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Biomedical subjects

K E Clark

Publications and source records attributed to K E Clark.

At least 73 records · Page 4Linked to original sources
PubMed1984

Effect of histamine receptor agonists and antagonists on the uterine vasculature.

Histamine H1 and H2 receptors are known to exist in uterine smooth muscle; however, neither receptor has been clearly identified in the uterine vasculature. In the present study, 12 nonpregnant ewes were chronically instrumented with catheters in the carotid artery, jugular vein, uterine arteries, and electromagnetic flow probes on the uterine arteries for continuous measurement of uterine blood flow. Dose response curves were determined for bolus injections of Histamine (1-10 micrograms), the H1 receptor agonist 2PEA (10-100 micrograms), and the H2 receptor agonist Dimaprit (30-300 micrograms) before H1 receptor blockade with pyrilamine, following H1 receptor blockade, and following H2 receptor blockade with metiamide. Uterine vasodilator responses to histamine and 2PEA were essentially abolished by pyrilamine, while responses to dimaprit were not altered. Following addition of metiamide, responses to histamine were reduced further and responses to dimaprit were abolished. Baseline uterine blood flow was not altered by either H1 or H2 receptor blockade or their combination. Intraarterial bolus injections of the mast cell histamine-releasing compound 48/80 (100-1000 micrograms) had no effect on uterine blood flow. These experiments demonstrate that the uterine vasculature of the ovine contains almost exclusively H1 receptors, does not contain compound 48/80 sensitive mast cells and is not dependent upon endogenous histamine to maintain blood flow.

Animals↗
PubMed1983

Modulation of angiotensin II pressor responsiveness by circulating levels of angiotensin II in pregnant sheep.

During human and ovine pregnancy, systemic pressor responses to infused angiotensin II are decreased when compared to the nonpregnant state. An increased circulating level of angiotensin II has been proposed as one of the possible mechanisms responsible for this refractoriness. The present study was designed to determine if increased pressor responsiveness to exogenous angiotensin II occurs after circulating levels of angiotensin II in pregnant ewes are reduced. Pregnant (112 to 118 days' gestation) and nonpregnant sheep were instrumented with catheters in the femoral artery and vein. Dose-response curves to angiotensin I, angiotensin II, and norepinephrine were established prior to and during continuous short-term (2 to 3 hours' duration) and long-term (24 hours' duration) inhibition of angiotensin converting enzyme activity by either captopril or enalapril. Short-term infusions of converting enzyme inhibitors blocked the formation of angiotensin II from exogenously administered angiotensin I but did not alter pressor responsiveness to angiotensin II or norepinephrine in pregnant and nonpregnant sheep. Long-term infusions of the angiotensin converting enzyme inhibitor enalapril blocked responses to angiotensin I but did not alter pressor responses to norepinephrine in pregnant and nonpregnant sheep. In contrast, responses to angiotensin II were significantly potentiated in pregnant sheep but were not altered in nonpregnant sheep. These results suggest that increased circulating levels of angiotensin II in pregnant sheep are responsible for pregnancy-induced decreases in angiotensin II responsiveness.

Angiotensin II↗
PubMed1982

Effect of vasoactive intestinal polypeptide on uterine blood flow in pregnant ewes.

Vasoactive intestinal polypeptide has been localized in the uterine vasculature, uterine smooth muscle and the placenta of several species. Vasoactive intestinal polypeptide is a potent uterine vasodilator in nonpregnant sheep and also abolishes spontaneous uterine contractile activity, but the effects of this polypeptide on the uterine vasculature of the pregnant animal is currently unknown. The present experiments were performed in seven late-term pregnant sheep which were chronically catheterized to evaluate the uterine vascular effects of vasoactive intestinal polypeptide. An intra-arterial catheter was placed in a branch of the main uterine artery to allow administration of vasoactive intestinal polypeptide directly into the uterine vasculature. Uterine blood flow was continuously monitored via an electromagnetic flow transducer on both main uterine arteries. Vasoactive intestinal polypeptide infused at the rate of 1 to 30 micrograms/min produced dose-related reductions in uterine blood flow (33% +/- 9% at 30 micrograms/min). This decrease was due to a reduction in systemic arterial blood pressure, since calculated resistance in the uterine vasculature that received the vasoactive intestinal polypeptide did not change significantly. In addition, the contralateral uterine vasculature that did not receive direct intra-arterial infusions of vasoactive intestinal polypeptide showed identical changes. These data suggest that vasoactive intestinal polypeptide produces peripheral vasodilation at doses which have very little uterine effect locally. These data can be interpreted to mean either that high local endogenous production of vasoactive intestinal polypeptide prevents exogenously administered vasoactive intestinal polypeptide from exerting its vascular effects, or that vasoactive intestinal polypeptide is a very weak uterine vasodilator in pregnant ewes. The clarification of these possibilities will require further experimentation.

