Gene expression of the heat stress response in bovine peripheral white blood cells and milk somatic cells in vivo.

Heat stress in dairy cattle leads to reduction in feed intake and milk production as well as the induction of many physiological stress responses. The genes implicated in the response to heat stress in vivo are not well characterised. With the aim of identifying such genes, an experiment was conducted to perform differential gene expression in peripheral white blood cells and milk somatic cells in vivo in 6 Holstein Friesian cows in thermoneutral conditions and in 6 Holstein Friesian cows exposed to a short-term moderate heat challenge. RNA sequences from peripheral white blood cells and milk somatic cells were used to quantify full transcriptome gene expression. Genes commonly differentially expressed (DE) in both the peripheral white blood cells and in milk somatic cells were associated with the cellular stress response, apoptosis, oxidative stress and glucose metabolism. Genes DE in peripheral white blood cells of cows exposed to the heat challenge compared to the thermoneutral control were related to inflammation, lipid metabolism, carbohydrate metabolism and the cardiovascular system. Genes DE in milk somatic cells compared to the thermoneutral control were involved in the response to stress, thermoregulation and vasodilation. These findings provide new insights into the cellular adaptations induced during the response to short term moderate heat stress in dairy cattle and identify potential candidate genes (BDKRB1 and SNORA19) for future research.

Genomic heritabilities and genomic estimated breeding values for methane traits in Angus cattle.

Enteric methane emissions from beef cattle are a significant component of total greenhouse gas emissions from agriculture. The variation between beef cattle in methane emissions is partly genetic, whether measured as methane production, methane yield (methane production/DMI), or residual methane production (observed methane production - expected methane production), with heritabilities ranging from 0.19 to 0.29. This suggests methane emissions could be reduced by selection. Given the high cost of measuring methane production from individual beef cattle, genomic selection is the most feasible approach to achieve this reduction in emissions. We derived genomic EBV (GEBV) for methane traits from a reference set of 747 Angus animals phenotyped for methane traits and genotyped for 630,000 SNP. The accuracy of GEBV was tested in a validation set of 273 Angus animals phenotyped for the same traits. Accuracies of GEBV ranged from 0.29 ± 0.06 for methane yield and 0.35 ± 0.06 for residual methane production. Selection on GEBV using the genomic prediction equations derived here could reduce emissions for Angus cattle by roughly 5% over 10 yr.

Accuracy of prediction of genomic breeding values for residual feed intake and carcass and meat quality traits in Bos taurus, Bos indicus, and composite beef cattle.

The aim of this study was to assess the accuracy of genomic predictions for 19 traits including feed efficiency, growth, and carcass and meat quality traits in beef cattle. The 10,181 cattle in our study had real or imputed genotypes for 729,068 SNP although not all cattle were measured for all traits. Animals included Bos taurus, Brahman, composite, and crossbred animals. Genomic EBV (GEBV) were calculated using 2 methods of genomic prediction [BayesR and genomic BLUP (GBLUP)] either using a common training dataset for all breeds or using a training dataset comprising only animals of the same breed. Accuracies of GEBV were assessed using 5-fold cross-validation. The accuracy of genomic prediction varied by trait and by method. Traits with a large number of recorded and genotyped animals and with high heritability gave the greatest accuracy of GEBV. Using GBLUP, the average accuracy was 0.27 across traits and breeds, but the accuracies between breeds and between traits varied widely. When the training population was restricted to animals from the same breed as the validation population, GBLUP accuracies declined by an average of 0.04. The greatest decline in accuracy was found for the 4 composite breeds. The BayesR accuracies were greater by an average of 0.03 than GBLUP accuracies, particularly for traits with known genes of moderate to large effect mutations segregating. The accuracies of 0.43 to 0.48 for IGF-I traits were among the greatest in the study. Although accuracies are low compared with those observed in dairy cattle, genomic selection would still be beneficial for traits that are hard to improve by conventional selection, such as tenderness and residual feed intake. BayesR identified many of the same quantitative trait loci as a genomewide association study but appeared to map them more precisely. All traits appear to be highly polygenic with thousands of SNP independently associated with each trait.

