L-serine, a non-essential amino acid, plays a role in the biosynthesis of the amino acids, proteins, purine and pyrimidine nucleotides. It is important for the proper functioning of the nervous system. It has been considered in the treatment of patients with schizophrenia, depression, chronic fatigue syndrome and psychomotor retardation, and of the seizures encountered in patients with rare inborn errors of L-serine biosynthesis. However, there are no reports in the literature of the direct cardiovascular effects of L-serine. Using normotensive Sprague-Dawley rats, Sprague-Dawley rats rendered hypertensive by chronic treatment with the nitric oxide (NO) synthase inhibitior NG nitro L-arginine methyl ester (L-NAME) and spontaneously hypertensive rats (SHR), the present study examined the in vitro and in vivo effects of L-serine. In vitro studies focused on L-serine induced changes in phenylephrine constricted third order branches of rat mesenteric arterioles while the in vivo studies examined the effects of intravenous infusion of L-serine on mean arterial pressure (MAP) and heart rate (HR) in intact anaesthetized rats. L-serine (10 to 200 µmol/L) evoked concentration-dependent vasodilatation in phenylephrine constricted endothelium-intact, but not in endothelium-denuded, rat mesenteric arterioles. The vasodilator responses to L-serine were absent in the combined presence of apamin, a calcium activated small conductance potassium (SKCa) channel inhibitor, and TRAM-34, a calcium activated intermediate conductance potassium (IKCa) channel inhibitor, or ouabain, a sodium pump inhibitor and barium (Ba2+), an inward rectifying potassium (Kir) channel inhibitor, or when the vessels were depolarized by potassium chloride. The maximal vasodilatation response (Emax) to L-serine was higher in vessels from L-NAME treated rats (40%) than from control rats (20%). In anesthetized rats, L-serine evoked a rapid, reversible, dose-dependent fall in MAP (without a significant change in HR), which was more pronounced in L-NAME treated rats (> 60 mmHg) than in normotensive control rats (25 mmHg). The fall in MAP was inhibited (p<0.01) by apamin plus charybdotoxin pretreatment. Charybdotoxin was used in place of Tram-34 in in vivo studies since Tram-34 is not soluble in water or saline. In age matched Sprague-Dawley, Wistar-Kyoto (WKY) and SHR strains, D-serine had the same effects on MAP and HR as L-serine; however, L-serine evoked a greater maximal fall in MAP in all strains, and the effect was more pronounced in hypertensive rats. In contrast, the infusion of glycine, a metabolite of L-serine led to a dose-dependent fall in MAP in normotensive rats but a dose-dependent increase in MAP in both SHR and L-NAME treated hypertensive WKY rats. Both the depressor and pressor responses to glycine were abolished by pretreatment with the N-methyl D-aspartate receptor antagonist, MK-801. Regional hemodynamic studies performed using the fluorescent tagged microsphere distribution technique revealed that the fall in MAP and profound decrease in total peripheral resistance (TPR) evoked by acute L-serine infusion is due to increased blood flow in the splanchnic region and more particularly in the small intestinal vascular beds. This effect is blocked by the combined treatment with the KCa channel inhibitors, apamin plus charybdotoxin. Although resting MAP and TPR are higher, and cardiac output (CO) is lower both in SHR and in WKY rats rendered hypertensive by L-NAME treatment compared to normotensive WKY rats, L-serine infusion leads to a rapid fall in TPR and MAP, and an increase in CO in all models. This effect was more profound in the hypertensive rats. These findings suggest that L-serine could be helpful in overcoming splanchnic organ failure observed in patients with cardiopulmonary bypass. In addition, L-serine, either alone or in combination with other antihypertensive medications, could be considered in the management of endothelial dysfunctional states with reduced NO bioavailability such as hypertension and diabetes.

