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Distribution of cardiac output in the unstressed pregnant guinea pig
Distribution of cardiac output in the unstressed pregnant guinea pig LOU IS L. H. PEETERS GERRIE GRUTTERS CHESTER B. MARTIN,
JR.
Nijmegen, The Netherlands Cardiac output (CO) and organ flows were measured in five nonpregnant and 14 pregnant unstressed guinea pigs between the thirty-ninth and sixty-fifth postconceptional day by means of radionuclide·labeled microspheres. Blood pressure, heart rate, and cardiac output in nonpregnant animals were 60 torr, 234 bpm, and 248 ml/min, respectively. These parameters did not change significantly during pregnancy. The uterine fraction of cardiac outpUt increased to ""1SOA:. at term and there was an equivalent dacrease in the CO fractions to the carcass and skin. Blood flow per gram of wet weight increased during pregnancy by approximately 140% and 70% for the thyroid and gastrointestinal tract, respectively, but did not change significantly for the heart, brain, kidneys, and adrenals. In pregnant animals near term the weight of the heart, kidneys, intestines, and lungs was approximately 25% lower than that observed in nonpregnant guinea pigs. (AM. J. OasTET. GYNECOL 13a:11n, 1980.)
CARDIOVASCULAR CHANGES constitute an important part of the maternal adaptation to pregnancy. Information on this matter indicates marked species differences in both total cardiac output (CO) and its distribution. During primate 1• 2 and sheep 3 pregnancy CO increases by about 30% and 75%, respectively. Changes in CO distribution tend to be more pronounced when the CO fraction to the uterus in a particular species is larger. The uterine fraction of CO at term has been found to vary between 5% in the monkey2 and 16% in the sheep, 3 whereas the size of the uterus plus conceptus in these species grows to 6% and 8% of maternal weight, respectively. In the pregnant guinea pig the uterus plus conceptus may constitute as much as 30% of maternal weight,4 which is considerably larger than in other small animals such as the rabbit (8%) 5 and rat (18%). 6 Furthermore, the relatively large fetus in the near-term guinea pig grows at a rate of 7% per day. 7 Therefore, it is likely
Fr-om the Department of Obstetrics and Gynecology, Catholic University. Received for publication june 3, 1980. Accepted September 3, 1980. Reprint requests: Dr. Louis L. H. Peeters, Department Obstetrics and Gynecology, St. Radboud Hospital, University of Nijmegen, Geert Grooteplein Zuid 14, Nijmegen, The Netherlands. 0002-9378/80/251177+08$00.80/0
© 1980 The C. V. Mosby Co.
of
that during late pregnancy major cardiovascular alterations are necessary in this species to accommodate the rapid growth of the already large fetus. The objective of the present study was to investigate the physiologic changes in maternal cardiovascular dynamics during the course of pregnancy in the guinea pig. To avoid interference from anesthesia and surgical stress with normal cardiovascular8- 10 and rnetabolic' 1 function, experiments were performed in conscious, unstressed animals.
Material and methods Experiments were carried out in five nonpregnant and 14 pregnant albino guinea pigs ranging in weight from 813 to 965 and from 806 to 1,405 grams, respectively. All animals were obtained from the 'T. N. 0." Institution, Rijswijk, Holland. Pregnant animals with known postconceptional dates arrived in our laboratory shortly after conception. The animals were allowed at least 2!1! weeks for adaptation to their new environment. The animals received food and water ad libitum until operation. In pregnant animals operation was performed before the fifty-fifth postconceptional day (term = 68 days) because of a high abortion rate associated with operation later on in pregnancy. General anesthesia was induced with ketamine hydrochloride (2 mg · 100 g- 1 , subcutaneously), xylazine (400 p,g · 100 g- 1, intramuscularly) and atropine (5 1177
1178
Peeters, Grutters, and Martin
Decembn l''· l%l> \m.
cardiac output (mi. rnin- 1 . kg- 1 )
l D
D
300
D
D
D
0
D D
200
D
D
Do
D D
100
1c->"f-'-,----~--~~-~,---·--,]--~ pregnant
40
45
50
55
60
gestational age (days)
Fig. 1. CO during guinea pig pregnancy (o). The black square (•) indicates the mean ± SEM for the nonpregnant animals.
Table I. Hemodynamic measurements in guinea pig pregnancy Pregnant Nonpregnant (n = 5)
HR (bpm) Mean systemic BP (torr)
39-56 days 157-66 days (n = 8) (n = 6)
=
234 ± 13 60 ± 3
250 ± 22 60 ::t 3
11 230 58± 4
248 ::t 30 280 ± 38
269 ::t 21 276 ::t 18
231 ± 13 212 ::t 18
CO:
ml · min- 1 ml· min-'· kg- I
Values are means :t SEM.
p,g · 100 g- 1 , intramuscularly). Adequate anesthesia was maintained throughout operation by adding nitrous oxide by mask as required. The animals were placed in the dorsal recumbent position. By means of techniques described elsewhere, 12 polyethylene catheters of standardized caliber (outside and inside diameters = 0.80 and 0.40 mm, respectively) with a tapered and slightly curved tip were inserted into the left common carotid artery and a femoral artery and advanced into the left ventricle and abdominal aorta, respectively. The catheters were tunneled subcutaneously and exteriorized between the scapulae. Most animals recovered within 4 to 6 hours after operation. During this recovery period the animals were kept warm with an infrared light. Food intake was sharply reduced on the first day after operation but increased to preoperative quantities within 3 days. This phenomenon was considered to be an indication of complete fetal and maternal recovery since aborting and nonsurviving animals showed incomplete restora-
J.
Ohstet. Cnwcu!
tion of food intake. 1n order to minimize postoperati\c manipulation, the catheters were flushed once even other dav with heparinized saline (I: 400). The CO distribution was determined between the fifth and fourteenth postoperative days. This time coincided in nonpregnant animals with diestrus and in pregnant animals with a range between the thirty-ninth and sixty-fifth postconceptional day. For the measurements, the animals were placed in a cardboard box of about four times their body size. Heart rate (HR, in beats per minute) and blood pressure (BP, in torr) in the abdominal aorta were recorded promptly. Stable readings were usually obtained within 20 minutes and were assumed to indicate steady-state conditions. The CO distribution was determined by means of the microsphere technique. Microsphere technique. Radioactive "carbonized" microspheres, labeled with Sr 85 , with a diameter of 15 ± 2 p,m (SD), and suspended in 10% dextran, were obtained from the supplier (3M Company, St. Paul, Minnesota). Preparation and handling of the microspheres have been described previously in detail. 1a The microsphere suspension was diluted aseptically with normal saline to a final concentration of 400,000 microspheres per milliliter. A sample of this suspension was placed in a preweighed glass injection vial and warmed to 39° C. Based on previous experience in fetal lambs 14 a total of 60,000 microspheres per 100 gm of maternal weight was injected (with constant mixing) into the left ventricle over a 50-second period. Starting from 30 seconds before and continuing until 30 seconds after the injection, a reference sample of blood was withdrawn at a constant rate (0.80 ml/min) from the abdominal aorta. This method of mechanical integration 15 permits blood flow calculation by the formula: Organ flow (ml/min) == number of microspheres in organ . hd . . X Wit rawa1 rate. number of miCrospheres m arterial reference sample The CO was calculated as the sum of all organ flows. Before and after the infusion of microspheres the position of the left ventricular catheter was verified with the pressure transducer. HR and BP in the abdominal aorta were recorded for 5 minutes after completion of the microsphere experiment. A blood sample was then collected from the abdominal aorta for measurement of blood gases, pH, hemoglobin, and hematocrit. Subsequently the animal was killed with an overdose of Pentothal: the catheter position was checked at autopsy, and all organs were dissected. On two occasions with suspicious pressure tracings, the tip of the left
Distribution of cardiac output
Volume 1:~R Number K
1179
Table II. Organ weights (grams) during guinea pig pregnancy Pre{f'Wnt Organ
Total maternal mass Total fetal mass Uterus with contents Myometrium Mammary gland
Nonpregnant (n = 5)
39-56 da~s (n = sj
896 ± 3I
972 ±54 92 ± 22t
1.147 ± 61* 25I ± 23*
II8 ± 23t I2 ± I II± I
294 ± 29* 20 ± :i 9 ± I
2 ± I 2 ± I 6 ± 2
I
57-66 days (n = 6!
