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Biomedical subjects

K L Thornburg

Publications and source records attributed to K L Thornburg.

At least 19 recordsLinked to original sources
PubMed2006

Cortisol stimulates cell cycle activity in the cardiomyocyte of the sheep fetus.

The role of cortisol in regulating cardiac myocyte growth in the near-term fetal sheep is unknown. We hypothesized that cortisol would suppress cardiomyocyte proliferation and stimulate cardiomyocyte binucleation and enlargement, signs of terminal differentiation. Cardiomyocyte dimensions and percent binucleation were determined in isolated cardiac myocytes from seven cortisol-treated and seven control fetuses; percentage of myocytes positive for Ki-67 was determined in an additional four cortisol-treated and four control hearts. Cortisol was infused into the circumflex coronary artery at subpressor rates (0.5 microg/kg.min, 7 d). Cortisol infusion had no hemodynamic effects, compared with controls or pretreatment conditions. Cortisol treatment increased heart weight (44.0 +/- 8.7 g vs. control, 34.9 +/- 9.1 g, P < 0.05). Heart to body weight ratio was greater in treated hearts, compared with controls (10.3 +/- 1.9 vs. 7.7 +/- 0.9 g/kg, P < 0.01). Ventricular myocyte length, width, and percent binucleation were not different between groups. The proportion of treated myocytes in the cell cycle staining for Ki-67 was higher in the left ventricle (5.5 +/- 0.1 vs. 2.7 +/- 0.4%, P < 0.005) and right ventricle (4.4 +/- 0.4 vs. 3.7 +/- 0.7%, P < 0.05), compared with controls. Wet weight to dry weight ratios from cortisol-treated and control hearts were not different. In conclusion, whereas cortisol infused into the fetal sheep heart has no effect on cardiomyocyte size or maturational state, it stimulates entry of cardiomyocytes in the cell cycle. Thus, increases in fetal heart mass associated with subpressor doses of cortisol are due to cardiomyocyte proliferation and not hypertrophic growth.

Animals↗
PubMed2005

The effects of anaemia as a programming agent in the fetal heart.

The intrauterine environment plays a powerful role in determining the life-long risk of cardiovascular disease. A number of stressors are well known to affect the development of the cardiovascular system in utero including over/under maternal nutrition, excess glucocorticoid and chronic hypoxia. Chronic fetal anaemia in sheep is a complex stressor that alters cardiac loading conditions, causes hypoxic stress and stimulates large changes in flow to specific tissues, including large increases in resting coronary blood flow and conductance. Decreased viscosity can account for approximately half of the increased flow. It appears that immature hearts are 'plastic' in that increases in coronary conductance with fetal anaemia persist into adulthood even if the anaemia is corrected before birth. These large changes in conductance are possible only through extensive remodelling of the coronary tree. Adult hearts that were once anaemic in utero are more resistant to hypoxic stress as adults but it is not known whether such an adaptation would be deleterious in later life. These studies indicate the need for investigation into the basic mechanisms of coronary tree remodelling in the immature myocardium. New information on these mechanisms is likely to lead to better prevention of and therapies for adult-onset coronary disease.

Anemia, Neonatal↗
PubMed2003

Flow in the early embryonic human heart: a numerical study.

Computational fluid dynamic (CFD) experimentation provides a unique medium for detailed examination of flow through complex embryonic heart structures. The purpose of this investigation was to demonstrate that streaming blood flow patterns exist in the early embryonic heart and that fluid surface stresses change significantly with anomalous alterations in fetal heart lumen shape. Stages 10 and 11 early human embryo hearts were digitized as calibrated two-dimensional (2D) cross-sectional sequential images. A 3D surface was constructed from the stacking of these 2D images. CFD flow solutions were obtained (steady and pulsatile flow). Particle traces were placed in the inlet and outlet portions of these two stages. Sections of the embryonic heart were artificially reshaped. CFD flow solutions were obtained and surface stress changes analyzed. Streaming was shown to exist, with particles released on one or the other side of the cardiac lumen tending not to cross over and mix with particles released from the opposite side of the cardiac lumen. Shear stress changes (stage 10) occur in the altered lumens. Streaming exists in steady and pulsatile flow scenarios in the embryonic heart models. There are differences in local shear stress distributions with surface shape anomalies of the fetal heart lumen. These observations may help shed light on the potential role of fluid dynamic factors in determining patterns of abnormal heart development.

