Volume 164 Number 4

adrenergic receptor blockade with phenoxybenzamine hydrochloride ablated the maternal arterial blood pres­sure response to cocaine's administration, whereas the effect of cocaine on uterine blood flow was unchanged. In contrast, Moore et al." reported that pretreatment with phentolamine (a partial aI-adrenergic receptor blocker) did not change either the maternal blood pres­sure or uterine vascular response to infusion of cocaine. They speculated that cocaine may exert its vasocon­strictive effect through a mechanism that does not in­volve the a-adrenergic receptor. However, norepi­nephrine levels were not measured after both a,­adrenergic receptor blockade and cocaine infusion.

In view of the differences in placentation and uterine blood flow in ruminants and primates it is important to obtain data in experimental situations from non­human primate experimental animal models. Our study illustrates that even low doses of intravenous co­caine administered to a primate species results in va­soconstrictive cardiovascular changes. Although there are reported physiological and placental differences be­tween human and baboon pregnancies, '9. 20 response of the pregnant baboon to cocaine most likely resembles that that occurs in the human pregnancy. Our obser­vations of the pregnant baboon's response to intrave­nous cocaine lends support to the belief that systemic vasoconstriction is responsible for the adverse perinatal outcome observed in gravid women who abuse co­caine. L 6-10 The nonhuman primate model used in this study provides an opportunity to improve our under­standing of the hemodynamic responses to cocaine ingestion and the determination of cocaine's effect on the cardiovascular system, endocrine responses, and uterine contractility in pregnant nonhuman primates.

We are especially grateful to Willie Clagg for his as­sistance and wonderful care of the baboons used in this project, to Susan Jenkins for her assistance in data anal­ysis, and to Teresa McCain, Tracey Young, and Karen Moore for their help with this article.

REFERENCES

I. Neerhof MG, MacGregor SN, Retszky SS, Sullivan TP. Cocaine abuse during pregnancy: peripartum prevalence and perinatal outcome. AM .J OBSTET GYNECOL 1989; 161:633-8.

2. Ritchie .JM, Greene NM. Local anesthetics. In: Gilman AG, Goodman LS, Rail TW, Murad F, eds. The phar­macological basis of therapeutics. 7th ed. New York: MacMillan, 1985:309-10.

3. Whitby LG, Hertting G, Axelrod J. Effect of cocaine on the disposition of noradrenaline labelled with tritium. Na­ture 1960;187:604-5.

4. Hertting G, Axelrod J, Whitby LG. Effect of drugs on the uptake and metabolism of H' -norepinephrine. ] Phar­macol Exp Ther 1961;134:146-53.

Effect of cocaine on uterine blood flow in gravid baboon 1027

5. Cregler LL, Mark H. Medical complications of cocaine abuse. N Engl.J Med 1986;315: 1495-500.

6. Chasnoff I], Burns W], Schnoll SH, Burns KA. Cocaine use in pregnancy. N Engl] Med 1985;313:666-9.

7. Little BB, Snell LM, Klein VR, Gilstrap LC. Cocaine abuse during pregnancy: maternal and fetal implications. Obstet GynecoI1989;73:I57-60.

8. Chavez GF, Mulinare J, Cordero JF. Maternal cocaine use during early pregnancy as a risk factor for congenital urogenital anomalies. ]AMA 1989;262:795-8.

9 . Oro AS, Dixon SO. Perinatal cocaine and methamphe­tamine exposure: maternal and neonatal correlates.] Pe­diatr 1987;111:571-8.

10. Lichtenfeld P], Rubin DB, Feldman RS. Subarachnoid hemorrhage precipitated by cocaine snorting. Arch Neu­roI1984;41:223-4.

II. Moore TR, Sorg ], Miller L, Key TC, Resnik R. Hemo­dynamic effects of intravenous cocaine on the pregnant ewe and fetus. AM] OBSTET GYNECOL 1986; 155:883-8.

12. Woods JRJr, Plessinger MA, Clark KE. Effect of cocaine on uterine blood flow and fetal oxygenation. JAMA 1987;257:957-61.

13. Stark RI, Daniel SS.James LS, et al. Chronic instrumen­tation and long-term investigation in the fetal and ma­ternal baboon: tether system, conditioning procedures and surgical techniques. Lab Anim Sci 1989;39:25-31.

14. Nathanielsz PW, Poore ER, Brodie A, et al. Update on the molecular events of myometrial activity during preg­nancy. In: Nathanielsz PW, Parer JT, eds. Research in perinatal medicine (II). Ithaca, New York: Perinatology Press 1984: 88-111.

