Pharmacology Commons^™

Hypoxia And Fetal Programming Of Cardiovascular Dysfunction, Qin Xue

Loma Linda University Electronic Theses, Dissertations & Projects

Human epidemiological studies have shown a clear association of adverse intrauterine environment and an increased risk of ischemic heart disease in later adult life. Of all the stresses to which the fetus is subjected, perhaps the most important and clinically relevant is that of hypoxia. The goal of this project is to test the hypothesis that chronic hypoxia during gestation adversely affects fetal cardiovascular development and impairs cardiac function in offspring. In the first part of project, we tested the hypothesis that chronic hypoxia adversely regulates contractility of fetal pulmonary arteries and veins in sheep residing at high altitude (3,801 …

Mechanisms Of Neonatal Brain Injury In A Rat Pup Hypoxic-Ischemic Model, Wanqiu Chen

Loma Linda University Electronic Theses, Dissertations & Projects

Perinatal hypoxic-ischemic (HI) brain injury is a major cause of acute morbidity and chronic nemological mortality in infants and children, with a reported incidence of 2- 9 per 1000 births. The pathophyiological mechanisms leading to immature brain damage after HI are complex and relate to the developmental stage of the brain. The objective of our study is to understand the neonatal hypoxic-ischemic brain injury and to aid in the development of pharmacological treatments.

Hypoxic inducible factor 1 (HIF-1) is a transcription factor which is stabilized and activated by hypoxia. It is the most important factor involved in the cellular response …

Maturational Changes In Myosin Light Chain Kinase Activity In Ovine Carotids, Elisha Raju Injeti

Loma Linda University Electronic Theses, Dissertations & Projects

Vascular reactivity changes dramatically during postnatal maturation due in large part to developmental changes in myofilament calcium sensitivity. Recent findings suggest that reactivity of the thick filament component of calcium sensitivity is upregulated in fetal compared to adult arteries. In light of these findings, the present study tests the hypothesis that upregulation of fetal thick filament reactivity is due to upregulation of myosin light chain kinase (MLCK) activity. To test this hypothesis, MLCK abundance and its activity is measured in intact arteries. The results indicate that MLCK abundance is 6.03 ± 0.96 fold greater in adult than in fetal arteries. …

Maturational Changes In Cerebrovascular Thick- And Thin-Filament Regulation, Renan Joel Sandoval

Loma Linda University Electronic Theses, Dissertations & Projects

The present study focused on the main hypothesis that age-related changes in myofilament Ca²⁺ sensitivity involve simultaneous changes in the relations between cytosolic Ca²⁺ transients, myosin phosphorylation, and force development. To define the effects of late fetal and early postnatal maturation, parallel experiments were carried out using cerebral arteries from both term lamb fetuses (140-141 days of gestation) and nonpregnant adult sheep. Fetal and adult cerebral arteries were stimulated by either mechanically, electromechanically, and/or pharmacomechanically-induced contractions, and the relations of cytosolic Ca²⁺, MLC phosphorylation, and contractile tensions were measured. These measurements allowed for stimulus and age-dependent …

Regulation Of Alpha-1-Adrenoceptor-Mediated Contractions Of The Uterine Artery By Pkc, Hongying Zhang

Loma Linda University Electronic Theses, Dissertations & Projects

Pregnancy is associated with a significant decrease in uterine vascular tone and a striking increase in uterine blood flow, which ensures normal fetal development. Multiple mechanisms are involved in the adaptation of uterine artery contractility during pregnancy. Both protein kinase C (PKC) and activation of ai-adrenoceptors play important roles in the regulation of uterine artery contractility. In addition, PKC mediates the pregnancyassociated decrease in myogenic tone of the uterine artery, and interacts with ajadrenoceptors leading to modulation of ai-adrenoceptor-mediated contractions of vascular smooth muscle. Yet, whether or to what extent PKC regulates ai-adrenoceptormediated contractions of the uterine artery and their …

Prenatal Cocaine Exposure And Cardiac Programming, Soochan Bae

Loma Linda University Electronic Theses, Dissertations & Projects

Human epidemiological studies have shown a clear association of adverse intrauterine environment and an increased risk of ischemia heart disease in later adult life. Cocaine abuse during pregnancy has been shown to cause abnormities in the heart during fetal and postnatal development, but mechanisms underlying the detrimental effects of cocaine on the developing heart are not fully understood. The central hypothesis is that cocaine exposure during fetal development may cause in utero programming of apoptotic pathways, which may has lasting and prolong effect on heart development postnatally.