Carcass Skin
484 ± 28 I67 ± 9
439 ± 17 I66 ± 9
4S6 ± 18 181 ± 19
Brain Heart Kidneys Gastrointestinal tract Pancreas Spleen Liver
4.4 3.6 8.8 43 1.4 2.I 38
4.2 2.5 6.9 38 1.7 1.5 32
4.0 2.6 6.6 31 1.2 1.2 36
J
~
• ..-. .... .,.
uuuo.::~
Adrenals Thyroid Ovaries
± ± ± ± ± ± ±
O.I 0.4 0.4 I 0.4
o.s 2
± ± ± ± ± ± ±
0.1 0.2t 0.4t It 0.2 0.1 2
10.1 ± 1.2
6.1 ± l.Ot
7.8
0.90 ± O.I3 O.I5 ± 0.02 0.40 ± 0.09
0.68 ± 0.04 O.I3 ± 0.02 0.24 ± 0.02
0.82 O.I3 0.22
± ± ± ± ± ± ± ± ± ± ±
O.l 0.3t 03t I* 0.1 () 1 3 0.9
O.I2 0.02 0.02
Values are means ± SEM. *Significant change (unpaired t test, p < 0.05) as compared to early pregnancy (39 to 56 days). tSignificant change (unpaired t test, p < 0.05) as compared to the nonpregnant state.
ventricular catheter was located in the aortic valve. In these animals no myocardial blood flow could be calculated and CO was determined by adding an estimated myocardial flow. It was calculated that this estimation procedure could introduce a maximum error of less than 4%. The tip of the abdominal aorta catheter was always located between the level of the kidneys and the aortic bifurcation. Organ dissection. First the skin was removed and weighed. After the dissection of both mammary glands, multiple skin aliquots were taken from standardized areas and placed into preweighed counting vials. Then each of the following organs was carefully dissected and placed in preweighed vials: thyroid, thymus, lungs, heart, brain, and intra-abdominal organs except for intestines and uterus. Paired organs were placed in separate vials. Lungs and liver were cut into suitable pieces and divided over several vials. The gastrointestinal tract was opened longitudinally over its entire length and the contents were rinsed out with normal saline. The cleaned gastrointestinal tissue was divided into four portions that were anatomically easy to recognize: stomach, small intestines, cecum, and colon. These pieces were reduced to suitable aliquots and also placed in preweighed counting vials. The uterus was dissected next. The placentas were divided into upper and lower portions, as described previousiy, 16 and piaced in preweighed vials in the same order as their location within
the uterus. The dissection of the uterine horns, cervix, and vagina was performed as described by Chaichareon and co-workers. 17 The remainder of the maternal body, referred to as the "carcass," and consisting primarily of skeletal muscle, bone, connective tissue, and fat, was ground with a Waring Blendor, and aliquots of the homogenate were placed in preweighed vials. The height of all tissue aliquots in the vials was kept below 1.0 em to avoid a loss in counting efficiency. 13 Finally, the radioactivity in each aliquot and in the reference sample was determined with a well scintillation counter (Packard Autogamma Scintillation Counter 5220). For statistical reasons 18 the actual number of microspheres was determined in each sample from the counts per minute per microsphere and the counts per minute per sample. All reference samples contained at least 700 microspheres. In some animals the smallest organs, such as the thyroid and ovaries, contained less than 200 microspheres, giving rise to an increased statistical error in the related flow determination. Good mixing of the microspheres in the present study was suggested by the close correlation between the number of microspheres distributed to paired organs (kidneys and adrenals: r = 0.95 and 0.94 in nonpregnant animals [n = 5] and r = 0.96 and 0.92 in pregnant animals [n = 14]). In the text, means are given together with their standard errors. When needed, the results were evaluated
1180
Decem her l :) i qxo Am. ,I. ObstN. (;, 1wco!
Peeters, Grutters, and Martin
weight of gastro-intestinal
tract {grams)
Table III. Percent distribution of CO guinea pig pregnancy
--y:::53.6-0.4x r=0.64 p<0.05
50
Pregnani Organ
+--o__ _
40
o--cr-----o__ _
0
0
---tr--Q_
0
Lljj----- -----
:: I---
·~~--~---,,----,---,,0--0--~] 40
45
50
durin~
55 60 gestational age (days)
Fig. 2. Change in gastrointestinal weight in the course of
Uterus Mammary gland Carcass Skin Brain Heart
Kidneys Gastrointestinal tract Pancreas Spleen Llvert Lungs§
Nonpregnant (n = 5)
0.5 0.7 46 11.5 2.1
± 0.1 ± 0.2
±: 1 ±: 1.7 ±: 0.5
39-56 days (n = 8)
6.4 1.5 44 9.0 1.9
± 0.8*
±: ±: ±: ±:
0.2 4 0.9 0.2
I 57-66= day., (n
18.2 1.4 34 5.4 1.7
.....
61
±: ±: ±: ±: ±:
1.8t 0.3 I*
0.9* 0.2
1.0:::: 0.5
3.0 ± 0.3
14.3 ±: 0.5 16.4 ±: 1.7
11.1 ±: 1.3* 17.3 ±: 1.4
11.7 ±: 1.0* 20 ±: 2
2.3 ±: 0.4* 1.5 ±: 0.3 0.2 ±: 0.1 7± 1
1.4 ±: 0.3 1.3 ±: 0.4 0.4 ±: 0.1 f) +- 1
0.9 ±: 1.7 ±: 0.3 ±: 5±:
0.2 0.5 0.1 1
A
1
-'-
....:....
1\()
'!.::J
guinea pig pregnancy (o). The black square (!!) indicates the
mean ± SEM for the nonpregnant animals. uterine blood flow (ml. min-1) -------------------,
80l 0
60~
40~
0 0 0
0
0
20l ~0 non-
I
0
0
0 0
0
!J
0
~~-----.------~-----.------~----~
pregnant 40
45
50
Values are means ±: SEM. *Significant change (unpaired t test, p <0.05) as compared to the nonpregnant state. tSignificant change (unpaired t test, p <0.05) as compared to early pregnancy (39 to 56 days). tHepatic artery flow. §Fraction of injected microspheres recovered from the lungs (bronchial artery flow and systemic arteriovenous shunting).
55 60 gestational age (days)
Fig. 3. Relationship between total uterine blood flow (ml · min-') and gestational age (o). The black square (•) indicates the mean uterine blood flow for the nonpregnant animals. statistically by Student's t test (unpaired) or by linear regression analysis.