15. Figueroa .JP, Mahan S, Poore ER, Nathanielsz pw. Char­acteristics and analysis of uterine electro myographic ac­tivity in the pregnant sheep. AM J OBSTET GYI\ECOL 1985; 151:524-31.

16. Wurtman RJ, Axelrod J. Potter LT. The disposition of catecholamines in the rat uterus and the effect of drugs and hormones. J Pharmacol Exp Ther 1964; 144: 150-5.

17. Moisey OM, Tulenko T. Increased sensitivity to angio­tensin in uterine arteries from pregnant rabbits. Am ] Physiol 1983;244: H335-40.

18. Dolkart LA. Plessinger MA, Woods JR Jr. Effect of a,­receptor blockade upon maternal and fetal cardiovascular responses to cocaine. Obstet Gynecol 1990;75:745.

19. Phippard AF, Horvath ]S, Glynn EM, et al. Circulatory adaptation to pregnancy-serial studies of haemodyn­amics, blood volume, renin and aldosterone in the baboon (Papio hamadryas). J Hypertens 1986;4:773-9.

20. Ramsey EM, Houston ML, Harris JWS. Interactions of the trophoblast and maternal tissues in three closely re­lated primate species. AM ] OBSTET Gn:rcol. 1976; 124:647-52.

Discussion DR. ROBERT RESNIK, San Diego, California. As of

1985, it was estimated that 30 million Americans had used cocaine as least once, and that 5 million were reg­ular users.' Current data would also suggest that usage increase in the general population has been paralleled by that among women in the reproductive age group and those actually pregnant. These alarming and tragic statistics have led to numerous clinical studies over the past several years directed at defining the pregnancy outcomes of pregnant cocaine abusers and their off­spring. Such reports show a broad spectrum of unto-

1028 Morgan et al.

ward perinatal events including premature separation of the placenta, intrauterine growth retardation, pre­term labor, fetal distress, neonatal neurobehavioral ab­normalities, congenital malformations with a predilec­tion of the genitourinary tract, and isolated reports consistent with fetal cardiovascular accidents.

In 1986, in an attempt to explore the physiologic impact of cocaine in pregnancy, Moore et al! first re­ported the effects of intravenously administered co­caine on maternal and fetal cardiovascular hemody­namics in the chronically instrumented ewe. They first determined that the dose of cocaine required to pro­duce blood levels in the sheep, similar to those observed in human users, was between 0.3 and 0.5 mg/kg body weight. After intravenous administration of these doses, they noted the rapid onset of sharp increases in maternal mean arterial pressure and a 30% to 40% decrease in uterine blood flow. Within 4 to 5 minutes of cocaine administration there were also significant increases in fetal mean arterial pressure. These findings were confirmed by Woods et al. 3 who also reported increases in uterine vascular resistance, fetal tachycar­dia, and hypoxemia.

The new findings by Morgan et al. are of obvious importance because they represent the first of their kind in a primate. It is apparent that the physiologic responses observed after cocaine administration in the baboon are quite similar in both magnitude and tem­poral relationship to those observed in pregnant sheep. Morgan et al. are to be commended for these ambitious studies. Any investigator who has worked with primates appreciates the complexities of maintaining chronic preparations and obtaining reliable data.

When the information that has thus far been ob­tained from both species is considered, a clearer picture of the pathophysiology of cocaine use in pregnancy begins to emerge. It seems plausible that cocaine pro­duces its deleterious fetal effects by two mechanisms: first, by induction of profound decreases in uterine blood flow with resulting fetal hypoxemia; second, by its rapid placental transfer leading to intense fetal va­soconstriction. These physiologic observations in ani­mal models are consistent with the clinical disorders that have been reported. One might further speculate that fetal vasoconstriction may play a role in the de­velopment of congenital defects, although why the gen­itourinary tract appears to be preferentially vulnerable in human beings remains to be clarified" Recent in­formation derived from a rat model exposed to intra­peritoneal cocaine late in the period of organogenesis reveals the acute formation of hemorrhage and edema in the upper extremities, genital tubercle, and upper lip and nose."

I have two questions for Dr. Morgan. The difficulty in obtaining continuous physiologic measurements in the baboon is readily apparent and acknowledged. Nev-

April 1991 Am J Obstet Gynecol

ertheless, I am concerned that the number of obser­vations for each data point never exceeds three or four, and that these data are then expressed as the mean ±

SEM. Given this limitation in data points, I would ap­preciate it if you would comment further on the reli­ability of the observations.