Improving accuracy of genomic predictions within and between dairy cattle breeds with imputed high-density single nucleotide polymorphism panels.

Achieving accurate genomic estimated breeding values for dairy cattle requires a very large reference population of genotyped and phenotyped individuals. Assembling such reference populations has been achieved for breeds such as Holstein, but is challenging for breeds with fewer individuals. An alternative is to use a multi-breed reference population, such that smaller breeds gain some advantage in accuracy of genomic estimated breeding values (GEBV) from information from larger breeds. However, this requires that marker-quantitative trait loci associations persist across breeds. Here, we assessed the gain in accuracy of GEBV in Jersey cattle as a result of using a combined Holstein and Jersey reference population, with either 39,745 or 624,213 single nucleotide polymorphism (SNP) markers. The surrogate used for accuracy was the correlation of GEBV with daughter trait deviations in a validation population. Two methods were used to predict breeding values, either a genomic BLUP (GBLUP_mod), or a new method, BayesR, which used a mixture of normal distributions as the prior for SNP effects, including one distribution that set SNP effects to zero. The GBLUP_mod method scaled both the genomic relationship matrix and the additive relationship matrix to a base at the time the breeds diverged, and regressed the genomic relationship matrix to account for sampling errors in estimating relationship coefficients due to a finite number of markers, before combining the 2 matrices. Although these modifications did result in less biased breeding values for Jerseys compared with an unmodified genomic relationship matrix, BayesR gave the highest accuracies of GEBV for the 3 traits investigated (milk yield, fat yield, and protein yield), with an average increase in accuracy compared with GBLUP_mod across the 3 traits of 0.05 for both Jerseys and Holsteins. The advantage was limited for either Jerseys or Holsteins in using 624,213 SNP rather than 39,745 SNP (0.01 for Holsteins and 0.03 for Jerseys, averaged across traits). Even this limited and nonsignificant advantage was only observed when BayesR was used. An alternative panel, which extracted the SNP in the transcribed part of the bovine genome from the 624,213 SNP panel (to give 58,532 SNP), performed better, with an increase in accuracy of 0.03 for Jerseys across traits. This panel captures much of the increased genomic content of the 624,213 SNP panel, with the advantage of a greatly reduced number of SNP effects to estimate. Taken together, using this panel, a combined breed reference and using BayesR rather than GBLUP_mod increased the accuracy of GEBV in Jerseys from 0.43 to 0.52, averaged across the 3 traits.

Postpartum hemorrhage and arterial embolization.

Postpartum hemorrhage remains a major cause of morbidity and mortality for the obstetric patient. A timely, stepwise approach to management can reduce the negative impact of this complication. Improvements in pharmacotherapy and surgical techniques have also improved outcome. Uterine artery embolization is an especially promising approach to the management of severe or refractory obstetric hemorrhage which is generally underutilized but has several advantages over other more traditional techniques.

Serum ionized magnesium levels in normal and preeclamptic gestation.

OBJECTIVE: To compare serum levels of ionized and total magnesium with those of ionized calcium, total calcium, sodium, and potassium over the course of pregnancy in normal women and in women who develop preeclampsia. METHODS: We collected venous serum samples from 31 pregnant women during their first, second, and third trimesters. Gestational ages ranged from 6 to 37 weeks. Samples were analyzed for ionized and total magnesium, ionized and total calcium, sodium, and potassium using a biomedical chemistry analyzer. Data were analyzed with repeated-measures analysis of variance and two-way repeated-measured analysis of variance. RESULTS: In 22 normal pregnant women, both serum ionized and total magnesium levels decreased significantly with increasing gestational age. No changes in sodium, potassium, or ionized or total calcium were observed. Nine of the 31 subjects developed preeclampsia by term; serum total magnesium levels decreased significantly by the second trimester in these women compared with those of normal pregnant women. CONCLUSION: Our results provide evidence of decreases in ionized and total magnesium levels with increasing gestational age during normal pregnancy, as well as evidence of a magnesium disturbance in women who later develop preeclampsia. Future studies of magnesium balance in women at risk for developing complications of pregnancy are indicated.