Results The data for nonpregnant and two groups of pregnant animais on HR, mean BP, and CO are iisted in Table I, whereas the pattern of CO per kilogram with postconceptional age is illustrated in Fig. 1. None of these parameters changed significantly during pregnancy. Changes in the organ weights, the fractional distribution of CO, and the regional blood flow are displayed in Tables II, III, and IV, respectively. The data in Table II show that the size of the uterus in-
creased progressively during pregnancy. Furthermore, the weights of the heart, lungs, kidneys, and intestines in pregnant animals were 20% to 30% below nonpregnant values. Fig. 2 shows that during pregnancy the weight of the gastrointestinal tract decreased toward term. Data on the distribution of CO (Table Ill) demonstrate that in the last 10 days of pregnancy the rapidly increasing uterine fraction of CO was paralleled by a significant reduction in the CO fractions to the carcass and skin. Also the CO fractions to the kidneys and pancreas changed significantly during gestation. Absolute and relative organ flows are listed in Table IV. During pregnancy the upper placental blood flow accounted for almost the entire rise in uterine blood flow. The almost unchanged absolute blood flow to the myometrium indicates that the marked increase in myometrial mass (Table II) was coupled with a corresponding decrease in fiow per gram of tissue. Fig. 3 illustrates the progressive increase in UBF with gestation. This increase was due to an increase in PBF, which was closely correlated with the increase in total fetal weight (Fig. 4). The most pronounced changes in nonreproductive tissue flow were observed in the carcass and skin, where absolute flow decreased in late pregnancy by more than
Volume l:JR :-lumber H
Distribution of cardiac output
1181
Table IV. Regional blood flow during guinea pig pregnancy Pregrwnt
I ml · min-
57-66 days (n == 6)
39-56 days
Nonpregnant (n = 5}
(n
gm- 1
Orgar•
ml · min- 1
Mvometrium Upper placenta Lower placenta Mammary gland
2.1 ::t 0.8
80 ::t 17
2.0 ::t 0.6
36 ± 5
2.7 ::t 0.5 13 ::t 2* 0.4 ::t 0.1 * 4.1 ::t 0.7
Carcass Skin
115 ::t 14 29 ± 7
25 ± 4 15 ± 2
120 ± 14 24 :±: 3
1
100
ml · min- 1
= 8)
I ml · min-
1
100 gm- 1
ml · min- 1
I ml ·min-' 100 gm"
Uterus:
Brain Heart Kidneys Gastrointestinal tmrt: Stomach Small intestine Cecum Colon Pancreas Spleen
Liver:j: Adrenals Thyroid Ovaries
4.9 9.9 36 39 8.0 15.6 7.2 8.2 2.3 4.6 1.3 0.74 0.17 0.31
:±: 0.6 ± 1.5
± 5 ± 2 ± 1.1 ± 0.9 ± 0.4 ± 0.4 ± 0.6 ± 1.7 ± 0.3 ± 0.08 :t 0.03 :t 0.05
I lO 305 402 90 131 107 66
± 13 ± 46 :t 51 :t 5
:t 15 :±: 12
:t 4 68 ± 5
182 277 3.9 90 90 75
±51 ± 18 ± 0.6 :t 12 ± 18 ± 14
5.2 7.9 28 47 9.2 16.1 11.2 !0.0 5.6 4.1 0.7 0.60 0.24 0.54
20 ::t 121 ::t 11 ± 41::!:
4* 16* 2* 7
27 ± 4 15 ± 1
± 0.3 ± 0.9 ± 3 ± 5
± 1.0 ± 1.8 ± 1.2*
± !.3 ± 1.4 ± 0.7 ± 0.1
:t 0.06 ± 0.05
± 0.06*
126 290 413 131 15.5 127 134 96 337 256 2.0
± 10
± 58 ± 46 ± II* ± 11 ± 16 ± 15* ± !0* ± 51 ± 29 ± 0.2 87 ± 7 146 ± 31 240 ± 29*
2.4 36 0.12 3.1
::t 0.3 ± 4 ± 0.02
::!: 1.0
77 ± 8t 1:3 ± 3t 4.3 7.8 29 49 9.3 18.0 11.4 !0.2 3.3 3.7 0.9 0.52 0.23 0.30
:±: 0.4 ± 2.0
± 2 ± 2 ± 0.9
± 1.1 ± 0.4* ± 0.6* ± 0.7 ± 1.3 ± 0.1 ± 0.04 ± 0.06 ± 0.07
1
=
14 3 224 t 20t 5 t It :~3
7
18
t
2t
7
:~
2t
= 10 = !04
108 346 438 ::!': 156 :+:: 216 :.!: 168 ± 16i ::t !!9:.! 285;!: 259;!: 2.7 77 ± 217 :t 141 :t
34 II t 25* 14* 31* !!" 33 77 3
=()
9
41 2H
Values are means ± SEM. *Significant change (unpaired t test, p < 0.05) as compared to the nonpregnant state. tSignificant change (unpaired t test, p < 0.05) as compared to early pregnancy (39 to 56 days). tHepatic artery flow.
30% as compared to early pregnancy (Table IV). Changes in blood flow to other nonreproductive tissues were, in general, small. Only the perfusion of the gastrointestinal tract increased significantly during pregnancy. However, while the flow per gram of tissue increased by 70%, absolute blood flow increased by only 26% because of the lower tissue weight during pregnancy. Blood flow increases in different regions of the gastrointestinal tract were largest in the cecum and smallest in the stomach.
Comment These observations are probably the first reported on CO distribution in unstressed pregnant guinea pigs. Blood flows in this study were determined by means of the microsphere technique. Although this method has been used in pregnant and nonpregnant guinea pigs for several years, its validity in this species has never been explored. In the present study it was found in nonpregnant animals that 5% of the injected microspheres were recovered from the lungs, which is a lower amount than that which has been reported for microspheres of similar size in unanesthetized rabbits. 19 In a preliminary study in two pregnant guinea pigs, a
negligible number of microspheres was collected in a blood sample withdrawn simultaneously with the arterial reference sample from the upper portion of the inferior vena cava. Since the fraction of injected microspheres in the lungs also did not increase during pregnancy, it was concluded that 15 p.m microspheres are not shunted in significant amounts across the hemochorial placenta of the conscious guinea pig. The microsphere injection as performed in the present study neither gave rise to any noticeable maternal discomfort nor induced any appreciable change in HR and BP. However, experiments carried out in preparation for this studv indicated that injecting a dose about three times as large as in the present study or infusing the suspension at twice the speed we employed could give rise to a transient rise in maternal BP and, occasionally, nystagmus. These effects have been previously described for the rabbit 20 and dog. 21 The injection of an ice-cold microsphere suspension may induce shivering. Finally, adequate mixing of microspheres at the injection site was suggesred by the dose correlation between the number of microspheres recovered from paired organs. The data on HR and BP in the nonpregnant animal
1182 Peeters, Grutters, and Martin Am.
December Ui, l\l80 J. Obstet. Gvnecol.
total upper placental blood flow (mi. min-1)
80
60
y = 0.16x-0.63 r= 0.93 p<0.0001
c
40
20
c
100
200
300
total fetal weight (grams)
Fig. 4. Relationship between total upper placental blood flow and total weight of the conceptus.
cardiac output fractions (percent)
80
lllillskin
carcass
•
uterus
60
40
20
nonpregnant 40
45
50
55
60
gestot ionol age (days)
Fig. 5. The relationship of blood flow between the uterus, on the one hand, and the carcass and skin, on the other hand, in the course of guinea pig pregnancy.
obtained in the present study were similar to those reported previously for unrestrained guinea pigs. 22 • 23 Neither parameter changed significantly in the course of pregnancy. In several species mean arterial BP tends to decrease, and HR to increase, during pregnancy. The CO of 280 ml/min in the nonpregnant guinea pig was similar to that reported for the rat. 24 As expected from the relationship between CO and body weight, 25 the CO of the guinea pig per kilogram was twice as high as that of the rabbit 26 and monkey 2 and more than three times as high as that found in man 21 and sheep. 3 In contrast with the sheep 3 and the human, 1 the guinea pig does not experience an increase in CO during pregnancy. Apparently all circulatory demands in the
Fig. 6. The redistribution of CO during pregnancy in the guinea pig.
pregnant state are effectively met by a redistribution of CO. Perhaps this is related to the fact that the CO of small mammals is already quite high in the nonpregnant state. A marked increase in the uterine fraction of CO to as much as 20% at term dominated the redistribution of CO during guinea pig pregnancy. In other mammals this percentage has been found to vary between 5% and 18%, the fraction being generally in proportion to the term fetal-maternal weight ratio. 3• 5• 6· 28 Therefore, the higher CO fraction to the uterus in the near-term guinea pig is probably related to the higher fetalmaternal weight ratio in this species. Because of the correlation between placental blood flow and total weight of the conceptus (Fig. 4). the placental blood flow per unit of fetal weight was almost constant between the fifty-fifth and sixty-fifth postconceptional day. In contrast, Bjellin and co-workers 16 reported a gradual decrease of placental blood flow per kilogram of fetal weight with gestation. This observation might be related to the acute setup of their study. A detailed discussion on regional blood flow in the pregnant uterus of the guinea pig will be presented in a separate report. Blood flow to the mammary gland was found to increase in guinea pig pregnancy although the increase was less striking than the one reported for the sheep. 29 The rise in mammary flow was proportional to the weight increase, indicating no change in relative flow. Although ovarian blood flow was significantly increased during pregnancy, the increase varied markedly and seemed related to the number of conceptuses in the ipsilateral horn, as reported by Bjellin and coworkers.16 The reduction in ovarian blood flow in late pregnancy might be related to the increasing endocrine role of the placenta with advancing gestation.
Distribution of cardiac output
Volume l:lH Number H
In the last IO days of pregnancy, changes in nonreproductive tissue flow were dominated by decreases in CO fractions to the carcass and skin, ·which seemed to be associated with the rapidly increasing uterine fraction of CO. The resulting decrease in absolute flow was particularly impressive in the large vascular bed of the carcass (Fig. :)). Since BP remained unchanged, lower blood flows in the carcass and skin were a result of an increase in vascular resistance. It is not clear whether this increase in vascular resistance is due to neural, endocrine, or metabolic factors. The pregnancy-induced CO redistribution in the guinea pig resembles that in the near-term ewe.a suggesting that similar mechanisms mav be operating in these species. Since epinephrine infusion in the near-term ewe causes vasoconstriction in the uterus and a marked vasodilatation in the carcass.ao it is possible that the redistribution of CO in the pregn
REFERENCES I. Lees, M. M., Taylor, S. H., Scott, D. B., and Kerr, M.G.:
A study of cardiac output at rest throughout pregnancy, Br. J. Obstet. Gynaecol. 74:319, 1967. 2. Lees, M. M., Hill, J.D., Ochsner, A.]., III, Thomas, C. L., ;,nrl Nnvv
3. 4. 5. 6. 7. 8. 9.