My second question has to do with the mechanism of cocaine action. As you stated, cocaine has been shown to inhibit the reuptake of norepinephrine at the pre­synaptic nerve terminal. Moore et al. were unable to inhibit the cocaine-induced increase in mean arterial pressure or decrease in uterine blood flow by pretreat­ment with the a-blocker phentolamine. More recently, Dolkart6 reported that ai-adrenergic receptor blockade with phenoxybenzamine inhibited cocaine-induced ma­ternal vasoconstriction but not the decrease in uterine blood flow. In light of this paradox, I wonder whether you would care to comment on these observations, with particular reference to the effects of cocaine on other neurotransmitters with vasoactive potential.

Again, I want to congratulate you for what surely were difficult and tedious studies. Although small in number, your observations strongly suggest a similarity in the physiologic response to cocaine in the sheep and baboon.

REFERENCES

1. Abelson HI, Miller JD. A decade of trends in cocaine use in the household population. Nat Inst Drug Abuse Mono Ser 1985;61:35.

2. Moore TR, Sorg J, Miller L, Key TC, Resnik R. Hemo­dynamic effects in intravenous cocaine on the preg­nant ewe and fetus. AM J OBSTET GYNECOL 1986;155: 883.

3. Woods JR Jr, Plessinger MA, Clark KE. Effect of cocaine on uterine blood flow and fetal oxygenation. JAMA 1987;257:957.

4. Chasnoff IJ, Chisum GM, Kaplan WE. Maternal cocaine use and genitourinary tract malformations. Teratology 1988;37:201.

5. Webster WS, Brown-Woodman PD. Cocaine as a cause of congenital malformations of vascular origin: experimental evidence in the rat. Teratology 1990;41:687.

6. Dolkart LA, Plessinger MA, Woods JR Jr. Effects of Oll­

receptor blockade upon maternal and fetal cardiovascular responses to cocaine. Obstet Gynecol 1990;75:745.

DR. STEVE N. CARITlS, Pittsburgh, Pennsylvania. I do not believe you measured intrauterine pressure, but I wonder whether there were phasic changes in uterine blood flow that might indicate whether there was an increase in intrauterine pressure.

Also, the period of observations seemed to be about 30 minutes. Were any of these animals studied for lon­ger periods of time to determine whether there was a delayed effect on any of the parameters you were mea­suring? Finally, what was the state of these animals?

Volume 164 Number 4

Were they agitated or calm? Also, were they horizontal or upright?

DR. JAMES WOODS, Rochester, New York. I would like to focus Dr. Resnik's question even a little bit more specifically. The fact that phentolamine and phenoxybenzamine have been unable to abolish com­pletely the total uterine vascular effect of cocaine raises the possibility that cocaine is working through other neurotransmitters, such as dopamine.

About 2Y2 years ago your group showed that dopa­mine does cause uterine artery vasoconstriction and could be a vehicle for this cocaine-induced effect.' Have you followed up that study with dopamine blockers to evaluate that issue further?

The second question really relates to the issue of cocaine and pregnancy itself. We know in the sheep that cocaine produces almost a twofold greater cardio­vascular response in pregnancy than it does in the non­pregnant state! Moreover, we now know that proges­terone seems to be the vehicle that is mediating this unusual drug reaction. In fact, we can reproduce this in the nonpregnant state if one gives progesterone and then gives cocaine.'

Have you duplicated any of your infusions either after these pregnant baboons are delivered of infants or more specifically, in the nonpregnant state to com­pare cocaine-induced cardiovascular effects in preg­nant versus nonpregnant baboons?

REFERENCES

1. Fishburne Jl, Dormer KJ, Payne GG, et al. Effects of am­rinone and dopamine on uterine blood flow and vascular responses in the gravid baboon. AM J OBSTET GYNECOL

1988; 158:829. 2. Woods JR Jr, Plessinger MA. Pregnancy increases cardio­

vascular toxicity to cocaine. AM J OBSTET GYNECOL 1990; 162:529.

3. Plessinger MA, Woods JR Jr. Progesterone increases car­diovascular toxicity to cocaine in nonpregnant ewes. AM J OBSTET GYNECOL 1990;163:1659-64.

DR. JAMES C. WARREN, St. Louis, Missouri. I have one question. I would like some hard data on how your dosages really compare with human users in terms of milligram per kilogram of body weight. I assume they are in the range, but I would like some better infor­mation on that, please.

DR. MORGAN (Closing). To answer Dr. Resnik's first question as to the reliability of our observations, I think that any time an investigation is initially performed it needs to be duplicated, either by ourselves with differ­ent dosages or by other investigators in a similar animal model. Until that occurs, we really will not know what is truth. We did observe statistical significance with the paired Student t test. This statistical test is the most stringent that is used for these particular types of ob­servations.

