Report of the National Heart, Lung, and Blood Institute Working Group on epigenetics and hypertension

Hypertension, defined as a condition associated with 65140-mm Hg systolic blood pressure or 6590-mm Hg diastolic blood pressure, affects >1 billion people worldwide,1 and in 2009 it cost the US healthcare system more than $73 billion.2 Despite the availability of many antihypertensive therapies, individual responses vary, and efficacy remains a concern. Current treatments have yielded only modest reductions in the overall disease risk even in countries where therapeutics are available and affordable. The initiating causes and the pathogenic mechanisms for disease and its comorbidities remain largely unknown, and prognostic markers for adult hypertension that could improve its diagnosis, prevention, and, ultimately, its management are not yet available. As a result, 4828$3.6 trillion more over the next 10 years.

Effect of 48-Hour Infusion of the Synthetic Oxytocin Antagonist, [1-Beta Mercapto(Beta-(Ch2)5)1(Ome)Tyr2,Orn8]-Oxytocin, On Myometrial Activity of Pregnant Sheep At 139-140 Days of Gestation

Currently there is considerable interest in the actions of oxytocin antagonists ont he pregnant myometrium. Few studies have been conducted involving long-term infusions of oxytocin antagonists to late-pregnant experimental animals. We set out to determine whether continuous infusion of an oxytocin antagonist ([1-beta-mercapto(beta-(CH2)5)1(OMe)Tyr2,Orn8]-oxytocin) would influence basal levels of myometrial activity of the contracture type and maternal prostaglandins in pregnant sheep. The antagonist was infused into a uterine vein at 80-mu-g.h-1 for 48 h starting at 139 days of gestational age. The antagonist significantly reduced total myometrial electromyogram activity and the frequency of contractures but did not change contracture duration. Antagonist infusion did not produce any significant alterations in maternal carotid or uterine vein 13,14-dihydro-15 keto prostaglandin F2-alpha concentrations. Contractures probably represent an intrinsic instability of the resting membrane potential of uterine muscle and these results suggest that oxytocin may play a role in regulating their frequency in sheep during thc last third of gestation

Lack of effect of melatonin on myometrial electromyographic activity in the pregnant sheep at 138-142 days gestation (term = 147 days gestation)

A 24-h rhythm has been demonstrated in fetal and maternal melatonin plasma concentrations in pregnant sheep in the last third of gestation. Melatonin in the maternal circulation can cross the placenta and is the major source of melatonin in the fetal circulation. Melatonin has been postulated to act as a prostaglandin (PG) synthetase inhibitor in the uterus. PG synthetase inhibitors decrease myometrial contractility. To assess transplacental passage of melatonin and potential influences of melatonin on uterine contractility, we infused melatonin continuously into the maternal jugular vein in seven pregnant sheep at 138-142 days gestation (term in our instrumented animals is 147 days gestation) at three infusion rates for successive 1-h periods during the late morning to late afternoon. There was no change in the total time during which the myometrium was active, as indicated by myometrial electromyographic activity or the myometrial contracture frequency during the 3 h before and after melatonin infusions and for each hour of the infusions. The MCR for melatonin in the ewe was 4128 +/- 410 ml/min (mean +/- SE; n = 7; weight, 50-70 kg). The resting maternal to fetal melatonin concentration ratio was 0.8; this ratio was maintained at 2.28 during melatonin infusion to the ewe at a wide range of maternal melatonin concentrations. Melatonin concentrations in the range of 3-200 times normal had no effect on the maternal plasma PGF2-alpha metabolite concentration, but caused a 40.4% fall in fetal plasma PGE2 (P < 0.05). We conclude that changes in maternal and fetal plasma melatonin concentrations within the physiological range observed throughout the day do not alter myometrial contractility, but do alter fetal PGs

Induction of premature delivery in sheep following infusion of cortisol to the fetus. I. The effect of maternal administration of progestagens