M. T·
M:HPrn:~l
nbrPnt:JL :Jnrl mvnmPtrial
hi~d flo~· of-~h~~he-s-;;~-~~~k~y~d~;i;;g -~~~ri~~ ~~;;t;~~~ tions. AM.]. OasTET. GYNECOL. ll0:68, 1971. Rosenfeld, C. R.: Distribution of cardiac output in ovine pregnancy, Am. J. Physiol. 232:H231, 1977. Fuchs, F.: The red cell volume of the maternal and foetal vessels of the guinea pig placenta, Acta Physiol. Scand. 28:162, 1952. Duncan, S. L. B.: The partition of uterine blood flow in the pregnant rabbit, J. Physiol. (Lond.) 204:421, 1969. Csepli. J., Menyhart, j.. Lengyel, S., Bodnar, J., and Turoczi, F.: Blood circulation in pregnant rats, Acta Chir. Acad. Sci. Hung. 9: 143, 1968. Draper, R. L.: The prenatal growth of the guinea pig, Anat. Rec. 18:369, 1920. Vatner, S. F., and Braunwald, E.: Cardiovascular control mechanisms in the conscious state, N. Engl. J. Med. 293:970, 1975. Wyler. F.: Effect of general anesthesia on distribution of
cardiac output and organ blood ftov; in the rabbit: Halothane and chloralose-urethane,]. Surg. Res. 17:381, 1974. 10. Sasaki, Y., and Wagner, H. N., Jr.: Measuremem of the distribution of cardiac output in unanesthetized rats, j. Appl. Physiol. 30:879, 1971.
1183
creased significantly during pregnann. The fall in absolute flow was not significant. because of the reduction in nro-~n wPicrht A rt="rlnctinn in rion tn ·-··--!:)·-·· -... (~() h·;u ····-··-·-... thP --·~-o~·--
-~-~-,------
~---
kidneys has also been observed in the sheep. This phenomenon might hFe been triggered b~ a mechanism similar to the one which caused the inneaS<'d vascular resistance in the carcas~ and skin. The guinea pig fetus grows at a rate of ;c;;. a day in the last 2 weeks of pregnancy.' This rapid growth rate gives rise to a variety of metabolic changes. 11 Food intake increases markedly. A steady increase in gastrointestinal blood How during the course of pregnancy may be related to this increased nutritional demand. Whether the concomitant fall in intestinal weight could also be attributed to the increased rnetaboli( demands of pregnancy is not clear. \\'eight reduction of other viscFr<~l Sf'Frns to a svsternic rddJFr than ------- nn!ans -o- sU!!!!est - oo -. a local effect. Further investigation. such d' measurement of wet weight/dry weight ratios and possiblv tissue composition, is needed to solve thi~ q11e-;tion. The cardiovascular adaptation in the pregnant guinea pig is summarized in Fig. 6. The redistribution of CO was characterized mainly by a shift of flm-. from the carcass to the pregnant uterus. Flow changes in the visceral organs were small and probablv related to a variety of metabolic changes necessary to accommodate the rapid growth of the relativelv large fetll'.
11. Sparks. J. W., Pegorier, J. P., Girard. J., and Battaglia. F. C.: Substrate concentration changes during pregnancy in the guinea pig studied under unstressed stt'adv state conditions. Submitted for publication. 12. Sji'>quist. P. 0. B., Bjellin, L., and Carter, A.M.: Effect of a vasopressine analo!Iue (N"-IIlvcvl-!Ilvcvl-~~:lvcvl-8-lvsine) on organ blood flo; in the p~egn;n't guin'e; pig. Act~ Pharmacol. Toxicol. 40:369. 1977. 13. Rosenfeld, C. R., Killam, A. P., Battaglia~ f. C.~ ~.fakowski, E. L., and Meschia, G.: Effect of estradiol-17{:1 on the magnitude and distribution of uterine blood flow in nonpregnant, oiiphorectomized ewes, Pediatr. Rc,. 7: 1:>9, 1973. 14. Peeters, L. L. H., Sheldon, R. E., Jones, ~~ D., Jr, Makowski, E. L., and Meschia. G.: Blood How to fetal organs as a function of arterial oxygen content. AM. J 0BSTET. GYNECOL. 135:637, 1979. 15. Makowski, E. L., Meschia, G .. Droegemueller, W., and Battaglia, F. C.: Distribution of uterine blood flow in the pregnant sheep, AM.j. OasTET. GYNECOL.101:409, 1968. 16. Bjellin, L., Sji'>quist, P.-O. B., and Carter, A.M.: Uterine, maternal placental and ovarian blood flow throughout pregnancy in the guinea pig, Z. Geburtshilfe Perinatal. 179:179, 1975. 17. Chaichareon, D. P., .Rankin, J. H., and {;inther, (). J.: Factors which affect the relative contributions ot ovarian and uterine arteries in the blood supply of reproduct.ive organs in guinea pigs, Bioi. Reprod. 15:281, 1976. 18. Buckberg. G. D., Luck, J. C .. Payne. D. B .. Hoffman, J. I. E., Archie, .J. D., and Fixler, D. E.: Some sources of
1184 Peeters, Grutters, and Martin Am.
19. 20.
21. 22.
23. 24. 25.
error in measuring regional blood flow with radioactive microspheres,]. Appl. Physiol. 31:598, 1971. Creasy, R. K., Kahanpaii, K. V., and de Swiet, M.: Trapping of radioactive microspheres in the pregnant and nonpregnant rabbit, Acta Physiol. Scand. 90:252, 1974. Warren, D.J., and Ledingham, J. G. G.: Measurement of cardiac output distribution using microspheres. Some practical and theoretical considerations, Cardiovasc. Res. 8:570, 1974. Roth,]. A., Greenfield, A. L., Kaihara, S., and Wagner, H. N., Jr.: Total and regional cerebral blood flow in unanesthetized dogs, Am.]. Physiol. 219:96, 1970. Farmer, J. B., and Levy, G. P.: A simple method for recording the electrocardiogram and heart rate from conscious animals, Br. ]. Pharmacal. Chemother. 32:193, 1968. Spitzer, A., and Edelmann, C. M., Jr.: Maturational changes in pressure gradients for glomerular filtration, Am. J. Physiol. 221:1431, 1971. Coleman, T. G.: Cardiac output by dye dilution in the conscious rat,J. Appl. Physiol. 37:452, 1974. Patterson, J. L., Jr., Goetz, R. H., Boyle,]. T., Warren, ]. V., Gauer, 0. H., Detweiler, D. K., Said, S. I., Hoer-
26.
27. 28. 29.
30.
December 15, 19t!O J. Obstet. Gvnecol.
nicke, H., McGregor, M., Keen, E. N., Smith, M. H., Jr.. Haadie, E. L., Reynolds, M., Flatt, W. P., and Waldo, D. R.: Cardiorespiratory dynamics in the ox and giraffe with comparative observations on man and other mammals. Ann. N.Y. Acad. Sci. 112:393, 1965. Humphreys, P. W., and ]eels, N .: Changes in cardiac out· put and total peripheral resistance during the carotid sinus baroreceptor reflex in the pregnant rabbit, ] . Physiol. (Lond.) 272:45, 1977. Hytten, F. E., and Leitch, 1.: In The Physiology of Human Pregnancy, Oxford, 1971, Blackwell Scientific Publications. Metcalfe, F., Romey. S. L., Ramsey, L. H., Reid, D. E., and Burwell, C. S.: Estimation of uterine blood flow in normal pregnancy at term, J. Clin. Invest. 34:1632, 1955. Rosenfeld, C. R., Morris, F. H., Jr., Makowski, E. L., Mes· chia, G., and Battaglia, F. C.: Circulatory changes in the reproductive tissues of ewes during pregnancy, Gynecol. Obstet. Invest. 5:252, 1974. Rosenfeld, C. R., Barton, M.D., and Meschia, G.: Effects of epinephrine on the distribution of blood flow in the pregnant ewe, AM. J. OBSTET. GYNECOL. 124:156, 1976.
