Biomedical subjects

K E Clark

Publications and source records attributed to K E Clark.

At least 55 records · Page 3Linked to original sources

PubMed1990

Fetal hemodynamic and fetoplacental vascular response to exogenous arginine vasopressin.

Fetal hemodynamics and fetoplacental blood flow were measured in chronically instrumented ovine fetuses during intravenous infusion of arginine vasopressin. Vasopressin was infused at rates ranging from 1 to 300 ng/min/kg estimated fetal mass. This range of infusion rates produces plasma arginine vasopressin levels observed throughout a wide range of fetal stress. No maternal effects were observed at any infusion rates used in this investigation. Fetal heart rate declined linearly with the log of the infusion rate. Mean fetal arterial pressure showed a sigmoidal response to log arginine vasopressin infusion rate, reaching a plateau at 30 ng/min/kg. Umbilical vascular resistance increased throughout the entire range of infusion rates. Fetoplacental blood flow decreased with increasing infusion rate but decreased only 4% to 13% throughout the range of infusion rates that produce plasma arginine vasopressin levels commonly observed during fetal stress. Because umbilical vascular resistance continued to rise after arterial pressure reached a plateau, fetoplacental blood flow decreased 31% at the highest infusion rate. However, the plasma vasopressin level associated with this infusion rate is probably in excess of that associated with severe fetal distress. The fetoplacental vascular bed is, therefore, either relatively insensitive to arginine vasopressin, or is capable of autoregulation in the face of high circulating levels of arginine vasopressin.

Animals↗

PubMed1990

Relationship between the ovine fetal umbilical artery blood flow waveform and umbilical vascular resistance.

Ultrasonic umbilical artery blood flow velocity waveform indexes decrease throughout gestation as umbilical blood flow increases. However, it is not known whether the decrease in indexes such as systolic/diastolic ratio is a direct result of a change in umbilical vascular resistance. Umbilical artery blood flow was measured as vasoactive agents angiotensin II, arginine vasopressin, norepinephrine, serotonin, and the thromboxane A2 sympathomimetic agent U-46619 were infused into the inferior vena cava of chronically instrumented ovine fetuses. Angiotensin II, arginine vasopressin, norepinephrine, serotonin, and U-46619 all significantly increased fetal arterial pressure levels. Angiotensin II, arginine vasopressin, and U-46619 significantly reduced umbilical blood flow and fetal heart rate. All five pressor agents increased umbilical vascular resistance. Systolic/diastolic ratios were obtained from pulsatile umbilical blood flow tracings. Systolic/diastolic ratios before infusions were significantly correlated with baseline values of umbilical blood flow (r = -0.55) and umbilical vascular resistance (r = 0.52). Systolic/diastolic ratios decreased with increasing infusion rates of angiotensin II, arginine vasopressin, norepinephrine, and serotonin, and increased with infusion of U-46619. There was no significant correlation between systolic/diastolic ratio and either umbilical blood flow or umbilical vascular resistance during infusion of angiotensin II, arginine vasopressin, or serotonin. Systolic/diastolic ratio decreased with increasing umbilical vascular resistance during norepinephrine infusion (r = -0.44). Systolic/diastolic ratio changed in the predicted direction only when umbilical vascular resistance was increased by infusion of U-46619 (r = 0.80). We conclude that umbilical artery waveform analysis is not an adequate predictor of acute changes in umbilical blood flow or vascular resistance.

Animals↗

PubMed1990

Differential responses of uterine and umbilical vasculatures to angiotensin II and norepinephrine.