Blood Flow Velocity↗
PubMed2003

Angiotensin II stimulates hyperplasia but not hypertrophy in immature ovine cardiomyocytes.

Rat and sheep cardiac myocytes become binucleate as they complete the 'terminal differentiation' process soon after birth and are not able to divide thereafter. Angiotensin II (Ang II) is known to stimulate hypertrophic changes in rodent cardiomyocytes under both in vivo and in vitro conditions via the AT1 receptor and intracellular extracellular regulated kinase (ERK) signalling cascade. We sought to develop culture methods for immature sheep cardiomyocytes in order to test the hypothesis that Ang II is a hypertrophic agent in the immature myocardium of the sheep. We isolated fetal sheep cardiomyocytes and cultured them for 96 h, added Ang II and phenylephrine (PE) for 48 h, and measured footprint area and proliferation (5-bromo-2'-deoxyuridine (BrdU) uptake) separately in mono- vs. binucleate myocytes. We found that neither Ang II nor PE changed the footprint area of mononucleated cells. PE stimulated an increase in footprint area of binucleate cells but Ang II did not. Ang II increased myocyte BrdU uptake compared to serum free conditions, but PE did not affect BrdU uptake. The MAP kinase kinase (MEK) inhibitor UO126 prevented BrdU uptake in Ang II-stimulated cells and prevented cell hypertrophy in PE-stimulated cells. This paper establishes culture methods for immature sheep cardiomyocytes and reports that: (1) Ang II is not a hypertrophic agent; (2) Ang II stimulates hyperplastic growth among mononucleate myocytes; (3) PE is a hypertrophic agent in binucleate myocytes; and (4) the ERK cascade is required for the proliferation effect of Ang II and the hypertrophic effect of PE.

Angiotensin II↗
PubMed2003

The influence of various physiological challenges on permanent changes to the cardiovascular system.

The concept of fetal programming provides an intellectual framework that links physiological adaptations that occur during development to permanent changes in postnatal regulatory systems. Recent research in the area of cardiovascular programming has highlighted the mechanisms by which these changes exert their effects. The aim of this review is to integrate some of the literature on nutritional changes, exposure to excess glucocorticoids and other challenges during development as they provide support for various mechanisms of programming of the cardiovascular system.

Animals↗
PubMed2003

Anaemia stimulates aquaporin 1 expression in the fetal sheep heart.

Interstitial fluid fluxes are much greater in the fetus than in the adult, and filtration rates are increased over control in most tissues of the anaemic fetus. Increased capillary filtration may lead to cardiac oedema which, in turn, severely impacts cardiac function. Mechanisms that underlie these differences in flux are incompletely understood. One possible mechanism is an increase in capillary water permeability. Therefore, the goal of our study was to determine the level of expression of the water channel aquaporin 1 (AQP1) during cardiac development and in the anaemic fetal sheep heart. Hearts from chronically instrumented anaemic sheep fetuses and hearts from normal early fetal, late fetal, neonatal and adult sheep were used for Northern and Western analyses and immunohistochemistry. We found that AQP1 mRNA levels were lower in the young fetal left ventricle than in the adult left ventricle (P < 0.05). We also found that cardiac AQP1 expression was increased in anaemic fetuses compared to age-matched controls (P < 0.05). Expression of AQP1 in all groups was greatest in the microvascular endothelium. These data suggest that AQP1 plays an important role in the physiological accommodation to fetal anaemia.

Adaptation, Physiological↗
PubMed2002

Augmentation of coronary conductance in adult sheep made anaemic during fetal life.