In a pregnant rat model, chronic hypoxia increased apoptosis in the fetal heart …

Regulatory Mechanisms Of Uterine Artery Contractility : Effect Of Pregnancy, Daliao Xiao

Loma Linda University Electronic Theses, Dissertations & Projects

Regulation of uterine blood flow during pregnancy is important not only for the growth and survival of the fetus but also for cardiovascular well-being of the mother. Pregnancy is associated with a significant decrease in uterine artery vascular tone and a dramatic increase in uterine blood flow. Previous studies have been focused on adaptation of the endothelium to pregnancy and indicated that increased NO sythesis/release plays an important role in vasodilation of the uterine artery in pregnancy. However, little is known about the adaptation of contractile mechanisms of the uterine artery to pregnancy. The central hypothesis of the proposed studies …

Interaction Between Adrenergic And Nitric Oxide-Releasing Nerves In Cerebral Arteries, Emmanuel Ngu Mbaku

Loma Linda University Electronic Theses, Dissertations & Projects

Of all body tissues, the brain is the least tolerant of ischemia so much that interruption of cerebral blood flow by 5 sec can cause syncope, with irreversible tissue damage if the ischemia last a few minutes. In this respect, the body has an imperative duty of ensuring constant and adequate blood supply to the brain. It does so through a series of intrinsic and extrinsic control factors of which adrenergic and nitric oxide-releasing nerves are components. My research examined the interaction between these two nerve-types with emphasis on the mechanisms involved as well as on changes in their functions …

Modulatory Effects Of Citrus Flavonoids Towards The Metabolism And Mutagenicity Of Environmental Carcinogens, Wayne L. Bear

Loma Linda University Electronic Theses, Dissertations & Projects

The environmental carcinogens classified as heterocyclic amines (HCA’s) and the tobacco-specific nitrosamine NNK generally require internal enzymatic activation. This activation occurs via cytochrome P450 (CYP) enzymes and leads to metabolites that bind to human DNA which may in turn cause mutations which may then in turn lead to carcinogenesis. Certain nonnutritive plant compounds termed phytochemicals may protect against HCA and NNK-induced mutagenesis and carcinogenesis. We investigated the potential protective effects of five different phytochemicals of the flavonoid class which naturally occur in citrus. These flavonoids were diosmin, naringin. naringenin, rutin, and quercetin. Our results suggest that naringenin and quercetin were …

Age Related Changes In Contractile Sensitivity To Cyclic Gmp And Intracellular Calcium Compartmentalization In Ovine Arteries, Surya Margono Nauli

Loma Linda University Electronic Theses, Dissertations & Projects

The study examines the hypothesis that maturation changes the ability of cGMP to produce cerebral vasodilatation and alters the relative intracellular calcium pool sizes in ovine arteries. In ovine basilars taken from near-term fetal and young adult sheep, 8- pCPT-cGMP relaxed potassium- and serotonin-induced tone with pD2 values of 4.4±0.1 and 4.9±0.1 (fetal basilar) and 4.0±0.1 and 4.7±0.1 (adult basilar), respectively. In fura-2 loaded arteries, 8-pCPT-cGMP significantly lowered increases in cytosolic calcium concentration induced by serotonin but not potassium regardless of age. When calcium sensitivity was calculated in the same arteries as the slope of the relation between calcium concentration …

Towards Gene Therapy Of Parkinson’S Disease: Implantation Of Ruc-Gdnf Secreting Mammalian Cell Lines Into Rat Brain, Hua Liu

Loma Linda University Electronic Theses, Dissertations & Projects

The purpose of this study is to develop a new approach for monitoring the function of implanted cells by a Renilla luciferase -glial cell line derived neurotrophic factor (RUC-GDNF) fusion protein in CSF. The RUC-GDNF protein is expected to report GDNF secreted from the cell by bioluminescence through luciferase activity.