Although the uterine vascular responses to endogenous vasoactive substances have been extensively investigated in pregnant sheep, the fetal umbilical responses to angiotensin II (ANG II) and norepinephrine (NE) have not been well characterized. Twenty-five pregnant ewes between 105 and 115 days of gestation were anesthetized and instrumented for hemodynamic measurements, systemic fetal and maternal intravenous infusions, and local maternal uterine arterial infusions of ANG II and NE. Fetal and maternal arterial pressure and heart rate, maternal uterine blood flow (total of left and right middle uterine arteries), and fetoplacental blood flow (common umbilical artery) were measured during continuous infusions of ANG II or NE. Fetal infusions of ANG II (0.03-1.0 micrograms.min-1.kg estimated fetal body wt-1) increased fetal arterial blood pressure by as much as 44% over base-line values, decreased umbilical blood flow by as much as 63%, and increased umbilical vascular resistance by up to 345%. Fetal infusions of NE (0.1-3 micrograms.min-1.kg-1) increased fetal arterial pressure 42% and increased umbilical vascular resistance by up to 38% but did not significantly alter fetoplacental blood flow. No significant maternal changes were observed during fetal infusions. Maternal infusion of ANG II increased maternal arterial pressure by as much as 59% and significantly increased uterine vascular resistance at the two highest doses but significantly decreased uterine blood flow only at the highest dose (17%; P less than 0.05). Maternal infusions of NE increased arterial pressure by as much as 113%, decreased uterine blood flow by as much as 76%, and increased uterine vascular resistance 3- to 10-fold over the base-line value.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗

PubMed1990

Effects of chronic instrumentation on fetal growth.

Chronically-instrumented fetal sheep are a commonly used animal model for the study of fetal growth and metabolism. In the current study, we wanted to test the hypothesis that instrumentation alone would alter fetal growth patterns. Thirty-two animals in three groups were used: (i) non-instrumented animals (n = 10); (ii) instrumented with catheters in the maternal and fetal femoral artery and vein and electromagnetic flow probes on the main uterine arteries (n = 10): (iii) animals instrumented as group 2, but with the addition of a doppler flow probe on the common umbilical artery and a common umbilical vein catheter (n = 12). Animals in group 2 and 3 were monitored until 137 to 140 days of gestation, at which time they were sacrificed for fetal morphometric measurements. Instrumentation significantly (P less than 0.05) decreased fetal body weight, length, and thymus weights. Liver-to-body ratios increased (P less than 0.05) in both surgically-instrumented groups. The addition of the umbilical artery doppler flow probe and an umbilical venous catheter did not lead to any further alterations in fetal growth. The current study demonstrates that surgical instrumentation alone can lead to significant alterations in fetal growth.

Animals↗

PubMed1989

Alloxan-induced diabetes mellitus in the pregnant ewe: metabolic and cardiovascular effects on the mother and her fetus.

Diabetes mellitus was acutely produced in nine pregnant sheep by the intravenous administration of alloxan 40 mg/kg in the maternal inferior vena cava. Maternal and fetal plasma concentrations of glucose, lactate, beta-hydroxybutyrate, insulin, glucagon, and PaO2, oxygen content, and pH were determined before and at days 1, 3, and 5 after the injection of alloxan. Two animals aborted between days 1 and 3 after alloxan administration. In the other animals, significant changes occurred from baseline to day 5: maternal hyperglycemia (56.8 +/- 5.2 vs. 227.3 +/- 54.6 mg/dl; p less than 0.01), maternal hypoinsulinemia (6.2 +/- 3.5 vs. 1.0 +/- 0.4 microU/ml, p = 0.016); maternal hyperketonemia (beta-hydroxybutyrate: 0.79 +/- 0.27 vs. 4.69 +/- 2.64 mmol/L, p less than 0.01); fetal hyperglycemia (17.0 +/- 2.6 vs. 86.0 +/- 16.2 mg/dl, p less than 0.001); fetal hyperinsulinemia (8.4 +/- 4.5 vs. 19.2 +/- 6.4 microU/ml, p less than 0.001); fetal hyperketonemia (beta-hydroxybutyrate: 0.03 +/- 0.03 vs. 0.06 +/- 0.02 mmol/L, p less than 0.05); fetal hypoxemia (arterial PO2: 21.6 +/- 1.8 vs. 18.0 +/- 2.8 mm Hg, p less than 0.05, and oxygen content: 7.1 +/- 0.5 vs. 4.5 +/- 1.9 vol/dl, p less than 0.02). Thus alloxan administered in the pregnant ewe can produce major metabolic and endocrine derangements acutely simulating those occurring in human insulin-dependent diabetic pregnancy.

Animals↗

PubMed1989

Hypercalciuria with Bartter syndrome: evidence for an abnormality of vitamin D metabolism.