Maximal coronary conductance with adenosine in anaemic fetal sheep is twice that of non-anaemic fetuses. To investigate whether this increase in conductance persists into adulthood we studied twin sheep as fetuses and again as adults. Nine anaemic fetuses (118 days gestation) underwent isovolaemic haemorrhage for 18.0 +/- 4.6 days (means +/- S.D.) during which time the haematocrit was reduced from 39.9 +/- 5.2 % to 16.3 +/- 3.4 % and oxygen content from 8.6 +/- 1.3 to 2.3 +/- 0.2 ml dl-1. At 138 days the anaemic fetuses were transfused; at delivery the haematocrit was 29.3 +/- 6.8 % compared to nine control fetuses in which the haematocrit was 38.5 +/- 4.3 %. The weight at delivery was 3.5 +/- 0.36 kg in the anaemic fetuses vs. 4.2 +/- 0.83 kg in controls. Twenty-eight weeks later, we placed an occluder on the descending thoracic aorta and inferior vena cava, a flow probe around the proximal left circumflex coronary artery, and catheters in the left atrial appendage, jugular and carotid vessels. Maximal coronary conductance was determined in the adults by recording coronary blood flow as driving pressure was altered by inflating the occluders while adenosine was infused into the left atrium. Right atrial, left atrial, systolic and mean arterial pressures, systemic vascular resistance and haematocrit were not different between 'in utero anaemic' and control adults. The adults that were anaemic in utero weighed less than the controls 39.4 +/- 4.6 kg vs. 45.0 +/- 5.6 kg. Maximal conductance was greater in the adults that were anaemic in utero: 11.2 +/- 4.0 ml min(-1) (100 g)(-1) mmHg-1 as compared to 6.1 +/- 1.8 ml min(-1) (100 g)(-1) mmHg(-1) in the controls. Vascular reactivity of the mesenteric arteries was not different. These data suggest that coronary conductance can be modified in utero by anaemia (high flow and hypoxaemia) and that the remodelled coronary tree persists to adulthood.

Adenosine↗
PubMed2000

Hemodynamic changes in pregnancy.

The basic mechanisms that underlie alterations in the physiology of pregnancy are virtually unknown. Basal oxygen consumption increases by some 50 mL/min in pregnant women at term. Blood volume increases gradually over gestation as does red cell mass. Cardiac output increases by some 50% by mid-third trimester. Stroke volume and heart rate increase over the course of pregnancy with heart rate increasing gradually until term. The heart of the pregnant woman remodels dramatically in the first few weeks of pregnancy; end diastolic volume increases. Stroke volume is augmented by the increase in end diastolic volume and maintenance of ejection fraction through a possible increase in contractile force. Systolic and diastolic blood pressures drop during normal pregnancy. There is evidence of blood vessel remodeling in all vessels. Venous compliance and venous blood volume are increased. Renal plasma flow increases by some 70% in pregnancy with glomerular filtration rate increasing by 50% by unknown mechanisms. The complex hormonal environment is changing throughout pregnancy. In summary, under the influence of circulating chemical mediators blood flow is redistributed to the uterus, breast, and kidney.

Female↗
PubMed2000

Structural and functional responses of the bullfrog urinary bladder to distension caused by hydrostatic pressure gradients.

The responses to mucosal pressure elevation (physiological pressure: PP) were compared to responses to serosal pressure elevation (non-physiological pressure: NPP) in bullfrog urinary bladders (Rana catesbeiana). The bladders were mounted on vertical chambers as flat sheets. Distension was applied with 98.07 Pa. pressure gradients. PP resulted in increases in transepithelial electrical potential difference (TEP) and short-circuit current (SCC). Electrical resistance (R), urea permeability (P(urea)) and net water flux (J( v)) were not effected. NPP resulted in decreases in TEP (38%), SCC (13%), and R (36%). While P(urea) (97%) and J(v) (96%) increased. PP caused little or no change in the electron microscopic structure of frog bladder while NPP caused irreversible dilation of the lateral intercellular spaces. There were no observable changes in tight junctions under PP or NPP. The subepithelial elements of the bladder became detached from the epithelial layer during NPP suggesting a role for them during PP.

Animals↗
PubMed2000

Denudations as paracellular routes for alphafetoprotein and creatinine across the human syncytiotrophoblast.