JR.
Nijmegen, The Netherlands Cardiac output (CO) and organ flows were measured in five nonpregnant and 14 pregnant unstressed guinea pigs between the thirty-ninth and sixty-fifth postconceptional day by means of radionuclide·labeled microspheres. Blood pressure, heart rate, and cardiac output in nonpregnant animals were 60 torr, 234 bpm, and 248 ml/min, respectively. These parameters did not change significantly during pregnancy. The uterine fraction of cardiac outpUt increased to ""1SOA:. at term and there was an equivalent dacrease in the CO fractions to the carcass and skin. Blood flow per gram of wet weight increased during pregnancy by approximately 140% and 70% for the thyroid and gastrointestinal tract, respectively, but did not change significantly for the heart, brain, kidneys, and adrenals. In pregnant animals near term the weight of the heart, kidneys, intestines, and lungs was approximately 25% lower than that observed in nonpregnant guinea pigs. (AM. J. OasTET. GYNECOL 13a:11n, 1980.)
CARDIOVASCULAR CHANGES constitute an important part of the maternal adaptation to pregnancy. Information on this matter indicates marked species differences in both total cardiac output (CO) and its distribution. During primate 1• 2 and sheep 3 pregnancy CO increases by about 30% and 75%, respectively. Changes in CO distribution tend to be more pronounced when the CO fraction to the uterus in a particular species is larger. The uterine fraction of CO at term has been found to vary between 5% in the monkey2 and 16% in the sheep, 3 whereas the size of the uterus plus conceptus in these species grows to 6% and 8% of maternal weight, respectively. In the pregnant guinea pig the uterus plus conceptus may constitute as much as 30% of maternal weight,4 which is considerably larger than in other small animals such as the rabbit (8%) 5 and rat (18%). 6 Furthermore, the relatively large fetus in the near-term guinea pig grows at a rate of 7% per day. 7 Therefore, it is likely
Fr-om the Department of Obstetrics and Gynecology, Catholic University. Received for publication june 3, 1980. Accepted September 3, 1980. Reprint requests: Dr. Louis L. H. Peeters, Department Obstetrics and Gynecology, St. Radboud Hospital, University of Nijmegen, Geert Grooteplein Zuid 14, Nijmegen, The Netherlands. 0002-9378/80/251177+08$00.80/0
© 1980 The C. V. Mosby Co.
of
that during late pregnancy major cardiovascular alterations are necessary in this species to accommodate the rapid growth of the already large fetus. The objective of the present study was to investigate the physiologic changes in maternal cardiovascular dynamics during the course of pregnancy in the guinea pig. To avoid interference from anesthesia and surgical stress with normal cardiovascular8- 10 and rnetabolic' 1 function, experiments were performed in conscious, unstressed animals.
Material and methods Experiments were carried out in five nonpregnant and 14 pregnant albino guinea pigs ranging in weight from 813 to 965 and from 806 to 1,405 grams, respectively. All animals were obtained from the 'T. N. 0." Institution, Rijswijk, Holland. Pregnant animals with known postconceptional dates arrived in our laboratory shortly after conception. The animals were allowed at least 2!1! weeks for adaptation to their new environment. The animals received food and water ad libitum until operation. In pregnant animals operation was performed before the fifty-fifth postconceptional day (term = 68 days) because of a high abortion rate associated with operation later on in pregnancy. General anesthesia was induced with ketamine hydrochloride (2 mg · 100 g- 1 , subcutaneously), xylazine (400 p,g · 100 g- 1, intramuscularly) and atropine (5 1177
1178
Peeters, Grutters, and Martin
Decembn l''· l%l> \m.
cardiac output (mi. rnin- 1 . kg- 1 )
l D
D
300
D
D
D
0
D D
200
D
D
Do
D D
100
1c->"f-'-,----~--~~-~,---·--,]--~ pregnant
40
45
50
55
60
gestational age (days)
Fig. 1. CO during guinea pig pregnancy (o). The black square (•) indicates the mean ± SEM for the nonpregnant animals.
Table I. Hemodynamic measurements in guinea pig pregnancy Pregnant Nonpregnant (n = 5)
HR (bpm) Mean systemic BP (torr)
39-56 days 157-66 days (n = 8) (n = 6)
=
234 ± 13 60 ± 3
250 ± 22 60 ::t 3
11 230 58± 4
248 ::t 30 280 ± 38
269 ::t 21 276 ::t 18
231 ± 13 212 ::t 18
CO:
ml · min- 1 ml· min-'· kg- I
Values are means :t SEM.
p,g · 100 g- 1 , intramuscularly). Adequate anesthesia was maintained throughout operation by adding nitrous oxide by mask as required. The animals were placed in the dorsal recumbent position. By means of techniques described elsewhere, 12 polyethylene catheters of standardized caliber (outside and inside diameters = 0.80 and 0.40 mm, respectively) with a tapered and slightly curved tip were inserted into the left common carotid artery and a femoral artery and advanced into the left ventricle and abdominal aorta, respectively. The catheters were tunneled subcutaneously and exteriorized between the scapulae. Most animals recovered within 4 to 6 hours after operation. During this recovery period the animals were kept warm with an infrared light. Food intake was sharply reduced on the first day after operation but increased to preoperative quantities within 3 days. This phenomenon was considered to be an indication of complete fetal and maternal recovery since aborting and nonsurviving animals showed incomplete restora-
J.
Ohstet. Cnwcu!
tion of food intake. 1n order to minimize postoperati\c manipulation, the catheters were flushed once even other dav with heparinized saline (I: 400). The CO distribution was determined between the fifth and fourteenth postoperative days. This time coincided in nonpregnant animals with diestrus and in pregnant animals with a range between the thirty-ninth and sixty-fifth postconceptional day. For the measurements, the animals were placed in a cardboard box of about four times their body size. Heart rate (HR, in beats per minute) and blood pressure (BP, in torr) in the abdominal aorta were recorded promptly. Stable readings were usually obtained within 20 minutes and were assumed to indicate steady-state conditions. The CO distribution was determined by means of the microsphere technique. Microsphere technique. Radioactive "carbonized" microspheres, labeled with Sr 85 , with a diameter of 15 ± 2 p,m (SD), and suspended in 10% dextran, were obtained from the supplier (3M Company, St. Paul, Minnesota). Preparation and handling of the microspheres have been described previously in detail. 1a The microsphere suspension was diluted aseptically with normal saline to a final concentration of 400,000 microspheres per milliliter. A sample of this suspension was placed in a preweighed glass injection vial and warmed to 39° C. Based on previous experience in fetal lambs 14 a total of 60,000 microspheres per 100 gm of maternal weight was injected (with constant mixing) into the left ventricle over a 50-second period. Starting from 30 seconds before and continuing until 30 seconds after the injection, a reference sample of blood was withdrawn at a constant rate (0.80 ml/min) from the abdominal aorta. This method of mechanical integration 15 permits blood flow calculation by the formula: Organ flow (ml/min) == number of microspheres in organ . hd . . X Wit rawa1 rate. number of miCrospheres m arterial reference sample The CO was calculated as the sum of all organ flows. Before and after the infusion of microspheres the position of the left ventricular catheter was verified with the pressure transducer. HR and BP in the abdominal aorta were recorded for 5 minutes after completion of the microsphere experiment. A blood sample was then collected from the abdominal aorta for measurement of blood gases, pH, hemoglobin, and hematocrit. Subsequently the animal was killed with an overdose of Pentothal: the catheter position was checked at autopsy, and all organs were dissected. On two occasions with suspicious pressure tracings, the tip of the left
Distribution of cardiac output
Volume 1:~R Number K
1179
Table II. Organ weights (grams) during guinea pig pregnancy Pre{f'Wnt Organ
Total maternal mass Total fetal mass Uterus with contents Myometrium Mammary gland
Nonpregnant (n = 5)
39-56 da~s (n = sj
896 ± 3I
972 ±54 92 ± 22t
1.147 ± 61* 25I ± 23*
II8 ± 23t I2 ± I II± I
294 ± 29* 20 ± :i 9 ± I
2 ± I 2 ± I 6 ± 2
I
57-66 days (n = 6!
