the arterial samples by solution of the following equation: Organ flow (mi./min.) = Total c.p.m. for organ Withdrawal sreed Mean c. p.m. in arterial sample x (mi./min.
(1)
Cardiac output (CO) was obtained by the solution of the following equation: CO (mi./min.) = Total microspheres infused Mean microspheres in arterial sample
X
Withdrawal sred (mi./min.
(2)
Samples for arterial blood gases were drawn from the femoral artery before each epinephrine infusion during construction of dose-response curves and also before and after each isotope-labeled microsphere infusion. The ewes were killed within 24 hours after the second microsphere infusion and dissected for tissue preparation. The uterus, vagina, and cervix were
J.
Obstet. Gynecol.
removed en bloc and the cervix and vagina then dissected from the uterus. The endometrium and myometrium were separated by sharp and blunt dissection. The efficacy of this method has previuosly been confirmed by histologic examination. 7 The three components of the uterus (cotyledons, endometrium. and myometrium) were then weighed. The following organs were also removed and weighed: brain, mammary gland, lungs, heart, liver, spleen, pancreas. kidneys. ovaries, Fallopian tubes, thyroid gland, and adrenal glands. Representative samples of foreleg skin. mammary gland skin, hindleg muscle, chest wall muscle. and small bowel were also removed and placed directly into counting vials. Samples were counted in a Nuclear-Chicago automatic dual-channel gamma counter with a 3 inch crystal detector and a wide well. The 51 Cr was counted as an emission peak of 0.321 Kev. (window range. 0.271 to 0.371 Kev.) and the 141 Ce was counted at a peak of 0.145 Kev. (window range, 0.127 to 0.162 Kev.). L'nder these conditions 4.5 t.o 5.5 per cent of the 51 Cr counts appeared in the 141 Ce window and 0.3 to 0.7 per cent of the 141 Ce counts appeared in the 51 Cr window. The true counts per minute f(n· each isotope were calculated by the solution of the appropriate simultaneous equation. Control flows before epinephrine infusion and experimental flows during epinephrine infusion for each organ or tissue studied were calculated. The paired t test was used to determine degrees of significance between control and experimental flows. All mean values are presented as ±I standard error of the mean (S.E.M.).
Results Fig. 2 demonstrates the dose-response curves of mean systemic arterial pressure and uterine blood flow to the intravenous infusion of epinephrine. The curves depicting the changes in mean arterial pressure and uterine blood flow are similar in each of the animals studied. There is no significant change in the systemic pressure as the infused dose of epinephrine increases until there occurs a decrease in uterine arterial blood How of greater than 40 to 50 per cent. With the use of these dose-response curves, an infusion rate of epinephrine which would lead to the largest decrease in uterine blood flow without alteration in the systemic pressure was chosen for use in the subsequent microsphere studies. The dose employed in these studies ranged from 0.192 to 0.410 t-tg/min. ·kg. with a mean of 0.287 t-tg/min. ·kg. ± 0.034. At this rate of infusion there was a significant change in heart rate, increasing from 102 ± 9.1 to 122 ± 13.4 beats
Epinephrine on blood flow distribution 159
Volume 124 Number 2
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Fig. 2. The responses of uterine blood flow as measured with the flowmeters and mean systemic blood pressure to increasing doses of epinephrine. The shaded area represents the dose range employed in the microsphere portion of the study. (0.2 to 0.4 ~-tg!Kg. ·min.). Uterine blood flow is presented as per cent of control flows.
per minute (p < 0.05) but no significant alteration in the mean systemic pressure (control of 92.0 mm. Hg ± 3. 7 and experimental of 92.3 mm. Hg ± 6.0). A typical response of uterine blood flow to the epi· nephrine infusion is demonstrated in Fig. 1. After studying the first two animals and calculating the uterine arterial blood flow from the microsphere data, a discrepancy between this data and the simultaneously observed flowmeter data was noted. This had not been our experience in the past8 and led to the discovery of a malfunctioning component in the gamma counter. From previous experiments, which permitted the comparison of 61 simultaneous determinations of uterine blood flow by the microsphere and flow probe methods, we were able to construct an
equati~n8 which related the two measurements: Microsphere flow (mi./min.) = Flowmeter flow (ml./min.)- 36 mi./min.