We tested two hypotheses: 1) that fibrin-containing fibrinoid-filled denudations of the syncytiotrophoblast may provide a route for paracellular diffusion and 2) that placentas from women who had elevated maternal serum alphafetoprotein (MSAFP) in midgestation had raised permeability to AFP and greater denudation than in normal pregnancy. We measured AFP and creatinine clearance across term placental cotyledons from the above groups and used light microscope morphometric analysis to determine the volume density of fibrin-containing fibrinoid deposits. There was no significant difference between the two groups in terms of AFP and creatinine clearance or volume density of fibrin-containing fibrinoid deposits. The combined data showed a significant (P < 0.05) positive correlation between creatinine clearance, but not AFP clearance, and volume density of fibrin-containing fibrinoid. We conclude that syncytiotrophoblast denudations, with associated fibrinoid, do provide a route for diffusion of small hydrophilic solutes, but that other anatomic features of the placenta are rate limiting for transfer of AFP and similarly sized molecules.

Creatinine↗
PubMed2000

Right ventricular systolic pressure load alters myocyte maturation in fetal sheep.

The effects of right ventricular (RV) systolic pressure (RVSP) load on fetal myocyte size and maturation were studied. Pulmonary artery (PA) pressure was increased by PA occlusion from mean 47.4 +/- 5.0 (+/-SD) to 71 +/- 13.6 mmHg (P < 0.0001) in eight RVSP-loaded near-term fetal sheep for 10 days. The maximal pressure generated by the RV with acute PA occlusion increased after RVSP load: 78 +/- 7 to 101 +/- 15 mmHg (P < 0.005). RVSP-load hearts were heavier (44.7 +/- 8.4 g) than five nonloaded hearts (31.8 +/- 0.2 g; P < 0.03); heart-to-body weight ratio (10.9 +/- 1.1 and 6.5 +/- 0.9 g/kg, respectively; P < 0.0001). RVSP-RV myocytes were longer (101.3 +/- 10.2 microm) than nonloaded RV myocytes (88.2 +/- 8.1 microm; P < 0. 02) and were more often binucleated (82 +/- 13%) than nonloaded myocytes (63 +/- 7%; P < 0.02). RVSP-loaded myocytes had less myofibrillar volume than did nonloaded hearts (44.1 +/- 4.4% and 56. 1 +/- 2.6%; P < 0.002). We conclude that RV systolic load 1) leads to RV myocyte enlargement, 2) has minor effects on left ventricular myocyte size, and 3) stimulates maturation (increased RV myocyte binucleation). Myocyte volume data suggest that RV systolic loading stimulates both hyperplastic and hypertrophic growth.

Animals↗
PubMed1999

Molecular cloning, chromosomal mapping, and developmental expression of a novel protein tyrosine phosphatase-like gene.

Protein tyrosine phosphatases (PTPs) mediate the dephosphorylation of phosphotyrosine. PTPs are known to be involved in many signal transduction pathways leading to cell growth, differentiation, and oncogenic transformation. We have cloned a new family of novel protein tyrosine phosphatase-like genes, the Ptpl (protein tyrosine phosphatase-like; proline instead of catalytic arginine) gene family. This gene family is composed of at least three members, and we describe here the developmental expression pattern and chromosomal location for one of these genes, Ptpla. In situ hybridization studies revealed that Ptpla expression was first detected at embryonic day 8.5 in muscle progenitors and later in differentiated muscle types: in the developing heart, throughout the liver and lungs, and in a number of neural crest derivatives including the dorsal root and trigeminal ganglia. Postnatally Ptpla was expressed in a number of adult tissues including cardiac and skeletal muscle, liver, testis, and kidney. The early expression pattern of this gene and its persistent expression in adult tissues suggest that it may have an important role in the development, differentiation, and maintenance of a number of different tissue types. The human homologue of Ptpla (PTPLA) was cloned and shown to map to 10p13-p14.

Amino Acid Sequence↗
PubMed1999

Coronary flow regulation in the fetal sheep.

