Cholesterol-Induced Suppression of Endothelial Kir Channels Is a Driver of Impairment of Arteriolar Flow-Induced Vasodilation in Humans

Hypertension ◽  
2021 ◽  
Author(s):  
Sang Joon Ahn ◽  
Ibra S. Fancher ◽  
Sara T. Granados ◽  
Natalia F. Do Couto ◽  
Chueh-Lung Hwang ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Significant Negative Correlation ◽  
Dominant Negative ◽  
Mesenteric Arteries ◽  
Resistance Arteries ◽  
Knock Out ◽  
Major Mechanism

Dyslipidemia-induced endothelial dysfunction is an important factor in the progression of cardiovascular disease; however, the underlying mechanisms are unclear. Our recent studies demonstrated that flow-induced vasodilation (FIV) is regulated by inwardly rectifying K + channels (Kir2.1) in resistance arteries. Furthermore, we showed that hypercholesterolemia inhibits Kir2.1-dependent vasodilation. In this study, we introduced 2 new mouse models: (1) endothelial-specific deletion of Kir2.1 to demonstrate the role of endothelial Kir2.1 in FIV and (2) cholesterol-insensitive Kir2.1 mutant to determine the Kir2.1 regulation in FIV under hypercholesterolemia. FIV was significantly reduced in endothelial-specific Kir2.1 knock-out mouse mesenteric arteries compared with control groups. In cholesterol-insensitive Kir2.1 mutant mice, Kir2.1 currents were not affected by cyclodextrin and FIV was restored in cells and arteries, respectively, with a hypercholesterolemic background. To extend our observations to humans, 16 healthy subjects were recruited with LDL (low-density lipoprotein)-cholesterol ranging from 51 to 153 mg/dL and FIV was assessed in resistance arteries isolated from gluteal adipose. Resistance arteries from participants with >100 mg/dL LDL (high-LDL) exhibited reduced FIV as compared with those participants with <100 mg/dL LDL (low-LDL). A significant negative correlation was observed between LDL cholesterol and FIV in high-LDL. Expressing dominant-negative Kir2.1 in endothelium blunted FIV in arteries from low-LDL but had no further effect on FIV in arteries from high-LDL. The Kir2.1-dependent vasodilation more negatively correlated to LDL cholesterol in high-LDL. Overexpressing wild-type Kir2.1 in endothelium fully recovered FIV in arteries from participants with high-LDL. Our data suggest that cholesterol-induced suppression of Kir2.1 is a major mechanism underlying endothelial dysfunction in hypercholesterolemia.

scholarly journals Impairment of Flow-Sensitive Inwardly Rectifying K + Channels via Disruption of Glycocalyx Mediates Obesity-Induced Endothelial Dysfunction

2020 ◽  
Vol 40 (9) ◽  
Author(s):  
Ibra S. Fancher ◽  
Elizabeth Le Master ◽  
Sang Joon Ahn ◽  
Crystal Adamos ◽  
James C. Lee ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Dominant Negative ◽  
Mesenteric Arteries ◽  
Endothelial Glycocalyx ◽  
Obese Mice ◽  
Resistance Arteries ◽  
Flow Sensitivity ◽  
Flow Activation ◽  
Heparan Sulfates ◽  
Inwardly Rectifying