Effect of cocaine on uterine blood flow in gravid baboon 1029

As to the question, "what is the mechanism of action for the continued uterine blood flow reduction that occurs after blockade of the IX,-adrenergic receptors?" there are two mechanisms that can be related or can be interacting. There are both extrinsic and intrinsic resistances that affect uterine blood flow. What has been specifically investigated with the IX,-adrenergic block­ade is the intrinsic resistance, specifically blocking the effects of norepinephrine on the uterine vasculature.

At this meeting in 1987 Dr. Fishburne' showed that regional dopamine infusions into the common iliac ar­tery of pregnant baboons caused profound reductions in uterine blood flow. The likely dopamine-mediated increase in intrinsic resistance is also a probable cause for the reduction in uterine blood flow after cocaine administration.

Another possible mechanism is that cocaine could exert a direct effect on the uterine vasculature. Other local anesthetic agents such as lidocaine, administered as a paracervical block, have resulted in profound fetal bradycardia.2 These observations could be a result of intrinsic vasoconstriction of the uterine vasculature caused by the local anesthetic agents." 4

Increased extrinsic resistance, uterine contractility, could be related to the pharmacologic effects of co­caine. Dr. Griess5 in 1972 observed that a systemic in­fusion of norepinephrine caused an increase in uterine activity as measured by intrauterine pressure catheter. This uterine contractile response was somewhat blocked by the administration of phenoxybenzamine in various doses. As to the effect of norepinephrine on the baboon's uterine contractility, the IX,-adrenergic receptor blockade of that effect remains to be deter­mined.

We observed with these cocaine dosages and three others (0.5, 1.0, and 2.0 mg/kg), measuring uterine contractility with intrauterine pressure catheters and electro myographic electrodes, that there is a profound dose-mediated effect on uterine contractility in the nonhuman primate. This effect of cocaine needs to be explored as another possible mechanism for the re­duction in uterine blood flow.

As to Dr. Caritis' question on the measurement of intrauterine pressure. The uterine activity did increase and appeared to be related to the dose used. U nfor­tunately, we did not have the prostaglandin assays fin­ished in time for this particular report.

Observations were obtained over 30 minutes because of study design. However, for the other cocaine doses that I mentioned (0.5, 1.0, and 2.0 mg/kg) we collected data out to 60 minutes and saw similar though greater effects as those observed in this study.

With relation to the state of the animals, each baboon was in her normal upright posture, as in the gang cages. The only difference is that they were wearing a jacket attached to a tether, allowing them freedom to move around in the cage.

1030 Morgan at al.

The reaction to the cocaine was different from ani­mal to animal. After the higher doses, two of the ani­mals showed twitching of the ears and enlargement of the pupils. However, one observation present in all the baboons was that their buttocks became more intensely red with the increase in the dosage of cocaine. I do not know why this occurs.

To answer Dr. Woods' questions, we are currently preparing to undertake studies that involve dopamine blockade and nonpregnant baboon cocaine infusion studies.

Last, Dr. Warren asked whether the cocaine doses we used in this study are similar to those used by cocaine abusers. We have not obtained these data. The only data that I am aware of are that of Moore et al.6 who stated that the cocaine blood levels they obtained in their study were similar to peak levels obtained in male volunteers. We have frozen blood samples from which to obtain cocaine levels; however, these assays have not been performed.

Bound volumes available to subscribers

REFERENCES

April 1991 Am J Obstet Gynecol

1. Fisburne JI Jr, Dormer KJ, Payne GG, et al. Effects of amrinone and dopamine on uterine blood flow and vas­cular responses in the gravid baboon. AM J OBSTET Gy­NECOL 1988; 158:829.

2. Freeman RK, Gutierrez NA, Ray ML, et al. Fetal cardiac response to paracervical block anesthesia. AM J OBSTET GYNECOL 1972;113:583.

3. Greiss FL, StillJG, Anderson SG. Effects oflocal anesthesia agents on the uterine vasculature and myometrium. AM J OBSTET GYNECOL 1976;124:889.

4. Fishburne JI Jr, Greiss FC, Hopkinson R, et at. Responses of the gravid uterine vasculature to arterial levels of local anesthetic agents. AMJ OBSTET GYNECOL 1979;133:753.

5. Greiss FC. Differential reactivity of the myoendometrial and placenta vasculatures: adrenergic responses. AMJ OB­STET GYNECOL 1972;112:20.

6. Moore RT, Sorg J, Miller L, et al. Hemodynamic effects of intravenous cocaine on the pregnant ewe and fetus. AM J OBSTET GYNECOL 1986;155:883.

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