Hypertension occurs in nearly 10% of pregnancies, and is associated with infant and maternal morbidity and mortality. Prior studies of non-pregnant adults have demonstrated the effectiveness of a variety of relaxation therapies in reducing blood pressure. A pilot randomized controlled trial was conducted, the purposes of which were 1) to provide preliminary evidence regarding the usefulness of guided imagery (GI) in reducing blood pressure in hypertensive pregnant women, and 2) to answer feasibility questions for a larger trial. Pregnant women with hypertension prior to 37 weeks gestation (n = 69) were randomized to either 15-minute periods of guided imagery (n = 34), or of quiet rest (QR) (n = 35), twice daily for four weeks or until delivery, whichever came first. Daytime ambulatory mean arterial pressure (MAP), systolic and diastolic blood pressures, anxiety, rest and GI use were measured weekly, to a maximum of four weeks. Sixty women completed at least one week in the study; 46.4% completed four weeks. Compliance was excellent. Intention to treat analysis was used. In the unadjusted analysis, women allocated to GI had significantly lower average daytime ambulatory mean MAP elevations from baseline to their last week of study participation than women allocated to quiet rest (GI: M = 1.58 mmHg, SD = 7.63; QR: M = 5.93 mmHg, SD = 6.55; t = 2.36, p = .02). However, the effect was no longer statistically significant (p = 0.14) when adjusted for baseline mean arterial pressure and gestation. There was no statistically significant difference in the numbers of women who were prescribed antihypertensive medication after randomization (GI: n = 16, QR: n = 13, X2 = 0.74, p = .46). There was also no evidence of an effect of guided imagery on anxiety. Nearly 90% (n = 26) of the guided imagery group indicated they would use it again, either in a subsequent pregnancy or during stressful life events. Given the ease of use, low cost, acceptability to women, and lack of risk of guided imagery, an adequately-powered randomized controlled trial is warranted.

The hypothesis that source of protein in a nutritionally adequate diet during gestation, lactation and weaning alters food intake and characteristics of metabolic syndrome in the offspring was investigated. Pregnant Wistar rats were randomized to either the AIN 93-G casein (C) or soy protein (S) diets (n=12/group) during gestation only or during gestation and lactation. Male offspring in each dams’ diet group were weaned to either C or S diets (n=12/group). Food intake, body weight (BW), fat pad mass, systolic (SBP) and diastolic (DBP) blood pressure, and plasma homocysteine (p<0.05) were higher in offspring born to dams fed the S diet. Fasting blood glucose (BG), BG in response to a glucose gavage and Homeostatic Model of Assessment of Insulin Resistance (HOMA-IR) index were higher only in male offspring born to dams fed the S diet. Moreover, gene expression of Agouti Related Protein (AgRP) was higher in offspring born to dams fed the S diet at weaning. Extending the dams’ diet during gestation and lactation magnified the effect of the gestational S diet on BW and composition and glucose metabolism in male offspring. Although composition of the weaning diets interacted with that of the dams’ diets, the latter was the dominant factor in determining metabolic outcomes in the offspring. In conclusion, the soy protein diet, compared to the casein diet when consumed during gestation or throughout gestation and lactation increased food intake and the presence of characteristics of metabolic syndrome in the offspring.

The prevalence of hypertension (HTN) is high in Latinos (Latino/Latina) Americans due to social and ecological factors. Increased migration of Latino migrant/seasonal farmworkers (MSFW) to the U.S. augments the social, economic, environmental, and psychosocial factors associated with health and illness. Bronfenbrenner’s Ecological Systems Theory was used to guide this study. The purposes of this cross-sectional, correlational study were to explore Latino MSFWs’ adherence to HTN treatment (medication adherence, blood pressure [BP] self-care, and BP control) and to examine the influence of BP knowledge, perceived stress, acculturation, health literacy, and health care access (HCA) on adherence to HTN treatment. A total of 45 Latino (mean age 45 + 9) MSFWs receiving HTN treatment participated in this study. Spanish and English questionnaires were available for participants to measure adherence to HTN treatment and the five independent variables. Analysis included correlations, t-tests, hierarchical multiple regression, and hierarchical logistic regression. The majority of MSFWs were from Mexico, female (55.6%), had less than a 6th grade education. Most (82%) of the MSFWs had uncontrolled BP, and were not adherent to medications (42%), even with high BP knowledge scores (M = 6.5 ±1.3). MSFWs perceived a high level of stress (M = 16 + 6.9), low acculturation level (Anglo orientation: M = 2.9 + 0.9), and no employer-provided health insurance for personal illnesses or injuries (93%). Blood pressure knowledge, perceived stress, acculturation, health literacy, and HCA accounted for 49% of the variance in the BP self-care; however, only higher BP knowledge was a significant predictor of better BP self-care (p < .001). Furthermore, acculturation was a significant predictor of BP control (p < .01). This study explored select determinants of adherence to HTN treatment in Latino MSFWs in a culturally informed way. Although BP self-care behaviors appeared to be a consequence of BP knowledge, this study found low medication adherence in Latino MSFWs and uncontrolled BP explained by the two predictors, acculturation and health literacy. Perceived stress and health care access did not influence the adherence to HTN treatment. MSFWs had poor BP control and HTN treatment adherence. A culturally appropriate educational program is needed to help the MSFWs adherence to HTN treatment.