Objective: To determine if endothelial dysfunction in a mouse model of diet-induced obesity and in obese humans is mediated by the suppression of endothelial Kir (inwardly rectifying K + ) channels. Approach and Results: Endothelial dysfunction, observed as reduced dilations to flow, occurred after feeding mice a high-fat, Western diet for 8 weeks. The functional downregulation of endothelial Kir2.1 using dominant-negative Kir2.1 construct resulted in substantial reductions in the response to flow in mesenteric arteries of lean mice, whereas no effect was observed in arteries of obese mice. Overexpressing wild-type–Kir2.1 in endothelium of arteries from obese mice resulted in full recovery of the flow response. Exposing freshly isolated endothelial cells to fluid shear during patch-clamp electrophysiology revealed that the flow-sensitivity of Kir was virtually abolished in cells from obese mice. Atomic force microscopy revealed that the endothelial glycocalyx was stiffer and the thickness of the glycocalyx layer reduced in arteries from obese mice. We also identified that the length of the glycocalyx is critical to the flow-activation of Kir. Overexpressing Kir2.1 in endothelium of arteries from obese mice restored flow- and heparanase-sensitivity, indicating an important role for heparan sulfates in the flow-activation of Kir. Furthermore, the Kir2.1-dependent component of flow-induced vasodilation was lost in the endothelium of resistance arteries of obese humans obtained from biopsies collected during bariatric surgery. Conclusions: We conclude that obesity-induced impairment of flow-induced vasodilation is attributed to the loss of flow-sensitivity of endothelial Kir channels and propose that the latter is mediated by the biophysical alterations of the glycocalyx.

scholarly journals Plasma levels of leptin and ghrelin and their correlation with BMI, and circulating lipids and glucose in obese Tunisian women

2017 ◽  
Vol 9 (2) ◽  
pp. 161-168 ◽  
Author(s):  
Fethi Ben Slama ◽  
Nahawand Jridi ◽  
Mohamed Chiheb Ben Rayana ◽  
Abdelmagid Trimeche ◽  
Mohamed Hsairi ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Significant Negative Correlation ◽  
Obese Women ◽  
Glucose And Lipid Metabolism ◽  
Normal Women ◽  
Circulating Levels

AbstractBackgroundA National Survey on the Effect of Nutrition conducted in 1996−1997 showed a 14% overall prevalence of obesity in Tunisia with a female predominance. Leptin and ghrelin play crucial roles in regulating body weight and energy balance. Leptin, an anorectic hormone, and ghrelin, an orexigenic hormone, appear to interact with glucose and lipid metabolism.ObjectivesTo determine the circulating levels of ghrelin and leptin in obese Tunisian women and to investigate the correlations of these hormones with body mass index (BMI), and circulating lipids and glucose.MethodsForty obese women were recruited from patients in the “C” Unit of the National Institute of Nutrition and Food Technology. Twenty normal women were recruited as controls. Plasma levels of the studied variables were measured in patients from both groups and findings were analyzed.ResultsCirculating levels of leptin were significantly higher, while high-density lipoprotein (HDL)-cholesterol and ghrelin levels were significantly lower in the obese women. In the obese women, significant positive correlations were found between circulating levels of leptin and low-density lipoprotein (LDL)-cholesterol, BMI, and glucose; and ghrelin and HDL-cholesterol. Significant negative correlations were found between circulating levels of leptin and HDL-cholesterol and ghrelin; and ghrelin and leptin, LDL-cholesterol, BMI, and glucose. Multivariate analysis revealed that ghrelin was significantly associated with HDL-cholesterol, LDL-cholesterol, and blood glucose.ConclusionsThe significant negative correlation between leptin and ghrelin suggests that these two hormones may be antagonistic. Increased levels of ghrelin are correlated with decreased circulating levels of HDL-cholesterol and increased levels of LDL-cholesterol.

Moving beyond the “LDL hypothesis”

VASA ◽  
2015 ◽  
Vol 44 (5) ◽  
pp. 333-340 ◽  
Author(s):  
Christian Werner ◽  
Ulrich Laufs
Keyword(s):  
Ldl Cholesterol ◽  
Causal Relation ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Clinical Trial Data ◽  
Randomised Clinical Trial ◽  
Trial Data ◽  
Low Density Lipoprotein Cholesterol ◽  
Genetic Studies ◽  
Statin Drug

Abstract. Summary: The term “LDL hypothesis” is frequently used to describe the association of low-density lipoprotein cholesterol (LDL-cholesterol, LDL-C) and cardiovascular (CV) events. Recent data from genetic studies prove a causal relation between serum LDL-C and CV events. These data are in agreement with mechanistic molecular studies and epidemiology. New randomised clinical trial data show that LDL-C lowering with statins and a non-statin drug, ezetimibe, reduces CV events. We therefore believe that the “LDL-hypothesis” has been proven; the term appears to be outdated and should be replaced by “LDL causality”.