Some children with Bartter syndrome have hypercalciuria. To determine the mechanism for this phenomenon, we studied tubular function and calcium metabolism in six such children. All patients had hypokalemic alkalosis, normotension, hyperreninemia, growth retardation, low fractional distal chloride reabsorption (4/5), and elevated urinary prostaglandin E2 excretion (5/6). In addition, all had hypercalciuria (urinary calcium 6.5 to 25.0 mg/kg/day), with evidence of nephrocalcinosis in five. None, however, had evidence of rickets or hyperparathyroidism. There was a marked elevation in the serum concentration of 1,25-dihydroxyvitamin D in all, and four patients had a response to oral calcium loading suggestive of absorptive hypercalciuria. Five children have had long-term therapy with indomethacin. They have had improvement in hypokalemia and reduced urinary prostaglandin E2 excretion as well as reductions in the serum concentration of 1,25-dihydroxyvitamin D and in urinary calcium excretion. These data suggest that hypercalciuria in some children with Bartter syndrome is associated with an excess of 1,25-dihydroxyvitamin D. The improvement in hypercalciuria with prostaglandin synthesis inhibition may result in part from correction of this vitamin D abnormality.

Bartter Syndrome↗

PubMed1988

Review of fetal cardiovascular and metabolic responses to diabetic insults in the pregnant ewe.

Studies with pregnant sheep are reviewed, which were designed to investigate whether short-term episodes of maternal hyperglycemia or hyperketonemia were detrimental to the fetus, whether ketones can cross the ovine placenta, and whether the combination of maternal hyperglycemia and hyperketonemia would contribute to an increased risk of fetal morbidity. It is concluded that acute increases in maternal ketones appear to be more detrimental to the fetus than acute increases in maternal glucose, as assessed by fetal cardiovascular, metabolic, and blood gas changes.

Animals↗

PubMed1987

Effect of cocaine on uterine blood flow and fetal oxygenation.

Five pregnant ewes and their singleton fetuses were instrumented at 115 to 120 days' gestation (term, 145 days) for heart rate, blood pressure, uterine blood flow, and arterial blood gas sampling. In separate studies, cocaine was given to the ewe or fetus as a 0.5-, 1.0-, or 2.0-mg/kg intravenous bolus, and cardiovascular and arterial blood gas values were obtained for 60 minutes after the injection. The results showed that maternal administration of cocaine produced dose-dependent increases in maternal blood pressure and decreases in uterine blood flow. Uterine vascular resistance increased by 52%, 96%, and 168%, respectively. These responses were accompanied by marked fetal hypoxemia, hypertension, and tachycardia. Direct cocaine administration to the fetus produced smaller increases in fetal heart rate and blood pressure than those observed following maternal cocaine injection, and no significant changes in fetal arterial blood gas values. The conclusions are cocaine alters fetal oxygenation by reducing uterine blood flow and impairing oxygen transfer to the fetus; and fetal cardiovascular changes to maternal administration of cocaine may reflect fetal hypoxemia, increased fetal levels of cocaine or fetal catecholamines, or a combination of these events.

Animals↗

PubMed1987

Fetal beta-endorphin levels in response to reductions in uterine blood flow.

Fetal beta-endorphin release has been associated with fetal hypoxia. The purpose of this study was to assess the degree of uterine blood flow reduction needed to elicit fetal beta-endorphin release in the sheep since there is a large reserve of oxygen supply to the fetus. Uterine blood flow was reduced by 26 +/- 2, 46 +/- 3 and 66 +/- 2%, producing fetal oxygen content concentrations of 5.7 +/- 0.6, 4.4 +/- 0.7 and 2.6 +/- 0.3 ml/dl, respectively. Although fetal oxygen concentrations were significantly decreased in the groups with a reduction in uterine blood flow of 46 and 66%, beta-endorphin was elevated only in the latter group. It is speculated that fetal beta-endorphin is released at a level of hypoxia which leads to a decrease in fetal oxygen consumption. A reduction in uterine blood flow of 66% appears to produce a stressful environment for the fetus as measured by fetal plasma beta-endorphin levels.

Animals↗

PubMed1987

Viability of stored equine embryos.