Fetal ionized magnesium levels parallel maternal levels during magnesium sulfate therapy for preeclampsia.

OBJECTIVE: Little is known about ion regulation in fetuses. Our aim was to determine the effects of magnesium sulfate therapy on ionized (bioactive) magnesium in the cord blood of pregnancies complicated by preeclampsia. STUDY DESIGN: Seventy-four pregnant women were studied (37 preeclamptic and 37 controls matched for maternal age, gravidity, and gestational age). The preeclamptic women received intravenous magnesium sulfate 6 gm load followed by 2 gm/hour for > or = 4 hours; controls were not preeclamptic and received no magnesium. Maternal venous and fetal cord blood samples were obtained from study and control patients and were analyzed for sodium, potassium, total magnesium, ionized magnesium, total calcium, and ionized calcium. Comparisons between the groups were made and analyzed by the Mann-Whitney U test. RESULTS: There were no significant differences between the treatment and control group cord samples with respect to sodium or potassium. However, total magnesium and ionized magnesium were significantly elevated (p < 0.001) in cord samples of the treated group. At the same time ionized calcium and total calcium were reduced. Interestingly, ionized calcium levels were lower in preeclamptic women before magnesium sulfate therapy was begun, whereas total calcium levels were not different. Importantly, there was no difference between maternal and fetal ionized magnesium levels in either treatment or control groups. CONCLUSIONS: In preeclamptic women undergoing magnesium sulfate therapy, ionized magnesium levels in cord blood parallel maternal levels. Before magnesium therapy ionized calcium levels were lower in preeclamptic women than in matched controls. In the presence of elevated magnesium levels ionized calcium appears to be tightly regulated.

Differential regulation of seizure activity in the hippocampus of male and female rats.

OBJECTIVE: The aim of the current study was to directly examine and compare the susceptibility to N-methyl-D-aspartate-induced seizures in male versus female rats. We also sought to compare the anticonvulsant effects of magnesium sulfate in these two groups. STUDY DESIGN: Eighteen female and 10 male rats were stereotaxically implanted with a chronic bipolar recording electrode in the hippocampus and an injection cannula in the lateral cerebral ventricle. After 1 week rats randomly received an intravenous injection of 90 mg/kg magnesium sulfate or saline solution control. Fifteen minutes after the infusion rats were given the convulsant N-methyl-D-aspartate at a dose of 5 micrograms/microliters by direct intraventricular injection. Electrical seizure activity was thereafter assessed for 20 minutes. All data were analyzed by the Mann-Whitney U test and Student t test. RESULTS: In saline solution-treated rats receiving the convulsant N-methyl-D-aspartate, females had significantly lower total duration (p < 0.01) and total number of seizures (p < 0.05) compared with the male rats. The initial seizure was not affected by gender. In the female animals magnesium sulfate significantly reduced first seizure duration (p < 0.01) compared with saline solution controls. In males magnesium sulfate reduced both total duration (p < 0.05) and total seizure number (p < 0.05) compared with saline solution-treated animals. CONCLUSION: N-methyl-D-aspartate-induced seizure activity is more severe in males versus female rats. Magnesium sulfate's effect on N-methyl-D-aspartate-induced seizures is also dependent on gender. We speculate that seizure regulation may be hormonally influenced.

Adenosine modulates hypoxia-induced atrial natriuretic peptide release in fetal sheep.

