Stephen J. Lye

Myometrial desensitization to continuous but not to intermittent β-adrenergic agonist infusion in the sheep☆

Infusion of the long-acting beta-adrenergic agonist ritodrine (3 micrograms/kg/min) caused by rapid inhibition of uterine activity in the ovariectomized, nonpregnant sheep. This inhibition could only be maintained for 6.4 +/- 0.8 hours, with high-frequency activity returning by 11.4 +/- 2.6 hours despite continuous infusion of ritodrine. Intermittent administration of ritodrine did not prolong uterine relaxation, probably as a consequence of its long half-life. Continuous infusion of the short-acting beta-agonist isoproterenol (0.16 micrograms/kg/min) initially inhibited uterine contractions but high-frequency activity returned by 50 minutes. In contrast, intermittent infusion of isoproterenol (30 minutes on and 30 minutes off) significantly inhibited the frequency of contractions during each of the infusion periods for the duration of the study (13 hours). Our data demonstrate that either continuous administration of beta-agonists or intermittent administration of the long-acting beta-agonist ritodrine resulted in myometrial desensitization in the sheep. In contrast, intermittent administration of the short-acting beta-adrenergic agonist isoproterenol prevented the onset of myometrial desensitization.

β-Adrenergic receptor agonist infusion increases plasma prostaglandin F levels in pregnant sheep

Recent evidence of a stimulatory effect of beta-adrenergic receptor agonists on prostaglandin production by human fetal membranes in vitro prompted us to investigate whether prostaglandins are increased during beta-agonist infusion in vivo. On days 120 to 125 of gestation, blood samples were drawn from the aorta and vena cava of five crossbred ewes at 15-minute intervals for 1 hour before, during, and for 1 hour after a 3-hour infusion of isoproterenol (0.16 microgram/kg/min) or normal saline solution. Plasma prostaglandin F2 alpha levels increased (177% +/- 13% SEM over baseline; p less than 0.002) in maternal aorta, while plasma 13,14-dihydro-15-keto prostaglandin F2 alpha levels increased in both aorta and vena cava (354% +/- 47% and 309% +/- 75% over baseline, respectively; p less than 0.002) during isoproterenol infusion but not during saline solution infusion. No change was seen in plasma prostaglandin E2 levels. The increase in plasma stimulatory prostaglandins in the pregnant ewe during beta-agonist infusion is compatible with the increased uterine activity observed after myometrial desensitization by continuous beta-agonist infusion.

Discordant accelerated pulmonary maturation after adrenocorticotropic hormone—induced labor in twin sheep fetuses☆☆☆

To examine the role of parturition on lung maturation in sheep, we studied parameters of lung development in singleton fetuses treated with pulsatile adrenocorticotropic hormone or saline solution from day 127 or twin pregnancies in which one fetus only received pulsatile adrenocorticotropic hormone from day 127 until labor occurred. These parameters were compared with those of term fetuses (145 days). Pulsatile adrenocorticotropic hormone provoked labor in a mean (+/- SEM) of 102.6 +/- 6.6 and 181.0 +/- 18.0 hours in single and twin pregnancies, respectively. Adrenal/body weight ratios increased similarly in adrenocorticotropic hormone-treated single and twin fetuses at delivery, and basal cortisol levels were two- to threefold higher prepartum in adrenocorticotropic hormone-treated fetuses. Little change in plasma cortisol levels occurred in singletons treated with saline solution or in twins not infused with adrenocorticotropic hormone. The lung weight/body weight was not altered in any group. Lung distensibility and stability were doubled to term values in fetuses treated with pulsatile adrenocorticotropic hormone compared with controls and untreated twins. Mean lavage phosphatidylcholine levels rose from 0.07 to 0.11 mg/gm in saline solution-treated or untreated fetuses to 0.20 to 0.23 mg/gm in pulsatile adrenocorticotropic hormone-treated singletons or twins, compared with 0.63 mg/gm at term. Phosphatidylcholine production increased from 0.51 dpm/gm/hr in saline solution-treated fetuses to 0.73 and 0.89 dpm/gm/hr in the single and twin pulsatile adrenocorticotropic hormone-infused fetuses, respectively; phosphatidylcholine production was 0.62 dpm/gm/hr in the noninfused twin. Lungs of twins treated with pulsatile adrenocorticotropic hormone were morphologically more mature than those of untreated twins. We conclude that fetal endocrine responses to exogenous adrenocorticotropic hormone, rather than the stimuli associated with labor per se, are responsible for lung maturation in the fetal sheep.

STIMULATION OF OVINE MYOMETRIAL ACTIVITY BY 6-KETO PROSTAGLANDIN-E1

6-keto prostaglandin E1 (6KE) is a metabolite of PGI2, which we have shown previously inhibits spontaneous myometrial activity. In the present study we examined the effects of 6KE on uterine electrical and mechanical activity in non-pregnant ovariectomized sheep. 6KE stimulated uterine activity in a dose-dependent fashion. The effect was enhanced by pre-treatment with estradiol (E2). It was not influenced by pre-treatment with meclofenamic acid and was not associated with significant changes in the concentrations of 13,14 dihydro 15-keto PGF2 alpha in vena cava plasma. After E2 treatment, 6KE had 0.2-0.3 of the stimulatory activity of PGF2 alpha. In the absence of E2, the uterine response to both 6KE and PGF2 alpha was decreased. In animals in which spontaneous myometrial activity was inhibited by PGI2, the uterus remained responsive to 6KE. We conclude that in the ovariectomized non-pregnant sheep 6KE stimulates uterine activity, and that the effect is independent of endogenous PG production.