L-serine, a non-essential amino acid, plays a role in the biosynthesis of the amino acids, proteins, purine and pyrimidine nucleotides. It is important for the proper functioning of the nervous system. It has been considered in the treatment of patients with schizophrenia, depression, chronic fatigue syndrome and psychomotor retardation, and of the seizures encountered in patients with rare inborn errors of L-serine biosynthesis. However, there are no reports in the literature of the direct cardiovascular effects of L-serine. Using normotensive Sprague-Dawley rats, Sprague-Dawley rats rendered hypertensive by chronic treatment with the nitric oxide (NO) synthase inhibitior NG nitro L-arginine methyl ester (L-NAME) and spontaneously hypertensive rats (SHR), the present study examined the in vitro and in vivo effects of L-serine. In vitro studies focused on L-serine induced changes in phenylephrine constricted third order branches of rat mesenteric arterioles while the in vivo studies examined the effects of intravenous infusion of L-serine on mean arterial pressure (MAP) and heart rate (HR) in intact anaesthetized rats. L-serine (10 to 200 µmol/L) evoked concentration-dependent vasodilatation in phenylephrine constricted endothelium-intact, but not in endothelium-denuded, rat mesenteric arterioles. The vasodilator responses to L-serine were absent in the combined presence of apamin, a calcium activated small conductance potassium (SKCa) channel inhibitor, and TRAM-34, a calcium activated intermediate conductance potassium (IKCa) channel inhibitor, or ouabain, a sodium pump inhibitor and barium (Ba2+), an inward rectifying potassium (Kir) channel inhibitor, or when the vessels were depolarized by potassium chloride. The maximal vasodilatation response (Emax) to L-serine was higher in vessels from L-NAME treated rats (40%) than from control rats (20%). In anesthetized rats, L-serine evoked a rapid, reversible, dose-dependent fall in MAP (without a significant change in HR), which was more pronounced in L-NAME treated rats (> 60 mmHg) than in normotensive control rats (25 mmHg). The fall in MAP was inhibited (p<0.01) by apamin plus charybdotoxin pretreatment. Charybdotoxin was used in place of Tram-34 in in vivo studies since Tram-34 is not soluble in water or saline. In age matched Sprague-Dawley, Wistar-Kyoto (WKY) and SHR strains, D-serine had the same effects on MAP and HR as L-serine; however, L-serine evoked a greater maximal fall in MAP in all strains, and the effect was more pronounced in hypertensive rats. In contrast, the infusion of glycine, a metabolite of L-serine led to a dose-dependent fall in MAP in normotensive rats but a dose-dependent increase in MAP in both SHR and L-NAME treated hypertensive WKY rats. Both the depressor and pressor responses to glycine were abolished by pretreatment with the N-methyl D-aspartate receptor antagonist, MK-801. Regional hemodynamic studies performed using the fluorescent tagged microsphere distribution technique revealed that the fall in MAP and profound decrease in total peripheral resistance (TPR) evoked by acute L-serine infusion is due to increased blood flow in the splanchnic region and more particularly in the small intestinal vascular beds. This effect is blocked by the combined treatment with the KCa channel inhibitors, apamin plus charybdotoxin. Although resting MAP and TPR are higher, and cardiac output (CO) is lower both in SHR and in WKY rats rendered hypertensive by L-NAME treatment compared to normotensive WKY rats, L-serine infusion leads to a rapid fall in TPR and MAP, and an increase in CO in all models. This effect was more profound in the hypertensive rats. These findings suggest that L-serine could be helpful in overcoming splanchnic organ failure observed in patients with cardiopulmonary bypass. In addition, L-serine, either alone or in combination with other antihypertensive medications, could be considered in the management of endothelial dysfunctional states with reduced NO bioavailability such as hypertension and diabetes.