The effects of adenosine on atrial natriuretic peptide (ANP) secretion were determined in chronically catheterized fetal sheep (> 0.8 term). Adenosine was infused into the the right jugular vein for 1 h at 8 +/- 0.4 (5 fetuses), 160 +/- 8 (6 fetuses), and 344 +/- 18 micrograms.min-1.kg estimated fetal wt-1. Fetal arterial blood gases and pH were generally unaffected by adenosine, although mean arterial CO2 tension increased transiently by 2-5 Torr and pH fell progressively during the highest rate of infusion. During the intermediate and high infusion rates, fetal hemoglobin concentrations increased by 11-13% and mean fetal heart rate rose by 18% from a control value of approximately 167 beats/min. Mean arterial pressure was not affected during adenosine infusion. Adenosine significantly increased fetal plasma ANP levels, with maximum concentrations 1.80, 2.36, and 2.51 times greater than control means (142-166 pg/ml) for the respective infusion rates of 8, 160, and 344 micrograms.min-1.kg estimated fetal wt-1. In seven fetuses, reducing fetal arterial O2 tension by approximately 9-10 Torr from a control of 23 +/- 1.3 Torr increased plasma ANP concentrations approximately 2.4 times the control mean of 176 pg/min. Adenosine-receptor blockade with 8-(p-sulfophenyl)-theophylline reduced by 50% the maximum hypoxia-induced rise in plasma ANP concentrations. It is concluded that adenosine causes a dose-dependent rise in fetal plasma ANP concentrations and modulates fetal ANP release during hypoxia.

Pathologic response to induction chemotherapy in locally advanced carcinoma of the breast: a determinant of outcome.

BACKGROUND: The prognosis for patients with locally advanced carcinoma of the breast remains poor. This study examines the pathologic evidence of response of the mammary tumor and axillary nodes after preoperative chemotherapy. We sought to determine if there was a relationship between the histologic response and clinical outcome. STUDY DESIGN: Between 1987 and 1992, 36 patients with locally advanced carcinoma of the breast received three cycles of chemotherapy after incisional biopsy. Modified radical mastectomy was then performed. The breast and axillary nodes were examined pathologically for therapeutic effect and a grading scale was assigned. Postoperatively, patients received completion chemotherapy with the same agents used preoperatively followed by radiation therapy to the chest wall. RESULTS: Fourteen tumors (39 percent) showed near total therapeutic effect, five (14 percent) showed greater than 50 percent but less than total effect, 12 (33 percent) showed less than 50 percent effect, and five (14 percent) showed no effect. Nodal positivity was seen in 61 percent of the patients. Overall clinical response to induction chemotherapy was seen in 86 percent of the patients. There was poor correlation between clinical and pathologic response. Only 50 percent of the patients with complete clinical response were pathologically free of disease. Patients with excellent pathologic therapeutic response had a 79 percent overall five-year survival rate compared with 34 percent for tumors with a lesser response. This was irrespective of nodal status. While pathologic response was critical in determining outcome, clinical response was not. CONCLUSIONS: These results indicate that patients whose tumors have the best pathologic response to induction chemotherapy experience the best outcome.

Vaginal color Doppler assessment of uterine artery impedance correlates with immunohistochemical markers of endometrial receptivity required for the implantation of an embryo.

OBJECTIVE: To investigate the correlation between uterine artery impedance with immunohistochemical histologic, and ultrasonographic markers of uterine receptivity. DESIGN: A prospective study of subfertile women undergoing a frozen embryo replacement cycle. SETTING: A tertiary infertility clinic. PATIENTS: The study was based on 86 patients who had failed to become pregnant during a standard IVF treatment cycle and who had at least two good quality embryos cryopreserved. INTERVENTIONS: All patients had pituitary desensitization with the GnRH analogue buserelin acetate, followed by E2 and P replacement therapy. Vaginal color Doppler images of both uterine arteries were obtained on days 7, 14, and 21 of the first (trial) cycle. On day 21, an endometrial biopsy was taken for dating a 24-kd protein, placental protein 14, and E2 receptor assessment. After a menstrual bleed had been induced, administration of estrogen and P was reinstituted and embryos transferred to the uterus on the 3rd or 4th day of P administration. MAIN OUTCOME MEASURES: The mean pulsatility index of the left and right uterine arteries, a semiquantitative score of endometrial 24-kd protein, PP14, and E2 receptor assessment, endometrial histologic dating, and pregnancy outcome. RESULTS: Nineteen of 76 patients who had a successful ET became pregnant. The pulsatility index on day 14 of both the trial and ET cycles was significantly lower in those who achieved pregnancy as compared with those who did not conceive: 2.65 (range 1.3 to 3.4) versus 3.85 (1.8 to 6.8) and 2.85 (1.4 to 3.6) versus 4.15 (2.1 to 6.8), respectively. There were significant correlations between pulsatility index and 24-kd protein, E2 receptor, and endometrial histology but not with PP14 and endometrial thickness. CONCLUSIONS: Uterine artery impedance has a significant correlation with biochemical markers of uterine receptivity and accurately predicts the probability of pregnancy in frozen embryo replacement cycles. It is a useful method for assessing uterine receptivity in assisted conception programs.