Platelet Aggregation and Plasma Lipoproteins in Alcoholics During Alcohol Withdrawal

1986 ◽  
Vol 55 (02) ◽  
pp. 173-177 ◽  
Author(s):  
K Desai ◽  
J S Owen ◽  
D T Wilson ◽  
R A Hutton
Keyword(s):  
Platelet Aggregation ◽  
Alcohol Withdrawal ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Plasma Lipoprotein ◽  
Cholesterol Concentration ◽  
Arachidonic Acid Content ◽  
Low Density

SummaryPlatelet aggregation, platelet lipid composition and plasma lipoprotein concentrations were measured each week in a group of seventeen alcoholics, without overt liver disease, for one month, following acute, total alcohol withdrawal. The platelets were initially hypoaggregable but, within 1-2 weeks of cessation of drinking, they became hyperaggregable and then gradually returned towards normal values. Hyperaggregability could not be explained by increases in either the cholesterol or the arachidonic acid content of the platelets. Plasma very-low-density lipoprotein cholesterol levels remained high throughout the study, but the initially raised levels of high-density lipoprotein (HDL) cholesterol fell by 26%. Low-density lipoprotein (LDL) cholesterol concentration rose by 10% after two weeks of withdrawal but then returned to about the starting level. The resulting changes in the plasma LDL-cholesterol: HDL-cholesterol ratio, which had increased by more than 50% after two weeks of abstinence, essentially paralleled the time course of enhanced platelet reactivity in all but four of the alcoholics. These findings suggest that alterations in plasma lipoprotein concentrations during acute alcohol withdrawal may be a contributory factor to the haemostatic disorders present in such patients.

Risk factors for cardiovascular diseases and development of prehypertension

2018 ◽  
pp. 37-43
Author(s):  
В.В. Шерстнев ◽  
М.А. Грудень ◽  
В.П. Карлина ◽  
В.М. Рыжов ◽  
А.В. Кузнецова ◽  
...  
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
Cardiovascular Disease ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Serum Levels ◽  
Left Ventricular ◽  
Optimal Blood Pressure

Цель - исследование взаимосвязи факторов риска сердечно-сосудистых заболеваний и развития предгипертонии. Методика. Проведен сравнительный и корреляционный анализы показателей модифицируемых и немодифицируемых факторов риска сердечно-сосудистых заболеваний у обследованных лиц в возрасте 30-60 лет с «оптимальным» артериальным давлением, (n = 63, АД <120/80 мм рт.ст.) и лиц с предгипертонией (n = 52, АД = 120-139/80-89 мм рт.ст.). Результаты. Показано, что лица с предгипертонией по сравнению с группой лиц, имеющих «оптимальное» артериальное давление характеризуются статистически значимо повышенным содержанием холестерина и холестерина липопротеидов низкой плотности, интеллектуальным характером трудовой деятельности, а также значимыми сочетаниями факторов риска: повышенный уровень холестерина липопротеидов низкой плотности с интеллектуальным характером трудовой деятельности; повышенное содержание креатинина с уровнем триглициридов; наследственная отягощенность по заболеваниям почек и интеллектуальным характером трудовой деятельности; наследственная отягощенность по сахарному диабету и гипертрофия левого желудочка сердца. У лиц с предгипертонией документированы перестройки структуры взаимосвязи (количество, направленность и сила корреляций) между показателями факторов риска в сравнении с лицами, имеющими «оптимальное» артериальное давление. Заключение. Выявленные особенности взаимосвязей факторов риска сердечно-сосудистых заболеваний при предгипертонии рассматриваются как проявление начальной стадии дизрегуляционной патологии и нарушения регуляции физиологических систем поддержания оптимального уровня артериального давления. The aim of the study was to investigate the relationship between risk factors for cardiovascular disease and development of prehypertension. Methods. Comparative and correlation analyses of modifiable and non-modifiable risk factors for cardiovascular disease were performed in subjects aged 30-60 with «optimal» blood pressure (n = 63, BP <120/80 mm Hg) and prehypertension (n = 52, BP = 120-139 / 80-89 mm Hg). Results. The group with prehypertension compared with the «optimal» blood pressure group had significantly increased serum levels of low-density lipoprotein (LDL) cholesterol and high-density lipoprotein (HDL) cholesterol, sedentary/intellectual type of occupation, and significant combinations of risk factors. The risk factor combinations included an increased level of LDL cholesterol and a sedentary/intellectual occupation; increased serum levels of creatinine and triglycerides; hereditary burden of kidney disease and a sedentary/intellectual occupation; hereditary burden of diabetes mellitus and cardiac left ventricular hypotrophy. In subjects with prehypertension compared to subjects with «optimal» blood pressure, changes in correlations (correlation number, direction, and strength) between parameters of risk factors were documented. Conclusion. The features of interrelationships between risk factors for cardiovascular disease observed in prehypertension are considered a manifestation of early dysregulation pathology and disordered regulation of physiological systems, which maintain optimal blood pressure.