Carcass Skin
484 ± 28 I67 ± 9
439 ± 17 I66 ± 9
4S6 ± 18 181 ± 19
Brain Heart Kidneys Gastrointestinal tract Pancreas Spleen Liver
4.4 3.6 8.8 43 1.4 2.I 38
4.2 2.5 6.9 38 1.7 1.5 32
4.0 2.6 6.6 31 1.2 1.2 36
J
~
• ..-. .... .,.
uuuo.::~
Adrenals Thyroid Ovaries
± ± ± ± ± ± ±
O.I 0.4 0.4 I 0.4
o.s 2
± ± ± ± ± ± ±
0.1 0.2t 0.4t It 0.2 0.1 2
10.1 ± 1.2
6.1 ± l.Ot
7.8
0.90 ± O.I3 O.I5 ± 0.02 0.40 ± 0.09
0.68 ± 0.04 O.I3 ± 0.02 0.24 ± 0.02
0.82 O.I3 0.22
± ± ± ± ± ± ± ± ± ± ±
O.l 0.3t 03t I* 0.1 () 1 3 0.9
O.I2 0.02 0.02
Values are means ± SEM. *Significant change (unpaired t test, p < 0.05) as compared to early pregnancy (39 to 56 days). tSignificant change (unpaired t test, p < 0.05) as compared to the nonpregnant state.
ventricular catheter was located in the aortic valve. In these animals no myocardial blood flow could be calculated and CO was determined by adding an estimated myocardial flow. It was calculated that this estimation procedure could introduce a maximum error of less than 4%. The tip of the abdominal aorta catheter was always located between the level of the kidneys and the aortic bifurcation. Organ dissection. First the skin was removed and weighed. After the dissection of both mammary glands, multiple skin aliquots were taken from standardized areas and placed into preweighed counting vials. Then each of the following organs was carefully dissected and placed in preweighed vials: thyroid, thymus, lungs, heart, brain, and intra-abdominal organs except for intestines and uterus. Paired organs were placed in separate vials. Lungs and liver were cut into suitable pieces and divided over several vials. The gastrointestinal tract was opened longitudinally over its entire length and the contents were rinsed out with normal saline. The cleaned gastrointestinal tissue was divided into four portions that were anatomically easy to recognize: stomach, small intestines, cecum, and colon. These pieces were reduced to suitable aliquots and also placed in preweighed counting vials. The uterus was dissected next. The placentas were divided into upper and lower portions, as described previousiy, 16 and piaced in preweighed vials in the same order as their location within
the uterus. The dissection of the uterine horns, cervix, and vagina was performed as described by Chaichareon and co-workers. 17 The remainder of the maternal body, referred to as the "carcass," and consisting primarily of skeletal muscle, bone, connective tissue, and fat, was ground with a Waring Blendor, and aliquots of the homogenate were placed in preweighed vials. The height of all tissue aliquots in the vials was kept below 1.0 em to avoid a loss in counting efficiency. 13 Finally, the radioactivity in each aliquot and in the reference sample was determined with a well scintillation counter (Packard Autogamma Scintillation Counter 5220). For statistical reasons 18 the actual number of microspheres was determined in each sample from the counts per minute per microsphere and the counts per minute per sample. All reference samples contained at least 700 microspheres. In some animals the smallest organs, such as the thyroid and ovaries, contained less than 200 microspheres, giving rise to an increased statistical error in the related flow determination. Good mixing of the microspheres in the present study was suggested by the close correlation between the number of microspheres distributed to paired organs (kidneys and adrenals: r = 0.95 and 0.94 in nonpregnant animals [n = 5] and r = 0.96 and 0.92 in pregnant animals [n = 14]). In the text, means are given together with their standard errors. When needed, the results were evaluated
1180
Decem her l :) i qxo Am. ,I. ObstN. (;, 1wco!
Peeters, Grutters, and Martin
weight of gastro-intestinal
tract {grams)
Table III. Percent distribution of CO guinea pig pregnancy
--y:::53.6-0.4x r=0.64 p<0.05
50
Pregnani Organ
+--o__ _
40
o--cr-----o__ _
0
0
---tr--Q_
0
Lljj----- -----
:: I---
·~~--~---,,----,---,,0--0--~] 40
45
50
durin~
55 60 gestational age (days)
Fig. 2. Change in gastrointestinal weight in the course of
Uterus Mammary gland Carcass Skin Brain Heart
Kidneys Gastrointestinal tract Pancreas Spleen Llvert Lungs§
Nonpregnant (n = 5)
0.5 0.7 46 11.5 2.1
± 0.1 ± 0.2
±: 1 ±: 1.7 ±: 0.5
39-56 days (n = 8)
6.4 1.5 44 9.0 1.9
± 0.8*
±: ±: ±: ±:
0.2 4 0.9 0.2
I 57-66= day., (n
18.2 1.4 34 5.4 1.7
.....
61
±: ±: ±: ±: ±:
1.8t 0.3 I*
0.9* 0.2
1.0:::: 0.5
3.0 ± 0.3
14.3 ±: 0.5 16.4 ±: 1.7
11.1 ±: 1.3* 17.3 ±: 1.4
11.7 ±: 1.0* 20 ±: 2
2.3 ±: 0.4* 1.5 ±: 0.3 0.2 ±: 0.1 7± 1
1.4 ±: 0.3 1.3 ±: 0.4 0.4 ±: 0.1 f) +- 1
0.9 ±: 1.7 ±: 0.3 ±: 5±:
0.2 0.5 0.1 1
A
1
-'-
....:....
1\()
'!.::J
guinea pig pregnancy (o). The black square (!!) indicates the
mean ± SEM for the nonpregnant animals. uterine blood flow (ml. min-1) -------------------,
80l 0
60~
40~
0 0 0
0
0
20l ~0 non-
I
0
0
0 0
0
!J
0
~~-----.------~-----.------~----~
pregnant 40
45
50
Values are means ±: SEM. *Significant change (unpaired t test, p <0.05) as compared to the nonpregnant state. tSignificant change (unpaired t test, p <0.05) as compared to early pregnancy (39 to 56 days). tHepatic artery flow. §Fraction of injected microspheres recovered from the lungs (bronchial artery flow and systemic arteriovenous shunting).
55 60 gestational age (days)
Fig. 3. Relationship between total uterine blood flow (ml · min-') and gestational age (o). The black square (•) indicates the mean uterine blood flow for the nonpregnant animals. statistically by Student's t test (unpaired) or by linear regression analysis.