(3)
0.86 The uterine arterial flows for the first two animals studied were corrected with the use of Equation (3). As the per cent distribution of the microspheres was known and not affected by the gamma counter malfunction, it was possible to determine the arterial blood flow to each of the uterine tissues. Once the gamma counter was repaired this descrepancy did not recur. In a third animal we were unable to place the microspherc infusion catheter into the left ventricle.
Januaq 15, 1976
160 Rosenfeld, Barton, and Meschia Ano.
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Obstet. Grm·wl
Table II. The effect of a systemic infusion of epinephrine on total uterine blood flow and blood flow rate to the separate uterine tissues as measured with the microspherc method
Total uterine flow, without cervix (ml./min.): Control 566.7 720.6 Experimental 429.8 390.8 Per cent change -24.2 -45.8
l007.0 656.0 -34.9
748.8 391.7 -47.7
1818.0 508.6 -55.5
541.6 419.6 -22.5
793.7 478.5 -38.6
-38.5 ± 4.6*
CotyledoMry flcrw (ml.lmin.): Control 379.1 Experimental 299.6 -21.0 Per cent change
578.3 339.3 -41.3
848.9 589.7 -34.9
535.4 299.3 -47.7
1543.0 739.4 -52.1
443.1 368.1 -22.5
614.5 395.8 -35.6
-34.5
Myometrial flow ( ml./min.): Control 23.8 20.2 Experimental Per cent change 15.3
19.2 9.7 -49.7
45.7 26.0 -43.2
48.4 27.0 -44.1
53.5 21.3 -60.1
21.7 17.7 -16.3
27.7 19.5 -29.5
-36.9 ± 6.4*
Endometrial flow (ml. !min.): Control 163.8 IlO.O Experimental Per cent change -32.8
123.1 41.8 -66.0
112.8 40.0 -64.5
165.5 65.4 -60.5
221.6 47.9 -78.4
77.4 33.9 -56.3
151.5 72.2 -52.3
-58.7 ± 5.3*
t
t
Percentage cardiac output to the uterus: Control 7.94 Experimental 3.42
9.35 4.29
20.6 7.38
*
14.5 6.75
4.8*
13.1 ± 2.8 5.46 ± 1.9**
*p < 0.025. **The decrease is significant at p < 0.05. tCardiac output not available, see text. tCardiac output not available, no left ventricular catheter. See text.
Table III. Tissues and organs demonstrating a significant change in arterial blood flow during an epinephrine infusion Tissue or organ
Skeletal muscle Intra-abdominal fat Spleen Pancreas Mammary gland skin Total uterus
Per cent change*
p
+434.6 ± 112.4
0.025 <0.05 <0.01 <0.025 <0.05 <0.025
+ 180.0 ± 41.5 + 138.9 ± 29.2 -27.8 ± -44.2 ± -38.5 ±
7.6
10.1 4.6
*Mean ± S.E.M.
The catheter was left in the ascending portion of the thoracic aorta. Because of this, cardiac output and blood flow to those organs served by the ascending aorta were not calculated. Thus, we were able to analyze blood flow to all organs in only four animals, and flows to organs served by the descending aorta for an additional animal. Uterine blood flow data are available for all seven animals studied. Cardiac output was available in four animals. The mean cardiac output was 7,279 mi. per minute in the control period and 8,937 ml. per minute during the epinephrine infusion. The cardiac output increased 18 to 76 per cent in three animals and decreased 10.5 per cent in the fourth.