Animals↗
PubMed1982

Effect of maternal ketoacidemia on the pregnant ewe and the fetus.

Poorly controlled diabetic pregnancies are associated with hyperglycemia and elevated ketones. While glucose is known to cross the placenta, there is limited information regarding the placental transfer of ketones and their associated cardiovascular and metabolic effects in the fetus. Thus, the present study was undertaken to evaluate the transfer of the ketoacid beta hydroxybutyrate across the ovine placenta and to determine the effects of this ketoacid on maternal and fetal physiologic and metabolic parameters. Pregnant ewes (110 to 120 days' gestation) were instrumented with catheters in the lateral branch of both uterine arteries, uterine veins, femoral artery, and femoral vein, and electromagnetic flow probes were placed on both middle uterine arteries. Catheters were placed in the fetal carotid artery and jugular vein, and a catheter and balloon were placed in the amniotic fluid. Beta hydroxybutyrate (0.39 mmole/100 ml of uterine blood flow) and antipyrine (00.27 mmole/100 ml of uterine blood flow) as a second reference marker, were infused simultaneously into the uterine arteries for a period of 2 hours. The beta hydroxybutyrate concentrations in the uterine vein increased to 5.93 +/- 1.32 mmoles/L, and were associated with a significant increase in maternal heart rate and a slight but significant reduction in uterine blood flow. No changes in maternal arterial blood gas values were noted. The concentration of beta hydroxybutyrate in the fetal carotid arteries increased from 0.01 +/- 0.01 mmole/l to 0.15 +/- 0.03 mmole/L, and were associated with a significant reduction in fetal PaO2 (24.2 +/- 0.9 to 17.9 +/- 1.9 mm Hg) and an elevation of fetal lactate levels (1.86 +/- 0.17 to 5.07 +/- 1.56 mmoles/L).

3-Hydroxybutyric Acid↗
PubMed1982

Cardiovascular and biochemical effects of infusion of beta hydroxybutyrate into the fetal lamb.

Previous studies from our laboratory have shown that beta hydroxybutyrate crosses the ovine placenta in small amounts during maternal hyperketonemia and produces significant reductions in fetal PaO2 and increased fetal lactate levels. The present study evaluates the effects of fetal hyperketonemia on fetal and maternal cardiovascular and biochemical parameters. Pregnant ewes (110 to 120 days' gestation) were instrumented with catheters in the femoral artery, femoral vein, and uterine veins, and electromagnetic flow probes were placed on the middle uterine arteries. The fetal carotid artery and jugular vein were catheterized, and a catheter and balloon were placed in the amniotic fluid. Beta hydroxybutyrate (0.44 mmole/min) and antipyrine (0.03 mmole/min) were simultaneously infused directly into the fetal jugular vein for 90 minutes. The fetal beta hydroxybutyrate level increased from a baseline of 0.12 +/- 0.08 to 6.80 +/- 0.46 mmoles/L and was associated with a significant decrease in fetal PaO2 (23.7 +/- 2.4 to 16.0 +/- 0.4 mm Hg) and a large increase in the fetal lactate (1.85 +/- 0.27 to 5.43 +/- 0.92 mmoles/L) at 90 minutes. The present results suggest that during fetal hyperketonemia fetal oxygenation is significantly reduced and may contribute to the increased perinatal mortality in the pregnant diabetic patient.