Results The data for nonpregnant and two groups of pregnant animais on HR, mean BP, and CO are iisted in Table I, whereas the pattern of CO per kilogram with postconceptional age is illustrated in Fig. 1. None of these parameters changed significantly during pregnancy. Changes in the organ weights, the fractional distribution of CO, and the regional blood flow are displayed in Tables II, III, and IV, respectively. The data in Table II show that the size of the uterus in-
creased progressively during pregnancy. Furthermore, the weights of the heart, lungs, kidneys, and intestines in pregnant animals were 20% to 30% below nonpregnant values. Fig. 2 shows that during pregnancy the weight of the gastrointestinal tract decreased toward term. Data on the distribution of CO (Table Ill) demonstrate that in the last 10 days of pregnancy the rapidly increasing uterine fraction of CO was paralleled by a significant reduction in the CO fractions to the carcass and skin. Also the CO fractions to the kidneys and pancreas changed significantly during gestation. Absolute and relative organ flows are listed in Table IV. During pregnancy the upper placental blood flow accounted for almost the entire rise in uterine blood flow. The almost unchanged absolute blood flow to the myometrium indicates that the marked increase in myometrial mass (Table II) was coupled with a corresponding decrease in fiow per gram of tissue. Fig. 3 illustrates the progressive increase in UBF with gestation. This increase was due to an increase in PBF, which was closely correlated with the increase in total fetal weight (Fig. 4). The most pronounced changes in nonreproductive tissue flow were observed in the carcass and skin, where absolute flow decreased in late pregnancy by more than
Volume l:JR :-lumber H
Distribution of cardiac output
1181
Table IV. Regional blood flow during guinea pig pregnancy Pregrwnt
I ml · min-
57-66 days (n == 6)
39-56 days
Nonpregnant (n = 5}
(n
gm- 1
Orgar•
ml · min- 1
Mvometrium Upper placenta Lower placenta Mammary gland
2.1 ::t 0.8
80 ::t 17
2.0 ::t 0.6
36 ± 5
2.7 ::t 0.5 13 ::t 2* 0.4 ::t 0.1 * 4.1 ::t 0.7
Carcass Skin
115 ::t 14 29 ± 7
25 ± 4 15 ± 2
120 ± 14 24 :±: 3
1
100
ml · min- 1
= 8)
I ml · min-
1
100 gm- 1
ml · min- 1
I ml ·min-' 100 gm"
Uterus:
Brain Heart Kidneys Gastrointestinal tmrt: Stomach Small intestine Cecum Colon Pancreas Spleen
Liver:j: Adrenals Thyroid Ovaries
4.9 9.9 36 39 8.0 15.6 7.2 8.2 2.3 4.6 1.3 0.74 0.17 0.31
:±: 0.6 ± 1.5
± 5 ± 2 ± 1.1 ± 0.9 ± 0.4 ± 0.4 ± 0.6 ± 1.7 ± 0.3 ± 0.08 :t 0.03 :t 0.05
I lO 305 402 90 131 107 66
± 13 ± 46 :t 51 :t 5
:t 15 :±: 12
:t 4 68 ± 5
182 277 3.9 90 90 75
±51 ± 18 ± 0.6 :t 12 ± 18 ± 14
5.2 7.9 28 47 9.2 16.1 11.2 !0.0 5.6 4.1 0.7 0.60 0.24 0.54
20 ::t 121 ::t 11 ± 41::!:
4* 16* 2* 7
27 ± 4 15 ± 1
± 0.3 ± 0.9 ± 3 ± 5
± 1.0 ± 1.8 ± 1.2*
± !.3 ± 1.4 ± 0.7 ± 0.1
:t 0.06 ± 0.05
± 0.06*
126 290 413 131 15.5 127 134 96 337 256 2.0
± 10
± 58 ± 46 ± II* ± 11 ± 16 ± 15* ± !0* ± 51 ± 29 ± 0.2 87 ± 7 146 ± 31 240 ± 29*
2.4 36 0.12 3.1
::t 0.3 ± 4 ± 0.02
::!: 1.0
77 ± 8t 1:3 ± 3t 4.3 7.8 29 49 9.3 18.0 11.4 !0.2 3.3 3.7 0.9 0.52 0.23 0.30
:±: 0.4 ± 2.0
± 2 ± 2 ± 0.9
± 1.1 ± 0.4* ± 0.6* ± 0.7 ± 1.3 ± 0.1 ± 0.04 ± 0.06 ± 0.07
1
=
14 3 224 t 20t 5 t It :~3
7
18
t
2t
7
:~
2t
= 10 = !04
108 346 438 ::!': 156 :+:: 216 :.!: 168 ± 16i ::t !!9:.! 285;!: 259;!: 2.7 77 ± 217 :t 141 :t
34 II t 25* 14* 31* !!" 33 77 3
=()
9
41 2H
Values are means ± SEM. *Significant change (unpaired t test, p < 0.05) as compared to the nonpregnant state. tSignificant change (unpaired t test, p < 0.05) as compared to early pregnancy (39 to 56 days). tHepatic artery flow.
30% as compared to early pregnancy (Table IV). Changes in blood flow to other nonreproductive tissues were, in general, small. Only the perfusion of the gastrointestinal tract increased significantly during pregnancy. However, while the flow per gram of tissue increased by 70%, absolute blood flow increased by only 26% because of the lower tissue weight during pregnancy. Blood flow increases in different regions of the gastrointestinal tract were largest in the cecum and smallest in the stomach.
Comment These observations are probably the first reported on CO distribution in unstressed pregnant guinea pigs. Blood flows in this study were determined by means of the microsphere technique. Although this method has been used in pregnant and nonpregnant guinea pigs for several years, its validity in this species has never been explored. In the present study it was found in nonpregnant animals that 5% of the injected microspheres were recovered from the lungs, which is a lower amount than that which has been reported for microspheres of similar size in unanesthetized rabbits. 19 In a preliminary study in two pregnant guinea pigs, a
negligible number of microspheres was collected in a blood sample withdrawn simultaneously with the arterial reference sample from the upper portion of the inferior vena cava. Since the fraction of injected microspheres in the lungs also did not increase during pregnancy, it was concluded that 15 p.m microspheres are not shunted in significant amounts across the hemochorial placenta of the conscious guinea pig. The microsphere injection as performed in the present study neither gave rise to any noticeable maternal discomfort nor induced any appreciable change in HR and BP. However, experiments carried out in preparation for this studv indicated that injecting a dose about three times as large as in the present study or infusing the suspension at twice the speed we employed could give rise to a transient rise in maternal BP and, occasionally, nystagmus. These effects have been previously described for the rabbit 20 and dog. 21 The injection of an ice-cold microsphere suspension may induce shivering. Finally, adequate mixing of microspheres at the injection site was suggesred by the dose correlation between the number of microspheres recovered from paired organs. The data on HR and BP in the nonpregnant animal
1182 Peeters, Grutters, and Martin Am.
December Ui, l\l80 J. Obstet. Gvnecol.
total upper placental blood flow (mi. min-1)
80
60
y = 0.16x-0.63 r= 0.93 p<0.0001
c
40
20
c
100
200
300
total fetal weight (grams)
Fig. 4. Relationship between total upper placental blood flow and total weight of the conceptus.
cardiac output fractions (percent)
80
lllillskin
carcass
•
uterus
60
40
20
nonpregnant 40
45
50
55
60
gestot ionol age (days)
Fig. 5. The relationship of blood flow between the uterus, on the one hand, and the carcass and skin, on the other hand, in the course of guinea pig pregnancy.
obtained in the present study were similar to those reported previously for unrestrained guinea pigs. 22 • 23 Neither parameter changed significantly in the course of pregnancy. In several species mean arterial BP tends to decrease, and HR to increase, during pregnancy. The CO of 280 ml/min in the nonpregnant guinea pig was similar to that reported for the rat. 24 As expected from the relationship between CO and body weight, 25 the CO of the guinea pig per kilogram was twice as high as that of the rabbit 26 and monkey 2 and more than three times as high as that found in man 21 and sheep. 3 In contrast with the sheep 3 and the human, 1 the guinea pig does not experience an increase in CO during pregnancy. Apparently all circulatory demands in the
Fig. 6. The redistribution of CO during pregnancy in the guinea pig.
pregnant state are effectively met by a redistribution of CO. Perhaps this is related to the fact that the CO of small mammals is already quite high in the nonpregnant state. A marked increase in the uterine fraction of CO to as much as 20% at term dominated the redistribution of CO during guinea pig pregnancy. In other mammals this percentage has been found to vary between 5% and 18%, the fraction being generally in proportion to the term fetal-maternal weight ratio. 3• 5• 6· 28 Therefore, the higher CO fraction to the uterus in the near-term guinea pig is probably related to the higher fetalmaternal weight ratio in this species. Because of the correlation between placental blood flow and total weight of the conceptus (Fig. 4). the placental blood flow per unit of fetal weight was almost constant between the fifty-fifth and sixty-fifth postconceptional day. In contrast, Bjellin and co-workers 16 reported a gradual decrease of placental blood flow per kilogram of fetal weight with gestation. This observation might be related to the acute setup of their study. A detailed discussion on regional blood flow in the pregnant uterus of the guinea pig will be presented in a separate report. Blood flow to the mammary gland was found to increase in guinea pig pregnancy although the increase was less striking than the one reported for the sheep. 29 The rise in mammary flow was proportional to the weight increase, indicating no change in relative flow. Although ovarian blood flow was significantly increased during pregnancy, the increase varied markedly and seemed related to the number of conceptuses in the ipsilateral horn, as reported by Bjellin and coworkers.16 The reduction in ovarian blood flow in late pregnancy might be related to the increasing endocrine role of the placenta with advancing gestation.
Distribution of cardiac output
Volume l:lH Number H
In the last IO days of pregnancy, changes in nonreproductive tissue flow were dominated by decreases in CO fractions to the carcass and skin, ·which seemed to be associated with the rapidly increasing uterine fraction of CO. The resulting decrease in absolute flow was particularly impressive in the large vascular bed of the carcass (Fig. :)). Since BP remained unchanged, lower blood flows in the carcass and skin were a result of an increase in vascular resistance. It is not clear whether this increase in vascular resistance is due to neural, endocrine, or metabolic factors. The pregnancy-induced CO redistribution in the guinea pig resembles that in the near-term ewe.a suggesting that similar mechanisms mav be operating in these species. Since epinephrine infusion in the near-term ewe causes vasoconstriction in the uterus and a marked vasodilatation in the carcass.ao it is possible that the redistribution of CO in the pregn
REFERENCES I. Lees, M. M., Taylor, S. H., Scott, D. B., and Kerr, M.G.:
A study of cardiac output at rest throughout pregnancy, Br. J. Obstet. Gynaecol. 74:319, 1967. 2. Lees, M. M., Hill, J.D., Ochsner, A.]., III, Thomas, C. L., ;,nrl Nnvv
3. 4. 5. 6. 7. 8. 9.