Equine embryos were recovered nonsurgically 6.5 d after ovulation (Exp. 1) and those greater than 200 microns were stored in one of three media: 1) Ham's F10 + 10% fetal calf serum (FCS) under 5% CO2, 5% O2 and 90% N2 at 24 C (Ham's F10); 2) Minimal Essential Medium with Hank's balanced salts + 10% FCS in air (MEM) at 24 C or 3) MEM at 5 C n = 10/treatment). Embryos less than or equal to 200 micron (n = 10) were bisected microsurgically; one-half of each embryo was stored in Ham's F10 and the other half in either Dulbecco's phosphate-buffered saline + 10% FCS in air at 24 C (DPBS), or MEM in air at 24 C. At 0, 12 and 24 h, embryos were: 1) measured; 2) assigned a developmental score of 1 to 4 (1 = tight morula, 4 = expanding blastocyst) and 3) assigned a quality score of 1 to 5 (1 = excellent, 5 = degenerate). Whole embryos stored in MEM at 5 C or 24 C did not (P greater than .05) advance in development by 24 h, whereas those stored in Ham's F10 at 24 C were more (P less than .05) advanced (i.e., higher developmental score) by 24 h. From 0 to 24 h, 1 of 10, 6 of 10 and 7 of 10 whole embryos developed when stored in MEM 5 C, MEM 24 C and Ham's F10 24 C, respectively. Embryo quality was better at 24 h (P less than .05) for embryos stored in Ham's F10 at 24 C compared with MEM at 5 C.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

Effect of antipyrine on prostaglandin levels and uterine and umbilical blood flow.

Antipyrine and 4-aminoantipyrine have been used for approximately 20 years to measure uterine and umbilical blood flow. Fetal infusion of 4-aminoantipyrine has been shown to decrease myometrial activity and to significantly lower prostaglandin F2 alpha metabolite levels. Since prostaglandins are thought to be important in regulating uterine and umbilical blood flow, their decrease could cause significant changes in blood flow. The purpose of the present study was to evaluate the effects of antipyrine on uterine and umbilical blood flow as measured with electromagnetic flow probes and to determine whether antipyrine causes significant changes in levels of prostaglandin E2, prostaglandin F2 alpha metabolite, and prostaglandin I2 measured as 6-keto-prostaglandin F1 alpha. Antipyrine infusion produced significant reductions in the uterine venous levels of prostaglandin E2 and prostaglandin F2 alpha metabolite (p less than 0.05). These reductions in prostaglandin levels were not associated with any significant changes in maternal blood pressure, heart rate, uterine blood flow, or oxygen content. Although fetal prostaglandin levels tended to decrease during the antipyrine infusion, these changes were not significant. Fetal blood pressure, heart rate, umbilical blood flow, PaO2, and oxygen content were not significantly altered. These data suggest that the antipyrine method does not affect basal blood flow in the uterine or umbilical circulation even though uterine prostaglandin levels are significantly decreased.

6-Ketoprostaglandin F1 alpha↗

PubMed1986

Effect of maternal hyperketonemia in hyperglycemic pregnant ewes and their fetuses.

The fetus of the pregnant diabetic woman is exposed to hyperglycemia frequently accompanied by ketoacidosis. Previous studies have demonstrated that beta-hydroxybutyrate, a major ketone body, crosses the ovine placenta in significant amounts, leading to significant reductions in fetal PaO2 and increased fetal heart rate. In the present study the pregnant ewe was used to evaluate the maternal and fetal cardiovascular and metabolic responses to hyperketonemia in the presence of hyperglycemia and to determine if the combined diabetic insults were more detrimental to the fetus than hyperketonemia alone. A glucose priming dose of 25 gm was administered in the maternal femoral vein followed by a continuous glucose infusion of 200 mg/min to achieve steady maternal plasma glucose levels of 180 mg/dl. Once glucose levels were stable, beta-hydroxybutyrate was infused for 2 hours at a rate of 0.39 mmol/100 ml of uterine blood flow into both left and right uterine arteries. Infusion of glucose alone did not significantly alter fetal cardiovascular and blood gas parameters but did increase the fetal glucose level from 17 +/- 4 to 58 +/- 8 mg/dl. The simultaneous infusion of beta-hydroxybutyrate and glucose produced significant decreases in fetal PaO2 and oxygen content as were reported for hyperketonemia alone and significant time-related increases in fetal lactate levels and fetal heart rate. These data suggest that hyperketonemia in the pregnant ewe leads to quantitatively similar changes in oxygenation in both normoglycemic and hyperglycemic fetuses. These observations may in part help explain the increased perinatal mortality in the pregnant woman with uncontrolled diabetes.