Premature induction of delivery in fetuses infused with graded doses of cortisol was brought about in 123.5 ± 7.7 h (mean ± SEM, n = 6) after the start of cortisol infusion. This treatment caused a rise in fetal plasma cortisol similar to that observed at normal delivery. Maternal and fetal progesterone and 20α-dihydroprogesterone concentrations decreased to basal levels during infusion of cortisol to the fetus. Induction of premature delivery was delayed or prevented by concomitant treatment of the ewe with progestagen. Maternal intramuscular injection of 100 mg progesterone, 2 times daily, prevented delivery in four of four ewes treated during the time that cortisol was infused into the fetus (11-13 days). Maternal plasma progesterone and 20α-dihydroprogesterone concentrations were maintained during this period, but fetal plasma progesterone concentrations decreased to the same extent as in the fetuses infused with cortisol alone. A single intramuscular injection of 250 mg of medroxyprogesterone acetate to ewes on the day before commencement of infusion of cortisol to the fetus prevented delivery in four of six ewes during the time that cortisol was infused for 9, 13, 14, and 15 days, respectively. One ewe delivered a live lamb at 133.5 h and another at 147.7 h after the start of infusion of cortisol to the fetus. Maternal and fetal plasma cortisol, progesterone, and 20α-dihydroprogesterone concentrations were similar to those observed during infusion of cortisol alone to the fetus. Although fetal cortisol concentrations rose in a similar fashion, and to a similar extent, in all three groups during infusion of cortisol to the fetus, fetal 11-desoxycortisol concentrations only rose above basal levels close to the time of delivery in cortisol-infused fetuses or, in the progestagen-treated groups, when the fetus showed signs of being stressed

The relationship between myometrial activity and sleep state and breathing in fetal sheep throughout the last third of gestation

Between 106 and 144 days' gestation, periods of uterine electromyographic (EMG) activity and associated increases in uterine tone (contractures) were accompanied by a change in fetal ocular activity in 294 (63%) of 467 cases. In 260 (88.4%) of the changes, there was a switch from the active to nonactive state. The incidence of this change was significantly greater (

Insulin induced fetal hypoglycemia and fetal and maternal plasma prostaglandin concentrations in sheep in late gestation

Fetal hypoglycaemia consequent on food withdrawal for 48 h in sheep in late pregnancy is accompanied by an increase in fetal PGE2 plasma concentrations and myometrial contractility. To assess the contribution of fetal hypoglycaemia and related cellular glucopenia in the increased production of fetal PGE2 we studied the effect of 48 h insulin infusion to the fetus. Fetal whole blood glucose was lowered from 19 +/- 2 to 9 +/- 1 mg.dl-1. This experimental regimen maintains glucose availability to those fetal cells in which insulin increases glucose uptake. Fetal umbilical venous and femoral arterial PGE2 concentrations and umbilical veno-arterial PGE2 difference were unchanged, but maternal uterine veno-arterial difference for PGFM increased during the insulin induced fetal hypoglycaemia. Myometrial activity was also unchanged. We conclude that the increased fetal PGE concentration previously reported during food withdrawal is due to a deficiency of glucose to specific insulin dependent cells within vascular beds served by the fetal cardiovascular system. In addition, the findings suggest a need for a supply of glucose of fetal origin for cells that are responsible for increased PGFM concentrations in the maternal uteroplacental circulation

Electromyographic activity of the nonpregnant and pregnant sheep uterus

Myometrial electromyograms were studied in nonpregnant ewes, pregnant ewes throughout the second half of gestation, and during labor and delivery in normal spontaneous vaginal delivery and premature delivery induced by the continuous infusion of synthetic adrenocorticotropin 1-24, 1 μg . h, to the fetus at 120 and 130 days' gestation. The bursts of electromyographic (EMG) activity during estrus were very similar to those seen in the pregnant ewe in the second half of gestation. In the second half gestation, the bursts of EMG activity lasted a mean of 6.7 minutes and occurred at intervals of 54.7 minutes in utero, without an incision for fetal instrumentation, and were 7.2 minutes in duration, occurring every 46.6 minutes when the uterus had been incised. EMG activity occurred simultaneously at most recording sites within the uterus. There was no evidence to support the view that a uterine pacemaker exists with a fixed location. As delivery approached, the mean duration of each EMG burst began decreasing more than 24 hours before delivery, and the frequency of the bursts increased, demonstrating that the recording of uterine electromyograms provides a precise and sensitive method for the study of the early changes that lead to labor and delivery

Effect of food withdrawal on arterial blood glucose and plasma 13, 14-dihydro-15-keto-prostaglandin F2 alpha concentrations and nocturnal myometrial electromyographic activity in the pregnant rhesus monkey in the last third of gestation: A model for prete

Pregnant rhesus monkeys were studied between 109 and 149 days of gestation. Food withdrawal for 48 hours (with free access to water) was accompanied by a decrease in maternal whole blood glucose concentration and an increased maternal arterial plasma 13,14-dihydro-15-keto-prostaglandin F(2α) concentration. On successive nights of the 48-hour period of food withdrawal, there was an increase in the frequency of myometrial contractions as recorded by uterine electromyogram. In the period after food was returned, blood glucose, arterial 13,14-dihydro-15-keto-prostaglanding F(2α) concentration, and contraction frequency returned to baseline. Because of food withdrawal results in the appearance of the nocturnal contraction pattern seen at term, we suggest that this experimental paradigm may be used as a model for preterm labor