Table II shows the effect of epinephrine on myometrial, endometrial, and placental blood flows. When the separate uterine tissues are compared it can be seen that the endometrium exhibited a significantly greater decrease in blood flow (-58.7 per cent± 5.3) than either the myometrium (-36.9 per cent± 6.4, p < 0.025) or the placental cotyledons ( -34.5 per cent± 4.7 p < 0.005). There was no significant difference between the responses seen in the myometrium and placental cotyledons (p > 0.50). In the three ewes carrying singleton pregnancies, the responses to epinephrine in the pregnant and nonpregnant horns of the uterus were compared and no difference was observed. Cervical blood flow was also examined and found to decrease from 6.03 ± 1.06 to 3.94 ± 0.91 ml. per minute but these changes were not statistically significant. No significant changes were seen in ovarian and Fallopian tube flows. Because of the nature of the animal preparation and the method for measuring blood flow with the isotope-labeled microspheres, it was possible to compare blood flow changes within the uterus with changes of blood flow to other organs and tissues. The results of this comparison are presented in Tables III and IV and Fig. 3. Skeletal muscle obtained from the hindlimb and the chest wall, pooled samples from peritoneal and
Epinephrine on blood flow distribution 161
Volume 124 Number 2
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omental fat, and the spleen demonstrated significant increases in flow, whereas the uterine tissues, skin overlying the mammary gland, and the pancreas showed significant decreases in flow. There was a slight increase in flow to the hind leg skin that was not statistically significant. The data for organ blood flows in the four ewes in which cardiac output was determined were analyzed in order to determine the change in the distribution of cardiac output that occured during the infusion of epinephrine (Table IV). It should be noted that there was a significant decrease in the percentage of cardiac output going to the kidneys. The blood flow to the ovine mammary gland was noted to increase with gestational age of the animals in these experiments. Our data demonstrated control mammary blood flow of 15.9 ml. per minute at 85 days of gestation and 228 ml. per minute at 140 days of gestation. In each of the animals studied the infusion of epinephrine consistently caused a decrease in mammary blood flow ranging from 13 to 70 per cent but, because of the large variation in the control flows, the decrease demonstrated was not statistically significant (0.1 0 > p > 0.05). No significant changes were seen in arterial pH or Paco 2 during the studies. Values were consistent with those previously recorded. 9
Comment The vascular effects of catecholamines have been widely studied with systemic and individual organ infusions in both man and laboratory animals. 10 The new features of the present study are ( 1) the demonstration of epinephrine-induced vasoconstriction in
Table IV. Organs demonstrating a significant change in the percentage of cardiac ouput received, as determined in four ewes Per cent cardiac output* Organ
Control
Right kidney Left kidney Combined kidneys Spleen Pancreas Total uterus without cervix
5.3 ± 0.3 5.2 :t 0.5 10.5 :t 0.5 3.8 :t 0.4 2.1±0.4 13.1 :t 2.8
I Experimental 4.14 4.13 8.27 6.6 1.3 5.5
± 0.2 ± 0.5 :t
0.5
± 0.1 ± 0.3 ± 1.9
pt <0.05 N.S. 0.05 0.005 <0.025 <0.05
*Mean ± S.E.M. tPaired analysis, Student's t test.
each component of the vascular bed of the pregnant uterus and (2) the greater sensitivity of the reproductive tissues to the vasoconstrictive properties of epinephrine than the other organs or tissues of the body. The effect of catecholamines on uterine blood flow was first studied in detail by Robson and Schild. 11 Writing in 1938, they found that epinephrine produced uterine arterial vasoconstriction in both pregnant cats and spayed cats treated with estrone or with estrone and progesterone. The contractile response of the myometrium to catecholamines is known to depend on the hormonal state of the animal. 12 Their results indicated that the response of the uterine vasculature to epinephrine was free of female hormonal influence. In subsequent studies by Ahlquist and Woodbmf in pregnant dogs and by Adams and associates 1 in pregnant sheep, the vasoconstrictive effects of epineph-
162
Rosenfeld, Barton, and Meschia .\m.