Hypoxic inhibition of breathing in fetal sheep: relationship to brain adenosine concentrations.

Because hypoxic inhibition of fetal breathing may be caused by a rise in central adenosine levels, the effects of O2 deficiency on fetal brain adenosine concentrations were determined at levels of hypoxia that inhibited fetal breathing. Under halothane anesthesia, the brains of fetal sheep (0.8 term) were implanted with guide cannulas exteriorized through a Silastic rubber window in the uterus and flank of the ewe. At least 4 days after surgery, a microdialysis probe was inserted into a cannula with the membrane tip placed in the rostral brain stem. During 1 h of isocapnic hypoxia, mean fetal arterial PO2 was reduced from 24.0 +/- 0.9 Torr (control) to 13 +/- 0.6 Torr and arterial pH fell progressively from 7.354 +/- 0.007 to 7.273 +/- 0.023. Hypoxia decreased the incidence of fetal breathing movements from 33 +/- 5.2 to 5 +/- 2.2 min/h, with a normal incidence (29 +/- 3.5 min/h) during the hour after arterial PO2 returned to control values. Adenosine concentrations in microdialysis perfusate under control conditions averaged approximately 35 nM, increased up to 2.3-fold during the hour of O2 deficiency, and fell toward control values when normoxia was restored. We conclude that fetal brain adenosine levels are increased at levels of O2 deficiency that inhibit fetal breathing, which are results consistent with a role for adenosine in hypoxic inhibition of fetal breathing.

Magnesium is more efficacious than phenytoin in reducing N-methyl-D-aspartate seizures in rats.

OBJECTIVE: Although magnesium sulfate is one of the most commonly used agents for seizure prophylaxis in preeclampsia, its efficacy relative to other anticonvulsants is incompletely investigated. The underlying mechanisms of eclamptic seizures are unknown, and there is currently no universally accepted animal model for eclampsia. However, one commonly used method for studying the relative efficacy of antiepileptic drugs is through their effect on N-methyl-D-aspartate-induced seizures. Our aim was to compare the anticonvulsant effects of phenytoin and magnesium sulfate in an N-methyl-D-aspartate-induced seizure model. STUDY DESIGN: Twenty-one female rats were each stereotaxically implanted with a chronic indwelling bipolar recording electrode in the hippocampus and an injection cannula in the lateral cerebral ventricle. After 7 days animals were randomly given 90 mg/kg magnesium sulfate (n = 7), 50 mg/kg phenytoin, or saline solution (n = 7) intravenously. Fifteen minutes after the infusions animals were given 20 micrograms/microliters N-methyl-D-aspartate by direct intraventricular injection, and seizure activity was assessed for 20 minutes thereafter. All data were analyzed with the Mann-Whitney test. RESULTS: When compared with saline solution controls, total duration of seizure activity in animals treated with magnesium sulfate was significantly decreased (p < 0.05) and time to onset of seizure activity was significantly increased (p < 0.05). However, rats that received phenytoin did not show significant changes in these parameters. The post-N-methyl-D-aspartate seizure mortality rate was 50% in the saline solution controls and 29% in the phenytoin group, whereas none of the rats that received magnesium sulfate died. CONCLUSION: These results suggest that magnesium sulfate is a significantly more effective prophylactic agent than phenytoin for N-methyl-D-aspartate-induced seizures.

Comparison of natural with clomiphene citrate-stimulated cycles in in vitro fertilization: a prospective, randomized trial.