Current ex vivo gene therapy using GDNF is limited by lack of a monitoring mechanism to determine the expression of GDNF once transformed cells or vector DNA are injected into animal models. Since the therapeutic concentration of GDNF secreted into cerebrospinal fluid (CSF) by implanted cells is too low for …

Mechanisms Of Calcium Buffering And Aging In Neurons: Testing The Limits Of Homeostasis, William James Pottorf Ii

Loma Linda University Electronic Theses, Dissertations & Projects

Intracellular calcium ([Ca²⁺]i) is an ubiquitous second messenger that integrates multiple and diverse neuronal pathways that include development and maturation, gene expression, synaptic plasticity, transmitter release, excitability, and even cell death. Upon neuronal excitation the [Ca²⁺]i increases rapidly and the calcium buffering system reacts quickly to restore [Ca²⁺]i to basal levels in order to reset the cell for the next stimulus and avoid prolonged exposure to cytotoxic levels of high [Ca²⁺]i. The aging process appears to causes multiple changes in the ability of neurons to regulate [Ca²⁺]i homeostasis and an …

A Search For The Cause Of Excess Thiol Sensitivity In A Mutant Of Escherichia Coli, Hongying Zeng

Loma Linda University Electronic Theses, Dissertations & Projects

The subject of this study was a search for the biochemical basis of hypersensitivity to thiols in a mutant of Escherichia coli (IS16). A 1.3 kb chromosomal fragment from E. coli (introduced into the mutant on a plasmid) successfully abolished the hypersensitivity. This fragment contained only one intact gene, ubiX, which codes for polyprenyl-4-hydroxybenzoatelyase. The decarboxylation of octaprenyl-4- hydroxybenzoate in E. coli is catalyzed not only by the ubiX protein but also by the product of ubiD. The ubiquinone content of IS16 was only 2% of that of its parent strain, while the complementing plasmid increased it …

Maturational Changes In Cerebrovascular Ca2+ In Hypoxia, Shelley D. Zurcher

Loma Linda University Electronic Theses, Dissertations & Projects

The clinical consequences of hypoxic cerebrovascular insults in the neonate, can be severe. It would therefore be valuable to understand the mechanisms of hypoxia-induced cerebrovasodilation. These studies were done in ovine middle cerebral and common carotid arteries to help elucidate the mechanisms through which calcium handling is involved in hypoxic cerebral vasodilation, comparing newborns and adults. The present studies demonstrate that calcium sensitivity (measured by the pD2) and the maximum contractile response to calcium increased with maturation. In addition, hypoxia depressed the maximum response to calcium and this effect was greater in adult than in newborn arteries. These results suggest …

Cerebral Microcirculatory Effects Of Maturation, Scott R. Elliott

Loma Linda University Electronic Theses, Dissertations & Projects

The present studies demonstrate that in the second (2B) and fourth (4B) branches of newborn and adult sheep middle cerebral arteries, 5-HT2 serotonergic receptors mediate contractile responses to serotonin and that alpha-1 adrenergic receptors mediate contractile responses to norepinephrine. In addition, tissue sensitivity to 5-HT and NE decreases significantly with maturation, but does not vary with branch order. These age-related changes were associated with a decrease in affinity and maximum response in 2B and 4B segments of 5-HT and NE contracted arteries, respectively. Norepinephrine and 5-HT occupancy at the pD₂ rose significantly in 2B segments, but did not change …

Pharmacokinetics And Effects On Blood Chemistry Of Cyclosporine In Human Infants And Kid Goats, Floyd A. Beierle

Loma Linda University Electronic Theses, Dissertations & Projects

Kid goats (newborn) have been used in transplantation protocols to study the techniques and problems of infant human cardiac transplantation. Immunosuppression has been by cyclosporine in both species. However, the pharmacokinetics of cyclosporine (CSA) in both the kid goat and human infant were unknown. Therefore, the pharmacokinetics of CSA were investigated. A single dose study and a long term chronic administration study were undertaken in the goat. Six Nubian goats, ages 60-90 days, were given a single IV dose of CSA, 0.25 mg/kg, over a 10 minute period and 72 hr later an oral cyclosporine dose of 20 mg/kg. The …

Molecular Mechanisms Of Physalia Physalis Venom Modulation Of Cardiac And Vascular Functions, Eva Luo