scholarly journals Effects of Weight Gain after 20 Years of Age and Incidence of Hyper-Low-Density Lipoprotein Cholesterolemia: The Iki Epidemiological Study of Atherosclerosis and Chronic Kidney Disease (ISSA-CKD)

2021 ◽  
Vol 10 (14) ◽  
pp. 3098
Author(s):  
Shota Okutsu ◽  
Yoshifumi Kato ◽  
Shunsuke Funakoshi ◽  
Toshiki Maeda ◽  
Chikara Yoshimura ◽  
...  
Keyword(s):  
Weight Gain ◽  
General Population ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Population Based ◽  
Lipid Lowering ◽  
Low Density ◽  
Obesity Hypertension ◽  
Old Men

The aim of this study was to investigate the effects of long-term weight gain from the age of 20 on incidence of hyper-low-density-lipoprotein (LDL) cholesterolemia in the general population of Japanese people. Methods: We conducted a population-based retrospective cohort study using annual health checkup data for residents of Iki City, Nagasaki Prefecture, Japan. A total of 3179 adult (≥30 years old) men and women without hyper-LDL cholesterolemia at baseline, who underwent two or more health checkups were included in the analysis. Information on weight gain (≥10 kg) after 20 years of age was obtained using questionnaire. The outcome of this study was development of hyper-LDL cholesterolemia defined as LDL-cholesterol level ≥3.62 mmol/L and/or initiation of lipid-lowering medications. Results: During a mean follow-up period of 4.53 years, 665 of the 3179 participants developed hyper-LDL cholesterolemia (46.5/1000 person-years). The incidence of hyper-LDL cholesterolemia was higher in participants with a weight gain of ≥10 kg (55.3/1000 person-years) than among those with a weight gain of <10 kg (41.8/1000 person-years). This association remained statistically significant even after adjustment for age, sex, smoking, daily drinking, exercise, obesity, hypertension, and diabetes (multivariable hazard ratio 1.31, 95% confidence interval 1.08–1.58, p = 0.006). Conclusion: A weight gain of ≥10 after 20 years of age affected the development of hyper-LDL cholesterol regardless of age, sex, and obesity in a general population of Japanese.

scholarly journals Particles and corrected particles of LDL and non-HDL are stronger predicters of coronary lesion in postmenopausal women

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Chuang Li ◽  
Jingxun Chen ◽  
Siyue Wei ◽  
Mei Zhang ◽  
Yushun Chu ◽  
...  
Keyword(s):  
Risk Factors ◽  
Postmenopausal Women ◽  
Apolipoprotein B ◽  
Operating Characteristic ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Spearman Correlation ◽  
Coronary Lesion