M. T·
M:HPrn:~l
nbrPnt:JL :Jnrl mvnmPtrial
hi~d flo~· of-~h~~he-s-;;~-~~~k~y~d~;i;;g -~~~ri~~ ~~;;t;~~~ tions. AM.]. OasTET. GYNECOL. ll0:68, 1971. Rosenfeld, C. R.: Distribution of cardiac output in ovine pregnancy, Am. J. Physiol. 232:H231, 1977. Fuchs, F.: The red cell volume of the maternal and foetal vessels of the guinea pig placenta, Acta Physiol. Scand. 28:162, 1952. Duncan, S. L. B.: The partition of uterine blood flow in the pregnant rabbit, J. Physiol. (Lond.) 204:421, 1969. Csepli. J., Menyhart, j.. Lengyel, S., Bodnar, J., and Turoczi, F.: Blood circulation in pregnant rats, Acta Chir. Acad. Sci. Hung. 9: 143, 1968. Draper, R. L.: The prenatal growth of the guinea pig, Anat. Rec. 18:369, 1920. Vatner, S. F., and Braunwald, E.: Cardiovascular control mechanisms in the conscious state, N. Engl. J. Med. 293:970, 1975. Wyler. F.: Effect of general anesthesia on distribution of
cardiac output and organ blood ftov; in the rabbit: Halothane and chloralose-urethane,]. Surg. Res. 17:381, 1974. 10. Sasaki, Y., and Wagner, H. N., Jr.: Measuremem of the distribution of cardiac output in unanesthetized rats, j. Appl. Physiol. 30:879, 1971.
1183
creased significantly during pregnann. The fall in absolute flow was not significant. because of the reduction in nro-~n wPicrht A rt="rlnctinn in rion tn ·-··--!:)·-·· -... (~() h·;u ····-··-·-... thP --·~-o~·--
-~-~-,------
~---
kidneys has also been observed in the sheep. This phenomenon might hFe been triggered b~ a mechanism similar to the one which caused the inneaS<'d vascular resistance in the carcas~ and skin. The guinea pig fetus grows at a rate of ;c;;. a day in the last 2 weeks of pregnancy.' This rapid growth rate gives rise to a variety of metabolic changes. 11 Food intake increases markedly. A steady increase in gastrointestinal blood How during the course of pregnancy may be related to this increased nutritional demand. Whether the concomitant fall in intestinal weight could also be attributed to the increased rnetaboli( demands of pregnancy is not clear. \\'eight reduction of other viscFr<~l Sf'Frns to a svsternic rddJFr than ------- nn!ans -o- sU!!!!est - oo -. a local effect. Further investigation. such d' measurement of wet weight/dry weight ratios and possiblv tissue composition, is needed to solve thi~ q11e-;tion. The cardiovascular adaptation in the pregnant guinea pig is summarized in Fig. 6. The redistribution of CO was characterized mainly by a shift of flm-. from the carcass to the pregnant uterus. Flow changes in the visceral organs were small and probablv related to a variety of metabolic changes necessary to accommodate the rapid growth of the relativelv large fetll'.
11. Sparks. J. W., Pegorier, J. P., Girard. J., and Battaglia. F. C.: Substrate concentration changes during pregnancy in the guinea pig studied under unstressed stt'adv state conditions. Submitted for publication. 12. Sji'>quist. P. 0. B., Bjellin, L., and Carter, A.M.: Effect of a vasopressine analo!Iue (N"-IIlvcvl-!Ilvcvl-~~:lvcvl-8-lvsine) on organ blood flo; in the p~egn;n't guin'e; pig. Act~ Pharmacol. Toxicol. 40:369. 1977. 13. Rosenfeld, C. R., Killam, A. P., Battaglia~ f. C.~ ~.fakowski, E. L., and Meschia, G.: Effect of estradiol-17{:1 on the magnitude and distribution of uterine blood flow in nonpregnant, oiiphorectomized ewes, Pediatr. Rc,. 7: 1:>9, 1973. 14. Peeters, L. L. H., Sheldon, R. E., Jones, ~~ D., Jr, Makowski, E. L., and Meschia. G.: Blood How to fetal organs as a function of arterial oxygen content. AM. J 0BSTET. GYNECOL. 135:637, 1979. 15. Makowski, E. L., Meschia, G .. Droegemueller, W., and Battaglia, F. C.: Distribution of uterine blood flow in the pregnant sheep, AM.j. OasTET. GYNECOL.101:409, 1968. 16. Bjellin, L., Sji'>quist, P.-O. B., and Carter, A.M.: Uterine, maternal placental and ovarian blood flow throughout pregnancy in the guinea pig, Z. Geburtshilfe Perinatal. 179:179, 1975. 17. Chaichareon, D. P., .Rankin, J. H., and {;inther, (). J.: Factors which affect the relative contributions ot ovarian and uterine arteries in the blood supply of reproduct.ive organs in guinea pigs, Bioi. Reprod. 15:281, 1976. 18. Buckberg. G. D., Luck, J. C .. Payne. D. B .. Hoffman, J. I. E., Archie, .J. D., and Fixler, D. E.: Some sources of
1184 Peeters, Grutters, and Martin Am.
19. 20.
21. 22.
23. 24. 25.
error in measuring regional blood flow with radioactive microspheres,]. Appl. Physiol. 31:598, 1971. Creasy, R. K., Kahanpaii, K. V., and de Swiet, M.: Trapping of radioactive microspheres in the pregnant and nonpregnant rabbit, Acta Physiol. Scand. 90:252, 1974. Warren, D.J., and Ledingham, J. G. G.: Measurement of cardiac output distribution using microspheres. Some practical and theoretical considerations, Cardiovasc. Res. 8:570, 1974. Roth,]. A., Greenfield, A. L., Kaihara, S., and Wagner, H. N., Jr.: Total and regional cerebral blood flow in unanesthetized dogs, Am.]. Physiol. 219:96, 1970. Farmer, J. B., and Levy, G. P.: A simple method for recording the electrocardiogram and heart rate from conscious animals, Br. ]. Pharmacal. Chemother. 32:193, 1968. Spitzer, A., and Edelmann, C. M., Jr.: Maturational changes in pressure gradients for glomerular filtration, Am. J. Physiol. 221:1431, 1971. Coleman, T. G.: Cardiac output by dye dilution in the conscious rat,J. Appl. Physiol. 37:452, 1974. Patterson, J. L., Jr., Goetz, R. H., Boyle,]. T., Warren, ]. V., Gauer, 0. H., Detweiler, D. K., Said, S. I., Hoer-
26.
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December 15, 19t!O J. Obstet. Gvnecol.
nicke, H., McGregor, M., Keen, E. N., Smith, M. H., Jr.. Haadie, E. L., Reynolds, M., Flatt, W. P., and Waldo, D. R.: Cardiorespiratory dynamics in the ox and giraffe with comparative observations on man and other mammals. Ann. N.Y. Acad. Sci. 112:393, 1965. Humphreys, P. W., and ]eels, N .: Changes in cardiac out· put and total peripheral resistance during the carotid sinus baroreceptor reflex in the pregnant rabbit, ] . Physiol. (Lond.) 272:45, 1977. Hytten, F. E., and Leitch, 1.: In The Physiology of Human Pregnancy, Oxford, 1971, Blackwell Scientific Publications. Metcalfe, F., Romey. S. L., Ramsey, L. H., Reid, D. E., and Burwell, C. S.: Estimation of uterine blood flow in normal pregnancy at term, J. Clin. Invest. 34:1632, 1955. Rosenfeld, C. R., Morris, F. H., Jr., Makowski, E. L., Mes· chia, G., and Battaglia, F. C.: Circulatory changes in the reproductive tissues of ewes during pregnancy, Gynecol. Obstet. Invest. 5:252, 1974. Rosenfeld, C. R., Barton, M.D., and Meschia, G.: Effects of epinephrine on the distribution of blood flow in the pregnant ewe, AM. J. OBSTET. GYNECOL. 124:156, 1976.