3-Hydroxybutyric Acid↗

PubMed1986

Pregnancy causes a decrease in the number and affinity of myometrial angiotensin II receptors.

The pressor response to exogenously infused angiotensin II is decreased in normal human and ovine pregnancy when compared to the nonpregnant state. This study was designed to determine the mechanism for decrease in target organ sensitivity by examining pregnancy-induced changes in the affinity and number of angiotensin II receptors in myometrium from pregnant and nonpregnant sheep. Tissues were obtained from four ovariectomized sheep given 50 micrograms estradiol-17 beta on days 3 and 5 postsurgery and from four pregnant sheep (mean gestational age 136 days). Binding of 125I-angiotensin II was determined in particulate fractions of myometrium prepared by differential centrifugation. The 125I-angiotensin II binding to myometrial preparations was specific, saturable, and linear with protein concentration. In the nonpregnant group, binding capacity for angiotensin II in myometrium was 502 +/- 76 fmol/mg protein, whereas in the pregnant group it was 184 +/- 65 fmol/mg protein (P less than .01). Receptor affinity also was less (Kd 1.72 +/- 0.39 nM) during pregnancy compared with the nonpregnant sheep uterus (3.9 +/- 0.80 nM; P less than .01). These data support the hypothesis that the decrease in target organ sensitivity to exogenously administered angiotensin II during pregnancy in human and ovine species may be secondary to a decrease in the total number and affinity of specific angiotensin II receptors.

Angiotensin I↗

PubMed1985

Ovine placental vascular response to the local application of prostacyclin.

Rankin et al. have shown that prostacyclin does not dilate the ovine placenta, yet Clark et al. have shown that retrograde infusion of prostacyclin dilates the uterine vasculature. To determine the effects of prostacyclin on the sheep placenta, the two groups have collaborated. In five chronically catheterized near-term sheep, blood flows were measured by the radioactive microsphere technique. Control blood flows were measured and prostacyclin infused into the retrograde uterine artery catheter at 10 micrograms/min. The blood flows were again measured, and the area served by the catheter was then delineated by the injection of a green dye at the time of maternal euthanasia. The placenta and cotyledons were separated and the kidneys were obtained for assay. The systemic effects of prostacyclin were minimal and have been observed previously. The resistance of the myometrium fell from 566 +/- 99.9 to 322 +/- 63.9 mm Hg X ml-1 X min X gm (p less than 0.002). The placental tissue showed no change in resistance. When the tissues were combined, we observed a decrease in resistance from 0.38 +/- 0.18 to 0.32 +/- 0.14 mm Hg X ml-1 X min (p less than 0.004), thereby confirming the observation that there was indeed vasodilation downstream. However, the vasodilation was not in the placenta but in the myometrium, and we reconfirm our previous conclusion that prostacyclin does not dilate the sheep placenta.

Animals↗

PubMed1985

Effect of graded reductions in uteroplacental blood flow on the fetal lamb.

Graded reductions in uteroplacental blood flow (UBF), produced by an externally adjustable vascular occluder, were studied in unanesthetized pregnant sheep. This method was designed to simulate the physiological occurrence of reduced UBF to study its effects on fetal status. Sheep were divided into four groups in which average percent changes (+/- SE) in UBF, as measured by electromagnetic flow probes, were 7 +/- 2, -24 +/- 1, -49 +/- 1, and -63 +/- 2% for 1 h. Maternal and fetal cardiovascular (heart rate and blood pressure) and blood gas measurements of PO2 and PCO2, pH, and O2 content were determined before, during, and after recovery from UBF reduction. UBF reduction had no significant effect on maternal measurements. Changes in fetal PO2 and O2 content were directly related to the extent of vascular occlusion (P less than or equal to 0.05). Fetal pH markedly decreased after 1 h of 49% UBF reduction (P less than or equal to 0.05) and within 10 min after 63% UBF reduction (P less than or equal to 0.05). Fetal bradycardia (P less than or equal to 0.05) resulted from 63% reduction in UBF. Fetal heart rates at recovery were greater than base-line heart rate values (P less than or equal to 0.05) in the three groups whose UBF was restricted. The results of the present study suggest that the uterus of the pregnant ovine is perfused in sufficient excess to protect the fetus during short-term reductions of less than 50% UBF.