Abstract Background The optimum lipid indexes, predicting the coronary lesion in postmenopausal women are not clear. Objective To evaluate the optimum lipid predicter for coronary lesion in routine and advanced lipid tests. Method 300 postmenopausal women were enrolled and assigned into coronary heart disease (CHD) Group (242), and non-CHD Group (58). Routine and advanced lipid indexes were measured with standard laboratory test and nuclear magnetic resonance (NMR) spectroscopy. The correlation and predictivities for CHD of routine and advanced lipid indexes were performed with Logistic regression, Spearman correlation analysis and receiver operating characteristic (ROC). Results Age (hazard ratio (HR) 2.58, 95% confidence interval (CI) 1.08–5.86, P = 0.03), apolipoprotein B (ApoB) (HR 1.35, 95% CI 1.15–1.59, P < 0.001), corrected particles of low-density lipoprotein (LDL-p-corr) (HR 1.05, 95% CI 1.03–1.06, P < 0.001) and corrected particles of non-high-density lipoprotein (non-HDL-p-corr) (HR 1.02, 95% CI 1.01–1.03, P < 0.001) were the risk factors of CHD. LDL cholesterol (LDL-C), LDL-p, LDL-p-corr, HDL cholesterol (HDL-C), non-HDL cholesterol (non-HDL-C), non-HDL-p and non-HDL-p-corr were in linear correlation with Gensini score. Advanced lipid indexes LDL-p (area under curve (AUC) = 0.750, P = 0.02), LDL-p-corr (AUC = 0.759, P = 0.02), non-HDL-p (AUC = 0.693, P = 0.03) and non-HDL-p-corr (AUC = 0.699, P = 0.03) were more predictive for CHD than the routine ones (LDL-C and non-HDL-C). Conclusion In postmenopausal women, age, ApoB, LDL-p-corr and non-HDL-p-corr were risk factors of CHD. Compared with traditional lipid items, LDL-p, LDL-p-corr, non-HDL-p and non-HDL-p-corr may be better lipid indexes for CHD in postmenopausal women.

scholarly journals Efficacy of Bilberry and Grape Seed Extract Supplement Interventions to Improve Glucose and Cholesterol Metabolism and Blood Pressure in Different Populations—A Systematic Review of the Literature

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1692
Author(s):  
Teresa Grohmann ◽  
Caroline Litts ◽  
Graham Horgan ◽  
Xuguang Zhang ◽  
Nigel Hoggard ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Metabolic Syndrome ◽  
Ldl Cholesterol ◽  
Cholesterol Metabolism ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Grape Seed Extract ◽  
Grape Seed ◽  
Good Evidence ◽  
Seed Extract

Intervention with fruit extracts may lower glucose and lipid levels, as well as blood pressure. We reviewed the efficacy of bilberry and grape seed extracts to affect these outcomes across populations with varying health status, age and ethnicity, across intervention doses and durations, in 24 intervention studies with bilberry and blackcurrant (n = 4) and grape seed extract (n = 20). Bilberry and blackcurrant extract lowered average levels of glycated hemoglobin (HbA1c), at least in Chinese subjects, especially in those who were older, who were diagnosed with Type 2 Diabetes Mellitus (T2DM) and who were participating in longer-term studies. We also found good evidence that across studies and in subjects with hypercholesterolemia, T2DM or metabolic syndrome, intervention with bilberry and blackcurrant extract, and to some extent grape seed extract, significantly lowered total and low density lipoprotein (LDL) cholesterol levels after four weeks. Intervention with grape seed extract may reduce systolic and diastolic blood pressure in subjects with hypertension or metabolic syndrome. Differential responsiveness in cholesterol and blood pressure outcomes between stratified populations could not be explained by age, dose or study duration. In conclusion, bilberry and blackcurrant extract appears effective in lowering HbA1c and total and LDL cholesterol, whereas grape seed extract may lower total and LDL cholesterol, and blood pressure, in specific population groups.

scholarly journals Rationale and design of the expanded combination of evolocumab plus empagliflozin in diabetes: EXCEED-BHS3 trial