3-Hydroxybutyric Acid↗
PubMed1982

Effect of bisenoic prostaglandins and arachidonic acid on the uterine vasculature of pregnant sheep.

Prostaglandins have been implicated as regulators of uteroplacental blood flow during pregnancy. However, the investigation of the vascular effects of these humoral agents has been extremely limited. The present study has evaluated the effects of intra-arterial infusions of prostaglandin D2, E2, F2 alpha, I2, 6-keto-F1 alpha, thromboxane B2, and bolus injections of the prostaglandin precursor arachidonic acid into the uterine vasculature of late-term pregnant ewes. Prostaglandins E2, F2 alpha, 6-keto-F1 alpha, and thromboxane B2 all reduced uterine blood flow, with prostaglandins E2 and F2 alpha being much more active. Since prostaglandins E2 and F2 alpha increase uterine tone, a portion of their vascular effects appears to be due to myometrial compression. In contrast, prostaglandins D2 and I2 produced dose-related increases in uterine blood flow in pregnant animals and did not alter uterine tone or contractile activity. Arachidonic acid produced dose-related increases in uterine vascular resistance in three out of five animals and had no effect in the other two animals. The differential vascular effects produced by the individual prostaglandins and their precursor suggest that the overall effect of these compounds on the uterine vasculature will depend on the summation of the individual actions.

Animals↗
PubMed1982

Effect of the prostacyclin synthetase inhibitor tranylcypromine on uterine blood flow in pregnancy.

Prostacyclin is a potent vasodilator in a number of vascular beds including the uterus. However, the role of prostacyclin in maintaining uterine blood flow during pregnancy is not well established. Recent reports have appeared suggesting that tranylcypromine can selectively inhibit prostacyclin synthesis. Thus, the present study was undertaken using an unanesthetized chronically catheterized pregnant sheep preparation to evaluate the effects of direct intra-arterial infusions of tranylcypromine on the uterine vasculature of late-term pregnant ewes. Infusions of 1,3 and 10 mg/min of tranylcypromine led to dose-related reduction in uterine blood flow (16, 21 and 47 percent, respectively) and increased blood pressure (7, 10 and 23 percent, respectively). However, these alterations were not associated with reductions in the uterine production rates of the prostacyclin metabolite, 6-keto-PGF1alpha, as determined by unextracted plasma RIA. In addition, pre-treatment of animals with the alpha-adrenergic blocking agent, phenoxybenzamine, almost totally abolished uterine and systemic blood pressure responses to tranylcypromine. These data suggest that tranylcypromine either releases or elevates levels of an alpha adrenergic stimulant which constricts the uterine and systemic vasculature and does not alter prostacyclin levels at the dose tested.

6-Ketoprostaglandin F1 alpha↗
PubMed1982

A model for studying chronic reduction in uterine blood flow in pregnant sheep.

A model is described for the investigation of the effects of acute and chronic reduction in uterine blood flow in unanesthetized pregnant sheep. An externally adjustable vascular occluder has been designed to utilize the principles of a modified Goldblatt clamp. This occluder is made of nonbreakable plastic and is adjusted via a flexible cable encased in a sheath. The occluder has been tested in 17 pregnant sheep and has remained functional for periods up to 36 days, the length of implantation. This occluder has allowed graded reductions in uterine blood flow, which can be accurately and consistently reproduced. An example of flow reduction is shown in which uterine blood flow has been reduced by 24, 47, and 82% in late-term pregnant sheep. This method will allow the investigation of the effects of uterine hypoperfusion and fetal hypoxia in a precisely controlled unanesthetized pregnant sheep preparation.

Animals↗
PubMed1981

Indomethacin--placental transfer, cytotoxicity, and teratology in the rat.

Aspirin is a well-known teratogen in laboratory animals and is an inhibitor of prostaglandin synthesis. To further investigate the inhibition of prostaglandin synthesis as a mechanism of teratogenesis, we examined the teratologic potential, cytotoxic potential, and placental transfer of indomethacin in the rat. Indomethacin was not teratologic, not cytotoxic to cells in the embryonic hindlimb bud, and did not cross the placenta in physiologically significant amounts on days 11 to 12 of gestation. Near parturition, however, indomethacin crossed the placenta in pharmacologically significant amounts. The pharmacokinetics of placental drug transfer are discussed.