OBJECTIVE: To compare the outcome of natural with clomiphene citrate (CC)-stimulated cycles in IVF. DESIGN: Prospective, randomized study. SETTING: Tertiary referral center for assisted conception. SUBJECTS: Thirty patients randomized to receive either no treatment (n = 14) or CC, 100 mg, from days 2 to 6 (n = 16). INTERVENTIONS: Daily ultrasound (US) scan and measurements of serum LH and E2. Ovarian morphology was assessed on baseline US scan. Human chorionic gonadotrophin was administered when the mean diameter of the dominant follicle reached 17 mm. Transvaginal US-directed oocyte recovery was performed 35 hours later. MAIN OUTCOME MEASURES: The number of patients reaching oocyte recovery; numbers of oocytes collected, fertilized and embryos transferred; and clinical pregnancy and multiple pregnancy rates (PRs) were recorded. RESULTS: Ten cycles in the natural cycle group were abandoned before oocyte recovery compared with none in the CC group. There were significantly more follicles > 14 mm (2.4 +/- 0.3 [SE] compared with 0.9 +/- 0.2) and higher peak levels of E2 (375 +/- 67 pg/mL (1,378 +/- 247 pmol/L) compared with 204 +/- 17 pg/mL (748 +/- 61 pmol/L)) in those receiving CC compared with those receiving no drug. All 16 patients treated with CC had oocyte retrieval (mean, 1.8 +/- 0.3 oocytes) compared with only 4 in the natural cycle group (1 oocyte each). The oocyte recovery rate was 95%. Two patients conceived in the CC group (PR per ET, 18%) compared with none in the natural cycle group. Patients with polycystic ovaries developed more large follicles than those with normal ovaries. No patient developed ovarian hyperstimulation syndrome. CONCLUSIONS: Patients undergoing natural cycle IVF are more likely to have abandoned cycles, produce fewer follicles and oocytes, and are less likely to reach ET than patients treated with CC alone. Clomiphene citrate should be considered for use in the context of a conventionally organised IVF-ET program if a mild degree of ovarian stimulation is desired.

Adenosine mediates hypoxic release of arginine vasopressin in fetal sheep.

The effects of adenosine on plasma arginine vasopressin (AVP) concentrations were determined in chronically catheterized fetal sheep (> 0.8 term). Infusion of adenosine [0.35 +/- 0.01 (SE) mg.min-1.kg-1] into the inferior vena cava of six fetuses caused a transient fall in arterial PO2 (by approximately 3 Torr), a slight reduction in arterial pH, and a 5- to 6-mmHg decrease in diastolic pressure without significantly affecting systolic or mean arterial values. A lower rate of infusion (0.19 +/- 0.01 mg.min-1 x kg-1) in five fetuses had virtually no effect on arterial blood gases, pH, or arterial pressures. Both the low- and high-dose adenosine infusions significantly increased fetal plasma AVP concentrations (1.7 +/- 0.2 to 25 +/- 7 pg/ml and 1.6 +/- 0.1 to 54 +/- 8 pg/ml, respectively). Intravenous infusion of papaverine lowered fetal diastolic and mean arterial pressures by approximately 8 mmHg but had no significant effect on plasma levels of AVP. During an hour of isocapnic hypoxia (arterial PO2 12-13 Torr), fetal plasma AVP levels increased from 1.7 +/- 0.2 to 40 +/- 6 pg/ml. Intra-arterial infusion of the adenosine receptor antagonist 8-(p-sulfophenyl)-theophylline significantly blunted the hypoxia-induced rise in plasma AVP concentrations to a maximum mean level of 11 +/- 6 pg/ml. These results indicate that 1) adenosine causes a dose-dependent increase in plasma AVP concentrations and 2) a hypoxia-induced rise in fetal adenosine levels triggers vasopressin release.

Midluteal-phase vaginal color Doppler assessment of uterine artery impedance in a subfertile population.