rine on uterine blood flow were confirmed. Studies on the effect of systemic catecholamine infusions on blood flow to the gravid ovine uterus have been reported by Greiss. 3 In these studies, he reported a 50 per cent reduction in uterine vascular conductance following systemic infusions of greater than 0.5 ,ug/Kg./min. of epinephrine or norepinephrine. There was no significant difference in response over the period of gestation studied, 112 to 147 days. Our study. which demonstrates in ewes from 85 to 140 days of gestation a 39 per cent reduction in uterine arterial flows during systemic infusions of epinephrine ranging from 0.2 to 0.4 ,ug/Kg./min., is in good agreement with Greiss' data. The present study documents that, at the dose levels that were employed, the vasculature of all three uterine tissues (endometrium, myometrium. and placental cotyledons) are sensitive to the vasoconstrictive effects of epinephrine. It was further demonstrated that the response of the endometrial vasculature to epinephrine (a 59 per cent reduction in blood flow) was greater than that noted in either the placental cotyledons (a 35 per cent reduction) or the myometrium (a 37 per cent reduction), whereas the responses in these two tissues were similar. This documentation of a vascular response by all of the uterine tissues to epinephrine suggests the presence of alpha receptors in the arterioles of each of the uterine tissues and presents evidence that these receptor sites remain sensitive to the vasoconstrictive effects of epinephrine during pregnancy. Arterial blood flow to the mammary gland and to the skin overlying the mammary gland was decreased by the epinephrine infusion (see data). Mammary gland arterial blood flow has been shown to decrease in response to epinephrine. 13 · 14 In contrast to the mammary gland skin, skin from the ventral surface of the hind leg did not demonstrate a significant reduction in blood flow. Skin vasculature may vary in its reactivity to systemic catecholamine infusions according to its location. In the dose range of epinephrine studied here, 0.2 to 0.4 ,ug/Kg./min .. skeletal muscle, intra-abdominal fat, and splenic blood flows were all increased significantly, whereas blood flows to the pancreas were decreased. The vasodilatory effect of epinephrine on skeletal muscle has been attributed to beta/receptor stimulation. Low doses of epinephrine given intra-arterially into the forearm muscle of man produce a transient sharp rise in the arterial flow of greater than 100 per cent of control, followed by a lower, sustained flow that is greater than 50 per cent of control. 15 These results are supported by data from the present study which
J
Januarv L'i. 19711 Obstet. GynewL
demonstrate a striking increase in blood flow to chest wall and hindlimb muscle(> 400 per cent of control) in the face of unaltered mean systemic pressure. Epinephrine has been domonstrated to cause an increase in blood flow to adipose tissue in this study. The phenomenom has been demonstrated in canine subcutaneous adipose tissue infused with epinephrine at a concentration of 0.0 I ,ug per milliliter. 16 In the same study isoproterenol was noted to increase fat blood flow, suggesting that beta-receptor stimulation can lead to vasodilation in adipose tissue. The splenic vasculature has been widely studied and found to respond to infused catecholaminesY· 18 Beta-adrenergic stimulation led to increases in splenic blood flow, whereas alpha stimulation decreased flow. Epinephrine was demonstrated in the cat to increase splenic blood flow from 60 to I 60 per cent of control flows 17 • ts following doses from 0. I to 1.0 ,ug per kilogram. In the pregnant sheep studied here splenic blood flow also increased without a 'ystemic blood pressure increase. It is possible that with the use of higher doses of exogenous epinephrine. splenic vasoconstriction might have occurred. The arterial bed of the pancreas has been shown by other investigators to possess both alpha and beta receptors, 19 but the response of this organ to catecholamines is by no means settled. We were able to demonstrate a significant reduction in pancreatic blood flow of approximately 28 per cent, occurring 2 to 3 minutes after the initiation of the epinephrine infusion, and not associated with an alteration in systemic arterial pressure. Arterial blood flow to tissues such as heart, brain, kidney. liver, and bowel has been found to be altered by catecholamines in Yarious studies, but did not demonstrate a significant change following the 0.2 to 0.4 ,ug/Kg. ·min. epinephrine infusion employed here in pregnant sheep. Though no significant change in blood flow to the kidneys was documented during the epinephrine infusion, the per cent cardiac output reaching them was significantly reduced. As the skeletal muscle makes up a large part of the body mass in these animals. it is conceivable that the increase in flow to this tissue (>400 per cent) accounts for both the increase and redistribution of cardiac output. Epinephrine is of use in various clinical situations in obstetrics, such as an adjuvant for local anesthetic solutions. If epinephrine were inadvertently given in sufficient quantity into the vascular system during a local anesthetic injection, it might have a deleterious effect on uterine blood flow in the pregnant human. Slow intravenous or subcutaneous epinephrine in the human subject has little effect on mean blood pressure,
Epinephrine on blood flow distribution 163
Volume 124 Number 2
but does significantly decrease peripheral resistance and increase both cardiac output and heart rate. 10 In the experiments reported here, a dose of epinephrine that produced no significant change in mean systemic blood pressure did significantly increase muscle blood flow, did significantly increase heart rate, and in three
of four instances did increase cardiac output. The same dose also led to a 38 per cent reduction in total uterine blood flow in the pregnant ewe. On the basis of these findings, it can be suggested that deleterious effects might occur in a pregnant woman exposed to relatively low arterial concentrations of epinephrine.