Smoking and environmental tobacco smoke (ETS) exposure are major risk factors for cardiovascular disease (CVD), although the exact components and pathophysiological mechanisms responsible for this association remain unclear. Polycyclic aromatic hydrocarbons (PAHs), including benzo[a]pyrene (BaP), are ubiquitous environmental contaminants that form during organic material combustion and are thus found in cigarette smoke, vehicle exhaust particles, and air pollution. We hypothesize that PAHs are key agents responsible for mediating the cigarette smoke effects in the cardiovascular system, including increased oxidative stress, inflammation, and arterial stiffness.<p> Arterial stiffness is a powerful, independent predictor of cardiovascular risk and is regulated, in part, by vasoactive mediators derived from the endothelium. The first objective of this project was to determine whether pulse wave dP/dt collected from radiotelemetry-implanted rats is a reliable indicator of changes in arterial stiffness following administration of vasoactive drugs or acute ETS exposure. Anaesthetized rats were administered a single dose of saline (vehicle control), acetylcholine, norepinephrine, and N(G)-nitro-L-arginine methyl ester (L-NAME) via the tail vein, allowing a washout period between injections. Acetylcholine decreased and norepinephrine increased dP/dt compared to saline vehicle. Injection of the nitric oxide (NO) synthase inhibitor L-NAME decreased plasma nitrate/nitrite (NOx), but transiently increased dP/dt. For the ETS experiment, rats were exposed for one hour to sham, low dose ETS, or high dose ETS. Exposure to ETS did not significantly alter dP/dt or plasma endothelin-1 (ET-1) levels, but increased plasma NOx levels at the high ETS exposure and increased plasma nitrotyrosine levels in both ETS groups. In conclusion, acute changes in NO production via acetylcholine or L-NAME alter the arterial pulse wave dP/dt consistently with the predicted changes in arterial stiffness. Although acute ETS appears to biologically inactivate NO, a concomitant increase in NO production at the high ETS exposure may explain why ETS did not acutely alter dP/dt.<p> The second objective of this project was to compare the effects of subchronic ETS and BaP exposure on circadian blood pressure patterns, arterial stiffness, and possible sources of oxidative stress in radiotelemetry-implanted rats. Pulse wave dP/dt was used as an indicator of arterial stiffness, and was compared to both structural (wall thickness) and functional (NO production and bioactivity, ET-1 levels) features of the arterial wall. In addition, histology of lung, heart, and liver were examined as well as pulmonary and hepatic detoxifying enzyme activity (cytochrome P450 specifically CYP1A1). Daily ETS exposure for 28 days altered the circadian pattern of heart rate and blood pressure in rats, with a loss in the normal dipping pattern of blood pressure during sleep. Subchronic ETS exposure also increased dP/dt in the absence of any structural modifications in the arterial wall. Although NO production and ET-1 levels were not altered by ETS, there was increased biological inactivation of NO via peroxynitrite production (as indicated by increased plasma nitrotyrosine levels). Thus, vascular stiffness and failure of blood pressure to dip precede structural changes in rats exposed to ETS for 28 days. Exposure to ETS also caused increased number of lung neutrophils as well as increased CYP1A1 activity in lung microsomes.<p> Since ETS-induced increases in arterial stiffness occurred as early as day 7, radiotelemetry-implanted rats were exposed daily to intranasal BaP for 7 days. Similar to ETS, BaP exposure altered circadian blood pressure patterns and reduced blood pressure dipping during sleep. Thus, in support of part of our hypothesis, the PAH component of cigarette smoke may be responsible for the ETS-induced increase in blood pressure and the loss of dipping pattern during sleep. Increased neutrophil recruitment was observed in the lungs of both ETS- and BaP-exposed rats, suggesting that lung inflammatory reactions may be involved in the disruption of circadian blood pressure rhythms. Unlike ETS however, BaP exposure did not significantly alter pulse wave dP/dt, endothelial function, or lung CYP1A1 activity. Thus, contrary to our hypothesis, the reduction in NO bioactivity and increased arterial stiffness caused by ETS cannot be explained by BaP at the dose and length of the exposure in the current study. Production of reactive metabolites in the lung following ETS exposure may be responsible, at least in part, for the increases in oxidative stress in the vasculature, leading to reduced NO bioactivity and increased arterial stiffness. Oxidative stress caused by BaP exposure may have been insufficient to reduce NO bioactivity in the peripheral vasculature. Therefore arterial stiffness was not increased and factors other than NO may be responsible for the increase in blood pressure observed with ETS and BaP exposure.