Abnormalities, Drug-Induced↗
PubMed1981

Effects of hydroxyurea on hemodynamics of pregnant rabbits: a maternally mediated mechanism of embryotoxicity.

Hydroxyurea is a cytotoxic agent used in the management of chronic granulocytic leukemia. This compound is teratogenic and embryolethal in various animal species, and has been widely used in experimental studies aimed at understanding the possible mechanisms of drug-induced malformations. Previous studies from our laboratory have demonstrated that maternal subcutaneous injections of hydroxyurea produce immediate circulatory alterations in rabbit embryos similar to those observed subsequent to uterine artery occlusion. The present study was designed to investigate the possibility that the embryolethal and teratogenic properties of hydroxyurea might be due to alterations in maternal hemodynamics, i.e., constriction of the uterine vasculature, resulting in exposure of the embryo to uterine ischemia at critical stage of in utero development. This study demonstrates that hydroxyurea significantly alters blood pressure and heart rate and produces significant uterine vasoconstriction. The resulting reductions in uterine blood flow (77%) elicited by hydroxyurea may be associated with its immediate embryotoxicity.

Abnormalities, Drug-Induced↗
PubMed1981

Effect of prostaglandin E2 on cervical compliance in pregnant ewes.

Cervical compliance increases dramatically at parturition in sheep independent of uterine activity. Recently, in vitro production of prostaglandin E2 (PGE2) by the cervix has been shown to increase at parturition. This study investigated the effects of PGE2 on cervical compliance and uterine blood flow in pregnant ewes. Eight animals were chronically instrumented with pressure balloons within the cervical os and amniotic cavity, an electromagnetic flow probe on a uterine artery, and catheters in the maternal cervical os, femoral artery, femoral, uterine, and cervical veins, and fetal hindlimb vein. PGE2 (10 mg) was administered in a water-soluble gel into the cervical os every 4 hours times three doses at least 5 days after surgical preparation (124 to 142 days' gestation). In all eight ewes, cervical compliance increased within 8 to 12 posttreatment hours to levels comparable to that seen at spontaneous parturition. Five of the ewes did not progress into labor; compliance in these ewes returned to baseline 24 to 72 hours after the peak. Uterine blood flow was measured in five ewes during the PGE2 treatment and demonstrated no significant alterations. Maternal cardiovascular and fetal respiratory parameters were monitored throughout the experiment and remained stable. The present data suggest that PGE2 may be an important regulatory of the biochemical and physical changes which occur in the cervix at parturition.

Animals↗
PubMed1981

Effects of vasoactive polypeptides on the uterine vasculature.

Estrogen-induced increases in uterine blood flow appear to require de novo protein or polypeptide synthesis. In the present experiments a chronically catheterized nonpregnant sheep preparation was used to determine the uterine vascular effects of vasoactive intestinal polypeptide (VIP), neurotensin, and substance P. These effects were compared to those of bradykinin and the most potent vasodilator prostaglandin, prostacyclin. An intra-arterial catheter was placed in a branch of the main uterine artery to allow administration of the compounds directly into the uterine vasculature. Uterine blood flow was continuously monitored via an electromagnetic flow transducer on the maine uterine arteries. VIP, bradykinin, and prostacyclin were equally potent as vasodilators of the uterine vasculature, while neurotensin and substance P were totally devoid of vasoactivity. Unlike estradiol, bradykinin and VIP produced significant changes in systemic arterial pressure and heart rate, suggesting that these compounds may not have responsible for mediating the uterine vascular response observed after estrogen. However, VIP was a potent uterine vasodilator and was able to totally ablate uterine contractile activity, suggesting that this endogenously occurring polypeptide may be important in regulating uterine hemodynamics and contractile activity.

Animals↗
PubMed1981

Measurement of prostaglandins in embryonic tissue using radioimmunoassay.