REFERENCES 1. Adams, F. M., Assali, N., Cushman, M., and Westersten, A.: Interrelationships of maternal and fetal circulations, Pediatrics 27: 627, 1961. 2. Ahlquist, R. P., and Woodbury, R. A.: Influence of drugs and uterine activity upon uterine blood flow, Fed. Proc. 6: 305, 1947. 3. Greiss, F. C., Jr.: The uterine vascular bed: Effect of adrenergic stimulation, Obstet. Gynecol. 21: 295, 1963. 4. Greiss, F. C., Jr.: Differential reactivity of the myoendometrial and placental vasculatures: Adrenergic responses, AM.]. 0BSTET. GYNECOL. 112: 20, 1972. 5. Ladner, C., Brinkman, C. R., Weston, P., and Assali, N. S.: Dynamics of uterine circulation in pregnant and non-pregnant sheep, Am.]. Physiol. 218: 257, 1970. 6. Barton, M. D., Killam, A. P., and Meschia, G.: Response of ovine uterine blood flow to epinephrine and norepinephrine, Proc. Soc. Exp. Bioi. Med. 145: 966, 1974. 7. Rosenfeld, C. R., Killam, A. P., Battaglia, F. C., Makowski, E. L., and Meschia, G.: Effeect of estradiol-17-beta on the magnitude and distribution of uterine blood flow in nonpregnant, oophorectomized ewes, Pediatr. Res. 7: 139, 1973. 8. Rosenfeld, C. R., Morriss, F. H., Makowski, E. L., Meschia, G., and Battaglia, F. C.: Circulatory changes in the reproductive tissues of ewes during pregnancy, Gynecol. Invest. 5: 252, 1974. 9. Battaglia, F. C., Behrman, R. E., de Lannoy, C. W., Hathaway, W., Makowski, E., Meschia, G., and Seed, A. E.. Exposure to high altitude of sheep with different haemoglobins, Q.]. Exp. Bioi. 54: 423, 1969. 10. Innes, I. R., and Nickerson, M.: Drugs acting on postganglionic adrenergic nerve endings and structures
11. 12. 13.
14.
15. 16.
17.
18. 19.
innervated by them, in Goodman, L. S., and Gilman, A., editors: The Pharmacologic Basis of Therapeutics, New York, 1970, pp. 478-523. Robson,]. M., and Schlid, H. 0., Effect of drugs on the blood flow and activity of the uterus, ]. Physiol. 92: 9, 1938. Robson,]. M., and Schild, H. 0.: Response of eat's uterus to hormones of the posterior pituitary lobe, J. Physiol. 92: I, 1938. Hebb, C. 0., and Linzell,]. L.: Some conditions affecting the blood flow through the perfused mammary gland, with special reference to the action of adrenalin, Q. J. Exp Physiol. 36: 159, 1951. Houvenaghel, A.: Action of catecholamines on blood flow through the mammary gland in unanesthetized lactating small ruminants, Arch. Int. Pharmacodyn. 186: 190, 1970. Whelan, R. F., and de Ia Lande, I. S.: Action of adrenalin on limb blood vessels, Br. Med.]. 19: 125, 1963. Ballard, K., Cobb, C. A., and Rosell, S.,: Vascular and lipolytic responses in canine subcutaneous adipose tissue following infusion of catecholamines, Acta Physiol. Scand. 81:246,1971. Greenway, C. V., and Stark, R. D.: The vascular responses of the spleen to intravenous infusion of catecholamines, angiotensin, and vasopressin in the anesthetized cat, Br.]. Pharmacal. 38: 583, 1970. Ross, G.: Effects of catecholamines on splenic blood flow in the cat, Am.]. Physiol. 218: 1079, 1967. Barlow, T. E., Greenwell, ]. R., Harper, A. A., and Scratcherd, T.: The effect of adrenalin and noradrenalin on the blood flow, electrical conductance, and external secretion of the pancreas,]. Physiol. 217: 665, 1971.