2020 ◽  
Vol 11 ◽  
pp. 204062232095924
Author(s):  
Ikaro Breder ◽  
Jessica Cunha Breder ◽  
Isabella Bonilha ◽  
Daniel B. Munhoz ◽  
Sheila T. Kimura Medorima ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Open Label ◽  
Lipoprotein Subfractions ◽  
Regular Treatment ◽  
Hdl Function ◽  
Cell Adhesion Molecule 1

Background: Patients with type 2 diabetes mellitus (T2DM) remain at increased cardiovascular residual risk and endothelial dysfunction, even after optimizing metabolic control and treatment by sodium-glucose-2 transporter inhibitors (SGLT2-is). The present study was based on the hypothesis that proprotein convertase subtilisin/kexin 9 inhibitor (PCSK9i) therapy may mitigate endothelial dysfunction in T2DM patients who are on regular treatment by SGLT2-i. Methods: The EXCEED-BHS3 is a prospective, single-center, investigator-blinded, open-label, randomized clinical trial. Participants ( n = 110) will be randomized (1:1) to either empagliflozin 25 mg/day alone or empagliflozin 25 mg/day plus evolocumab 140 mg every 2 weeks in addition to optimal medical care. The primary endpoint was defined as the change in the 1-min flow-mediated dilation (FMD) after 16 weeks of treatment. The secondary endpoint is the FMD change after ischemia/reperfusion injury protocol (reserve FMD) after 16 weeks of treatment. Exploratory outcomes comprise the change in FMD and reserve FMD after 8 weeks of treatment and the change after 16 weeks of treatment in the following parameters: plasma levels of nitric oxide, vascular cell adhesion molecule-1 and isoprostane, high-density lipoprotein (HDL) and low-density lipoprotein subfractions profile, HDL function, blood pressure, body mass index, waist circumference and adipokines. Conclusion: This will be the first study to evaluate the add-on effect of PCSK9i on endothelial function of T2DM patients under regular use of empagliflozin. Trial registration: ClinicalTrials.gov identifier: NCT03932721

Effect of the periparturient period on serum lipid and cholesterol lipoprotein concentrations in goats (Capra hircus)

2011 ◽  
Vol 59 (4) ◽  
pp. 445-454 ◽  
Author(s):  
Ewa Skotnicka ◽  
Zbigniew Muszczyński ◽  
Maria Suska
Keyword(s):  
Serum Lipid ◽  
Ldl Cholesterol ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Hdl Cholesterol ◽  
Capra Hircus ◽  
Low Density ◽  
Total Lipids ◽  
Blood Samples ◽  
Periparturient Period

Blood samples were taken from 12 goats during the periparturient period (4 and 1 weeks before and 2, 10 and 30 days after delivery), and from 10 nonpregnant goats. The following variables were determined: total lipids (TL), triacylglycerol (TG), total cholesterol (TCH) and high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol fractions. One week before delivery TL (2.32 ± 0.12 g/l, P ≤ 0.05), TG (0.32 ± 0.16 mmol/l, P ≤ 0.001) and TCH concentrations (1.65 ± 0.42 mmol/l, P ≤ 0.05) were significantly increased as compared to non-pregnant goats (2.08 ± 0.28 g/l, 0.15 ± 0.05 mmol/l, 1.38 ± 0.19 mmol/l, respectively). After delivery, the concentrations of TL, TG, TCH and HDL decreased significantly. The lowest TG concentration was observed 2 days after delivery (0.18 ± 0.02 mmol/l), while TL (1.73 ± 0.21 g/l), TCH (0.95 ± 0.21 mmol/l) and HDL (0.74 ± 0.16 mmol/l) reached the lowest level 10 days after delivery. Two days after delivery a significant increase of LDL concentration was observed (0.38 ± 0.04 mmol/l); however, ten days after delivery a threefold decrease was shown in the LDL concentration (0.12 ± 0.04 mmol/l). A month after delivery all the variables studied reached levels similar to those measured in non-pregnant goats.

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