OBJECTIVE: To compare the midluteal uterine artery impedance to blood flow as measured by the pulsatility index in women with different causes of infertility with that of women with normal fertility and to correlate this with endometrial thickness. DESIGN: A prospective study of normal women undergoing insemination with donor semen and subfertile women with tubal damage, endometriosis, premature ovarian failure, anovulation, or unexplained infertility. SETTING: A tertiary infertility center. PATIENTS: One-hundred sixty-one women (25 to 40 years of age) who were attending the clinic for subfertility treatment and 23 normal women who were having artificial insemination with donor sperm because their partners were azoospermic. INTERVENTIONS: All women were examined by transvaginal ultrasonography, with color flow imaging and blood flow analysis, on day 21 of an unstimulated ovarian cycle. MAIN OUTCOME MEASURES: The mean pulsatility index of the left and right uterine arteries and the endometrial thickness. RESULTS: The patients were grouped according to the causes of infertility and compared with normal women. There were 23 women in the normal group (median pulsatility index, 1.91; range, 0.84 to 2.95), 35 with unexplained infertility (median pulsatility index, 2.45; range, 1.0 to 7.0), 91 with tubal damage (median pulsatility index, 2.65; range, 1.25 to 8.0), 8 with endometriosis (median pulsatility index, 2.32; range, 2.05 to 5.7), and 22 with anovulatory infertility (median pulsatility index, 3.03; range, 1.6 to 7.0). All the infertile groups had significantly different median pulsatility indexes when compared with the normal group, and the pulsatility indexes correlated with endometrial thickness. CONCLUSIONS: The impedance to uterine artery blood flow is significantly different in women with different causes of infertility as compared with women of normal fertility. Increased resistance to uterine blood flow in the midluteal phase may be an important contributing factor to some causes of infertility and the cause of some previously "unexplained" infertility.

Maternal and fetal cardiorespiratory responses to adenosine in sheep.

OBJECTIVE: We determined the cardiorespiratory effects of maternal adenosine administration on the ewe and fetus. STUDY DESIGN: Adenosine was infused intravenously to five pregnant ewes as graded (25 to 400 micrograms/min per kilogram) and constant (200 micrograms/min per kilogram) infusions and as a single injection (200 micrograms/kg). Heart rate, arterial pressure, and arterial blood gases and pH were monitored in the ewe and fetus; the data were analyzed with two-way analysis of variance with Duncan's test. RESULTS: Graded adenosine infusion produced a dose-dependent rise in maternal heart rate and hemoglobin concentration and a fall in diastolic and mean arterial pressures, effects that were maintained during 1 hour of constant infusion. Single injections transiently lowered diastolic pressure and induced a biphasic change in heart rate consisting of a bradycardia followed by a tachycardia with a return to control values. Adenosine administration to the ewe did not affect maternal arterial blood gases and systolic pressure nor alter fetal heart rate, arterial pressure, or arterial blood gases. CONCLUSION: Although adenosine causes cardiovascular changes in pregnant ewes, the effects are well tolerated and do not significantly affect the cardiorespiratory status of the fetus.

Cardiovascular responses to adenosine in fetal sheep: autonomic blockade.

The mechanism by which adenosine increases heart rate was investigated in 21 chronically catheterized fetal sheep (> 0.8 term). Intra-arterial infusion of adenosine (0.16 mg.min-1.kg fetal wt-1) for 1 h significantly increased fetal heart rate within 5 min with maximum values of approximately 68 beats/min above the control mean of 163 +/- 8 beats/min. The average diastolic blood pressure was reduced only during the first 10 min of infusion, and the average systolic and mean arterial pressures were not significantly affected. Mean venous pressure rose by approximately 48% after 20 min of adenosine infusion, but all other measurements did not differ significantly from the control value. The mean hemoglobin concentration during the last 30 min of infusion was increased by approximately 8%. Plasma concentrations of norepinephrine and epinephrine were elevated only during the first 30 min of adenosine administration, to values as high as 2.3 and 5 times the respective control mean. Adenosine significantly increased mean fetal heart rate by about 15-20 beats/min in fetuses with autonomic ganglion blockade or combined cholinergic, alpha-, and beta-adrenergic receptor blockade. Intra-arterial infusion of CGS 21680C, an A2-adenosine receptor agonist, also produced a fetal tachycardia of approximately 86 beats/min above the control mean and increased intrinsic fetal heart rate by approximately 38 beats/min. It is concluded that approximately 75% of the positive chronotropic effects of adenosine are produced by A2-receptor stimulation of the autonomic nervous system and that approximately 25% of the rise in heart rate induced by adenosine may be caused by activation of A2-receptors in myocardium.