Although prostaglandins appear to play an important role in numerous physiological processes in the adult, neonate, and fetus, very little is known about the role of these compounds in the embryo. This study demonstrates that rat embryo homogenates synthesized 6-oxo-PGF1 alpha, PGE and PGF in markedly different amounts from endogenous substrate. Synthesis was inhibited by indomethacin (10 microM) in varying degrees (70-89%) depending on the prostaglandin. The metabolite of PGF2 alpha, 13, 14-dihydro-15-keto PGF2 alpha (PGF2 alpha-M), was produced in limited amounts in the absence of exogenous NAD. In the presence of exogenous NAD and PGF however, embryonic homogenates produced PGF2 alpha-M. The potential role of prostaglandins during embryogenesis is discussed.

6-Ketoprostaglandin F1 alpha↗
PubMed1981

Effect of bisenoic prostaglandins on the uterine vasculature of the nonpregnant sheep.

The effects of the bisenoic prostaglandins on the uterine vasculature and uterine contractile activity have been evaluated in an unanesthetized chronically catheterized nonpregnant sheep preparation. Changes in uterine blood flow were monitored with electromagnetic flow probes while uterine contractile activity and tone were determined via an intra-uterine balloon connected to a pressure transducer. Prostaglandins A2, D2, E2, and prostacyclin (PGI2) were all found to be vasodilators. PGD2 and PGI2 were much more potent than PGA2 and PGE2 in dilating the uterine vasculature. The prostacyclin breakdown product 6-keto PGF1 alpha, PGF2 alpha, thromboxane B2, and the endoperoxide analogues U44069 and U46619 produced vasoconstriction of the uterine vasculature. Prostaglandins A2, D2 and F2 alpha increased while PGI2 decreased uterine contractile activity. PGF2 alpha also increased uterine tone suggesting that a portion of its vasoconstrictor activity may be due to mechanical compression of the uterine vasculature.

Animals↗
PubMed1981

Ultrasonic evaluation of fetal kidneys.

Fetal renal morphology, technique and frequency of reliable visualization of the kidneys, and renal size were evaluated in 177 apparently normal fetuses. The kidneys were not reliably identified before 15 post-menstrual weeks and were seen in fewer than 50% of cases prior to 17 weeks. However, between 17 and 22 weeks (the critical time for genetic counseling) one or both kidneys were seen in 90% of cases, with both being identified in 75%. After 20 weeks, one or both kidneys were identified in approximately 95%. With high-resolution equipment, positive identification of one or both fetal kidneys should be possible in a large percentage of cases after 20 post-menstrual weeks.

Female↗
PubMed1980

Comparison of human and sheep chorion laeve permeability to glucose, beta-hydroxybutyrate, and glycerol.

Significant permeability of in vitro human chorion laeve to glucose, glycerol, and beta-hydroxybutyrate (betaOH butyrate) and in vitro sheep chorion leave to glycerol and betaOH butyrate was measured. Diffusion across these tissues of glycerol and betaOH butyrate corresponded to the relative molecular size, charge, and lipid solubility of these compounds. The simple diffusion of glucose across human chorion leave was somewhat reduced by metabolic conversion of this compound during the transfer process. Demonstration of in vitro human placental tissue permeability to ketoacids and glycerol suggests that these compounds cross to the fetus when elevated in the maternal diabetic state.

3-Hydroxybutyric Acid↗
PubMed1980

CT evaluation of esophageal and upper abdominal varices.

Recognition of major abdominal visceral vessels is an integral part of the interpretation of upper abdominal computed tomography (CT) studies. Perivisceral portal systemic varices appear as lobulated or discrete rounded tubular densities in characteristic sites, including periesophageal, perigastric, and peripancreatic locations, the pararenal spaces, and the gallbladder fossa. To avoid confusion with lymphadenopathy and soft tissue tumors, the varices can be specifically identified using contrast enhancement techniques and fast scan times. In portal hypertension, contrast enhanced CT can be used to define both the extrahepatic portal system and the location of the perivisceral varices.

Abdomen↗