Thesis (M.S.)--James Madison University, 2009. / Includes bibliographical references.

Thesis (Ph. D.)--University of Texas at Austin, 2003. / Supervisor: Shirley C. Laffrey. Vita. Includes bibliographical references. Also available from UMI.

Perseverative cognition is the repetitive cognitive representation of a stressor, which includes the concepts of worry and rumination. These thoughts delay post-stress cardiovascular recovery, which may lead to an increased risk for cardiovascular disease. This may be due to the negative emotional content of perseverative cognition or because it involves cognitive effort. The aim of this study was to identify the unique influences of negative emotional content and cognitive effort during recovery. Participants (N = 120) were given a demanding task purportedly as a measure of intelligence and then given false negative feedback. Immediately following, participants engaged in one of four recovery instruction conditions: think about task performance, perform a cognitive load task, watch a distracting video, or remain quietly seated. EKG, impedance cardiography, and blood pressure were recorded throughout. Perseverative cognition and cognitive load both resulted in significantly less heart rate recovery compared to the distracting video. Higher test motivation and anxiety were related to more blunted reactivity and delayed recovery of respiratory sinus arrhythmia. Reduced recovery during perseverative cognition and cognitive effort indicate that the cognitive load produced by perseveration is the pernicious component that explains its link to increased risk for cardiovascular disease. Further, the relationship between motivation/anxiety and blunted reactivity and recovery suggest effort may be important in the link between perseverative cognition and cardiovascular disease.

Background: According to the World Health Organization (WHO), hypertension is a major risk factor for cardiovascular disease (CVD), renal impairment, peripheral vascular disease, and blindness. In Panama, a recent study estimated the prevalence of hypertension at 38.5% in the two main provinces of the country, with a rate of uncontrolled hypertension of 47.2%. Objectives: The aims of this study were to assess the feasibility of the study design and to describe the characteristics of the hypertensive population and the physician's adherence to Panamanian antihypertensive protocols and their relationship with uncontrolled hypertension. Methods: This is a cross-sectional study of adult hypertensive patients attending a primary healthcare facility in Panama City. Clinical charts from eligible participants were examined to describe the demographic and clinical characteristics related to uncontrolled hypertension and the use of antihypertensive protocols by medical doctors. Descriptive and central tendency statistics were used to characterize the study population. Bivariate relationships between demographic and clinical characteristics, and uncontrolled hypertension were explored using specific test for no association. Logistic regression modeling was used to examine the association between physician's adherence to antihypertensive protocols and the presence of uncontrolled hypertension. Results: In this study the mean age was 56.7 years (±13.6); 58.1% of participants were females; 71.3% of participants had body mass index >25.0kg/m2; and 53.0% of participants had stage 2 hypertension. Uncontrolled hypertension was present in 66.7% of the study sample. 82.9% of participants had one or more comorbidities. The medical doctors were compliant with antihypertensive protocols in 43.6% of participants, primarily due to lower compliance with lifestyle modification recommendations. In the multivariate analysis, a significant interaction was found with age, suggesting that age is a potential effect modifier. Conclusions: The rate of uncontrolled hypertension was high among this study population. Nearly half of the attending physicians did not follow the recommendations given by current antihypertensive protocols. Further research is necessary to explore the relationships between subject characteristics, such as age, number of comorbidities, and the presence of diabetes mellitus with uncontrolled hypertension