Animals↗

PubMed1984

Effects of circulating levels of vasoconstrictors on systemic pressor responsiveness to angiotensin II and norepinephrine.

Pregnancy is associated with vascular refractoriness to systemic pressor responses produced by angiotensin II. The present study was designed to determine if pregnancy-induced increases in circulating levels of angiotensin II are responsible for this refractoriness. Ten ovariectomized ewes received intravenous infusions of graded doses of angiotensin II (3, 10, 30, and 100 ng/kg/min) and norepinephrine (0.1, 0.3, 1.0, and 3.0 micrograms/kg/min) prior to (control response) and during (test response) the continuous infusion of either angiotensin II (8 ng/kg/min) or norepinephrine (0.2 microgram/kg/min). Systemic pressor responses (increases in blood pressure, millimeters of mercury) to graded doses of angiotensin II were significantly depressed during the continuous angiotensin II infusion while responses to norepinephrine were not modified. In contrast, elevation of baseline levels of a second vasoconstrictor, norepinephrine, did not alter pressor responsiveness to either angiotensin II or norepinephrine. These data suggest that vascular responses to exogenously administered angiotensin II can be selectively depressed by elevated baseline levels of angiotensin II in nonpregnant sheep.

Angiotensin II↗

PubMed1984

Uterine vascular effects of estetrol in nonpregnant ewes.

Estetrol is produced by the fetal liver and has been suggested to be a sensitive indicator of fetal well-being. Although the uterine vascular effects of estrogens (17 beta-estradiol, estriol, and estrone) have been extensively investigated in our laboratory and those of others, the ability of estetrol to dilate the ovine uterine vasculature is not presently known. The present experiment was designed to compare the vasoactivity of estetrol to that of a second pregnancy-associated estrogen, estriol. Five nonpregnant oophorectomized ewes were chronically instrumented with catheters in the femoral artery, femoral vein, uterine arteries, and electromagnetic flow probes on both uterine arteries. Upon recovering from operation, animals received unilateral intra-arterial (uterine) injections of either estriol (0.1, 0.3, 1, and 3 micrograms) or estetrol (1, 3, 10, and 30 micrograms). Ewes received only one dose of either estetrol or estriol daily and all doses were given in a randomized order. Uterine blood flow responses were continuously monitored and the time of onset, peak, and duration were recorded. The time of onset (38 +/- 2 minutes), time of peak response (75 +/- 1 minute), and duration (189 +/- 7 minutes) were approximately equal to those observed for estriol. On the basis of the data obtained in the present study we have determined that estetrol is 15 to 30 times less potent than estriol as a uterine vasodilator.

Animals↗

PubMed1984

Prostaglandin synthesis in rat embryo tissue: the effect of non-steroidal anti-inflammatory drugs in vivo and ex vivo.

Aspirin and salicylate are well-known but poorly understood teratogens in laboratory animals. Because aspirin inhibits PG synthesis, we systematically examined PG synthesis in rat embryo homogenates, the inhibition of PG synthesis in vivo and ex vivo by various non-steroidal anti-inflammatory drugs, and tested the hypothesis that the inhibition of PG synthesis is responsible for aspirin-induced limb defects in rats. We report that embryonic rat homogenates synthesize 6-keto-PGF1alpha, PGE, and PGF in large amounts from endogenous substrate, that aspirin and other non-steroidal anti-inflammatory drugs inhibit PG synthesis in vitro but not necessarily in vivo, and that contrary to our original hypothesis, the inhibition of PG synthesis is likely not responsible for aspirin-induced limb defects in rats.

6-Ketoprostaglandin F1 alpha↗