The two ventricles of the fetal sheep heart have anatomic and biochemical differences that account for their differing functional capabilities and blood flows. Coronary flows to both ventricles have been measured using radiolabeled microspheres [or left ventricular (LV) flow, by Doppler sensor on the circumflex coronary artery] during experiments of pressure loading and chronic and acute hypoxemia. Blood flow to the left ventricle with its lower wall tension is about two-thirds the flow per gram compared with the right ventricle (RV). Acute systolic pressure loading of the RV to its maximal work capability stimulates flow to double (from approximately 250 to 500 ml. min(-1). 100 g(-1)), but to a level less than stimulated by adenosine (750 ml. min(-1). 100 g(-1)). At all RV work loads, LV flow remains at two-thirds RV flow. Resting myocardial flow levels in fetuses that have been chronically hypoxemic are similar to maximal adenosine-stimulated flows of normal fetal sheep. This flow augmentation is evidently due to vascular remodeling because a normal "flow reserve" of approximately 500 ml. min(-1). 100 g(-1) during adenosine administration remains. Acute hypoxemia stimulates myocardial flow to extraordinary levels (>1.5 l. min(-1). 100 g(-1)), levels larger than can be obtained with chemical dilation alone. LV flows do not exceed adenosine-stimulated flows when nitric oxide synthase is antagonized. We conclude 1) fetal RV coronary flow increases with RV work but to levels less than during adenosine stimulation; 2) the fetal heart is designed to accommodate extremely high flows in response to acute hypoxemia, partially through large production of nitric oxide; and 3) the fetal coronary tree is dramatically remodeled in response to chronic hypoxemia.

Animals↗
PubMed1998

The sequential effects of estrogen administration and hypertension on cardiac function in ewes.

OBJECTIVE: Our objective was to study the effect of estrogen administration and moderate hypertension on left ventricular size, pump function, and contractility in chronically instrumented ewes. STUDY DESIGN: Ewes were either given 0.06 mg/kg 17beta-estradiol intramuscularly (n = 8) or were made hypertensive (n = 6) by inflation of an occluder around the aorta and were studied weekly. After 3 weeks each ewe received the opposite treatment. RESULTS: Estrogen administration caused an increase in left ventricular chamber size at a given pressure, fractional shortening (21.9% +/- 2.9% to 28.5% +/- 3.7%), and stroke volume (1.4 +/- 0.3 mL/kg to 1.6 +/- 0.3 mL/kg). Subsequent hypertension further increased left ventricular size at a given pressure but decreased fractional shortening (20.0% +/- 4.4%) and stroke volume (1.3 +/- 0.3 mL/kg). With hypertension first, there was no left ventricular enlargement, even with subsequent estrogen administration, and there were no changes in left ventricular pump function. End-systolic pressure and stress-dimension relationships did not change with either treatment. The end-systolic wall stress-fractional shortening relationship was likewise unchanged, suggesting that neither treatment changed contractility. CONCLUSIONS: The left ventricle previously exposed to hypertension does not remodel when exposed to estrogen, and cardiac pump function decreases when the estrogen enlarged heart is faced with moderate, subacute hypertension.

Animals↗
PubMed1995

Effects of ductus arteriosus occlusion on pulmonary artery pressure during in utero ventilation in fetal sheep.

Seven fetal sheep were prepared to study the short-term effects of in utero ventilation and ductus arteriosus occlusion on pulmonary artery pressure and on fetal right ventricular function assessed using the right atrial pressure-right ventricular stroke volume relationship. Nine days post-surgery (140 days gestation), blood gas and haemodynamic values were obtained before and during in utero ventilation with 100% O2, and during ventilation with the ductus arteriosus occluded. Oxygen content increased significantly from 7.2 to 14.5 ml dl-1 with ventilation and remained elevated at 14.4 ml dl-1 with ventilation with the ductus arteriosus occluded. In utero ventilation produced a left to right atrial pressure gradient and depression of the right atrial pressure-right ventricular stroke volume relationship. Ductus arteriosus occlusion during in utero ventilation reduced the left to right atrial pressure gradient, and along with a decrease in pulmonary artery pressure, resulted in an upward shift of the right atrial pressure-right ventricular stroke volume relationship, but only to the preventilation level. This study indicates that the fetal right atrial pressure-right ventricular stroke volume relationship is significantly altered, both by changes in the left to right atrial pressure gradient and by changes in pulmonary artery pressure seen with in utero ventilation and subsequent ductus arteriosus occlusion.

Animals↗