Loma Linda University Electronic Theses, Dissertations & Projects

Portuguese man-of-war (Physalia physalis)venom has profound effects on the cardiovascular system of man and animals. The venom produces vascular relaxation in norepinephrine precontracted, intact rabbit femoral arterial rings by stimulating vasodilatory prostaglandin synthesis in the endothelium. This action does not depend on endotheliumderived relaxing factor (EDRF). P. physalis venom produces a vascular constriction on KC1 depolarized, intact rings. This is completely inhibited by dibenzyline and yohimbine. Increased membrane permeability to calcium may be involved in direct vascular smooth muscle stimulation. The venom has a positive inotropic effect on rat atrial preparations, which is intensified by increased extracellular calcium concentration. …

The Effect Of 48 Hr Glucose Administration On The Hepatic P-450 System, John N. Buchholz

Loma Linda University Electronic Theses, Dissertations & Projects

The administration of glucose for 48 hrs to mice resulted in a shift of the dose response curve of phenobarbital, an indication that glucose administration significantly sensitized the animals to the effects of the drug. Glucose administration produced a reduction in the catalytic activity of hepatic microscopical P-450 as measured by the in vitro conversion of p-Nitrocellulose to p-Nitrophenol.

The administration of glucose to rats for 48 hrs resulted in prolonged anesthesia after the administration of pentobarbital. The spectral binding of hexobarbital and methadone to hepatic microsomal P-450 was found to be significantly reduced following glucose administration. The changes in …

The Effects Of Maternal Administration Of Methadone On Beta-Endorphin Content In The Brain And Pituitary Of The Rat Progeny, Randall L. Braun

Loma Linda University Electronic Theses, Dissertations & Projects

Methadone is often used in the maintenance and detoxification of opioid-dependent pregnant women. This use of methadone during pregnancy is known to be associated with teratogenic effects observed in the progeny. The present study is an attempt to gain insight into possible pathophysiologic mechanism(s) responsible for these teratogenic effects: specifically, a relationship between maternal methadone administration and the content of the endogenous opioid peptide, beta-endorphin, in the brain and pituitary of the rat progeny.

In brief, nulliparous mature female Sprague-Dawley rats received daily injections (5 mg./kg.) of methadone hydrochloride (methadone-treated) or a similar volume of physiological saline (controls), treatment started …

Covalent Binding And Other Mechanisms Of Primaquine Toxicity, Lucille S. K. Chau Yau

Loma Linda University Electronic Theses, Dissertations & Projects

A dose-dependent covalent binding of primaquine to mouse liver microsomal protein was found in both in vitro and in vivo studies. The binding in vitro was linear during the first 90 minutes of incubation and dependent on the concentration of mouse liver microsomal protein. The in vitro covalent binding was markedly enhanced by cofactors. Pretreatment of mice with phenobarbital, a cytochrome P450 inducer, increased the microsomal cytochrome P450 content and the in vitro covalent binding significantly. Binding was markedly inhibited when microsomal metabolism inhibitors (SK&F-525A, metyrapone and piperonyl butoxide), and sulfhydryl-contai ni ng compounds were added to the incubation system. …

Application Of Knowledge Of Medications By Senior Students In A Selected School Of Nursing, Patricia H. Okimi

Loma Linda University Electronic Theses, Dissertations & Projects

The problem arose from the need to study the present method of pharmacology instruction in a selected school of nursing. "How much knowledge of medications do selected senior students have, and how do they apply their knowledge in the administration of medications?"

For this study, the normative survey approach was used as the method of research. Eleven senior students of nursing engaged in the administration of medications, as team leaders, were observed and questioned on two different occasions during one quarter of their school year. The tool of research used to collect data was an observation code sheet developed for …

Pharmacological Studies Of Antidiabetic Chinese Herbs, Mun Fa Lee

Loma Linda University Electronic Theses, Dissertations & Projects

Rehmannia glutinosa, Atractylus ovata, and Polygonatum chinense have all been employed by the Chinese as oral antidiabetic agents and reported by Min (1928), Kin (1931), and Li et al. (1936) to possess hypoglycemic activity. This prompted the pharmacological studies of these herbs.

Materials and methods. Their pharmacognosy was condensed from all available Chinese and scientific literature. Preliminary chemical and physical analyses included determinations for moisture, ash, crude fat, carbohydrates, protein, phosphorus, pH, alkaloids, melting point, and spectroscopy. Employing the Somogyi-Nelson method, their glycemic activity was studied in rats, rabbits, and dogs. Stress reactions were minimized. The effect …