The inhibitory action of Diazoxide on uterine activity in the subhuman primate: Placental transfer and effect on the fetus

Abstract

A drug to suppress uterine activity with minimal or no side eflfects would be valuable for the prevention of premature or precipitous labor, or for the control of tetanic uterine contractions. Recently it has been reported that diazoxide*, a benzothiadiazine derivative, a smooth muscle relaxant [15] inhibits myometrial activity of the human uterus [3,9] with no apparent adverse reactions on the fetus [5,8]. However, the dose necessary to suppres uterine activity also causes maternal hypotension [5] and the drug has other pharmacologic actions including the induction of hyperglycemia. Because of the lack.of direct Information on the effect of the drug on the fetus, pilot experiments were conducted in our laboratory on the pregnant guinea pig and her fetus [11], Blood glucose rose to a similar degree in both mother and fetus, and when delivered, the fetuses were acidotic and severely depressed, probably äs a result of maternal hypotension. On the basis of these observations, it was feit that possible adverse effects of the drug on the fetus should be examined more carefully. This paper describes experiments on pregnant subhuman primates in which the inhibiting action of diazoxide on uterine activity, placental transfer of the drug and its effect on the cardiovascular and biochemical state of both mother and fetus were studied. Material and methodsExperiments were conducted on a total of 31 pregnant primates. These consisted of 9 rhesus monkeys (maccaca mulatta) and 7 Java monkeys (maccaca fasicularis), at gestational ages ranging from 132 to 155 days (term 168 days), and 15 baboons (papio hybrid) at gestational ages ranging from 150 to 171 days (term 185 days). Acid-base data from 42 additional pregnant primates studied earlier are included in order to evaluate changes in acid-base state of the fetus following the infusion of diazoxide. The model used has been described previously in detail [7], Briefly, catheters were placed in the fetal carotid artery or femoral artery and amniotic fluid at hysterotomy, and in the maternal femoral artery and vein. In addition, thermistor probes were placed in the fetal csophagus and maternal rectum. Post-operatively, light sedation was

Effects of diazoxide on maternal and fetal circulations in normotensive and hypertensive pregnant sheep

“…The fall in uterine blood flow caused by a bolus injection of diazoxide without plasma expansion was accompanied by moderate fetal hypoxia with a decrease in fetal pH, although overt fetal acidosis did not occur. These findings are in agreement with those reported by others [6,16] and support existing experimental evidence that the healthy sheep fetus can tolerate a marked reduction in uterine blood flow without signs of compromise [10]. However, it seems likely that the transient fetal hypoxia must be held responsible for the observed fall in fetal heart rate which, under these circumstances, will result in a fall in combined ventricular output [22].…”

“…Since in our experiments umbilical flow remained rather stable, important redistribution of fetal blood flows must have occurred, favoring the placenta. Against the background of this data it can be understood that, if the fetus is already acidotic, a diazoxide-induced reduction in uterine blood flow may result in progressive fetal deterioration [16]. In both groups of experimental animals plasma expansion appeared to prevent any effect of an intravenous bolus of diazoxide on fetal oxygenation and acid-base status, most likely because uterine blood flow was maintained or even increased in the face of a marked reduction in mean arterial pressure.…”

“…Experimental studies in various species of pregnant animals have been reported in the literature but none of the animals were hypertensive [3, 6,16,17,21]. Since an experimental model of renovascular hypertension, based on the GOLDBLATT-mechanism is available in pregnant sheep [5] the present study was designed to study the short-time maternal and fetal hemodynamic effects of a bolus injection of diazoxide in chronically instrumented normotensive and hypertensive pregnant ewes.…”

Effects of terbutaline on the fetal lamb during maternal oxytocin-induced uterine contractions

“…The most commonly used /3 2 -selective adrenergic agonists, orciprenaline, ritodrine, salbutamol, fenoterol (Th 1165a) äs well äs terbutaline have all been shown to be capable of suppressing labor. The risk of maternal tachycardia, hypotension o r respiratory depressionlimits the use of isoxsuprine and its derivatives, nonspecific j3-adrenergic agonists and other tocölytics (including diazoxide, alcohol, magnesium sulphate [12,13,18,20,24]. In contrast, this study shows that terbutaline does not have an adverse effect on blood pressure in the pregnant ewe.…”