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OBJECTIVE: To examine relations between obesity and serum concentrations of lipoprotein cholesterol, apolipoproteins, triglycerides and insulin in American and Western Samoans. Associations are also described between these CHD risk factors and abdominal adiposity, and the potential mediating role of insulin in these relationships is examined. DESIGN: Cross-sectional, using a sub-sample from an observational epidemiological study of cardiovascular disease risk factors among Samoans. MEASUREMENT: Obesity is estimated by the body mass index (BMI), and fat distribution by the abdomen-hip circumference ratio (AHR). All biochemical parameters were measured in the fasted stated. SUBJECTS: The sub-sample is 178 men and 147 women who were free from hypertension, diabetes and heart disease. RESULTS: In multivariate linear regression analyses in men the BMI was positively associated with levels of total cholesterol, the total-HDL cholesterol ratio, apolipoprotein B, and the log of triglyceride and insulin concentrations, and negatively associated with HDL and HDL2 cholesterol. The quadratic term for BMI was also found to be significantly predictive of all metabolic parameters in men, except for the log of serum insulin concentrations. Among the women, in contrast, BMI levels were significantly associated only with concentrations of HDL2 cholesterol, triglyceride and insulin. In men, the associations between the AHR and the metabolic parameters were similar to those described for the BMI, but showed no indication of non-linearity. Addition of the log of insulin to these models had little effect on the relations between the AHR and the lipid parameters, with the exceptions of total cholesterol and triglycerides. As with BMI, the AHR was much les predictive of metabolic parameters in women than in men, with a significant relation existing only with the log of insulin concentrations. CONCLUSIONS: These cross sectional data indicate that overall and abdominal adiposity are important correlates of serum lipid parameters among Samoan men, though the associations with BMI are attenuated at higher levels. Neither anthropometric indicator has much relation with these CHD risk factors among the women, perhaps due to extremely high levels of obesity in this group.

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The contribution of body fat distribution to sleep-disordered breathing in women has not been examined in detail (to our knowledge). Fifty women under 65 years of age were diagnosed as having obstructive sleep apnea (OSA) by all-night polysomnography in a 6-month period. Twenty-five women underwent body fat measurements of skin folds and circumferences. The 12 premenopausal and 13 postmenopausal women did not differ in regard to apnea hypopnea index (AHI), SaO2 nadir, body mass index (BMI), or anthropometric measurements. The AHI for these 25 patients was related to the severity of obesity assessed by triceps and subscapular skin folds, the sum of the skin folds, waist circumference, and BMI. The SaO2 nadir correlated with triceps and subscapular skin folds, the sum of the skin folds, and neck skin fold. Clinical features of this same group of 25 women were then compared with those of 45 men with OSA previously described by our laboratory. The women, despite similar age, had less severe OSA than the men (AHI of 34.4 +/- 5.4 vs 51.1 +/- 4.9, p < 0.05). Despite similar BMIs and waist circumference, the men had evidence of a greater degree of upper body obesity with a larger subscapular skin fold thickness, waist-hip ratio, and neck circumference. In addition, for a given degree of upper-body obesity, men had more severe sleep apnea. These findings may explain, at least in part, the greater severity of OSA in the men.

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STUDY OBJECTIVE: To assess anthropometric characteristics of patients with obstructive sleep apnea (OSA) and their relationship to cardiovascular risk factors (dyslipidemia, hypertension, glucose intolerance) and severity of breathing abnormalities during sleep. DESIGN: Case series. SETTING: Referral-based sleep disorder center serving Rhode Island and Southeastern Massachusetts. PATIENTS: Forty-five men, 26 to 65 years old, with OSA diagnosed by clinical and polysomnographic criteria. RESULTS: By national health survey criteria, 51 percent of patients were in the upper fifth percentile for weight, whereas 91 to 98 percent were in the upper fifth percentile for skinfold thicknesses (triceps, subscapular, triceps plus subscapular). Severe upper body obesity, as defined by a waist-hip ratio (WHR) greater than or equal to 1.00, was present in 51 percent of the patients. The WHR, however, did not correlate significantly with the severity of respiratory disturbances during sleep. The patients had higher prevalences of hypertension and impaired glucose tolerance than expected, but normal prevalences of hypercholesterolemia, low high-density lipoprotein cholesterol, and overt diabetes mellitus. Skinfold thicknesses correlated more closely with the severity of OSA than did body mass index (BMI) or neck circumference. CONCLUSION: Men with OSA have a marked excess of body fat that is not always reflected in measurements of body weight or BMI. Also, upper body obesity, hypertension, and impaired glucose tolerance occur more frequently than expected in this population. Severe adiposity may not only promote development of the respiratory abnormalities of OSA, but also may contribute directly to the increased cardiovascular risk associated with OSA.

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We examined the prevalence of daytime hypertension in a modern sample of patients with obstructive sleep apnea (OSA) and assessed the relative risk factors contributing to the development of hypertension in this disorder. Daytime hypertension was present in 92 (45 percent) of 206 male and female patients with OSA. Stepwise logistic regression revealed that only age and body mass index (BMI) were predictors of hypertension in this population. A subsample of 152 male patients with OSA was then compared to 904 men identified from a geographically and ethnically similar general population. When one controlled for age and BMI, the prevalence of hypertension in the two groups was the same except for those aged 25 to 44 years who were markedly obese (BMI greater than 31 kg/m2). In this group, 47 percent of the patients with OSA were hypertensive vs 26 percent of control subjects (p less than 0.05). Our data suggest that the high prevalence of hypertension in OSA is primarily related to age and the excess obesity seen in these patients. In morbidly obese young patients with OSA, factors directly related to OSA may also be contributing to the development of hypertension. With increasing age, other competitive risks may obscure any independent effect that OSA may exert.

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The obstructive sleep apnea (OSA) syndrome has been considered to be a cause of both transient blood pressure elevations during sleep and sustained hypertension during the awake state. The purpose of this review was to examine critically the existing literature regarding (1) the blood pressure alterations associated with OSA, (2) causal mechanisms relating specific blood pressure alterations to OSA, and (3) potential consequences of the systemic circulatory abnormalities associated with OSA. Particular attention was directed at studies that assessed the prevalence of OSA in patients with hypertension and that examined the effects on blood pressure of treatment of OSA. We conclude that patients with OSA have abnormal sleep blood pressure patterns, manifested most frequently by apnea-associated blood pressure elevations. Confounding factors such as obesity and antihypertensive drug therapy, and conflicting evidence regarding changes in daytime blood pressure after therapy for OSA, make it premature to conclude that OSA and daytime hypertension are directly associated. Circumstantial evidence suggests that the blood pressure alterations that occur during sleep could contribute to the high cardiovascular morbidity in patients with OSA. Further research into the relationship between OSA and hypertension should improve the future care of patients with these conditions and enhance our understanding of cardiopulmonary pathophysiology.

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We examined the effects on blood pressure, plasma lipoproteins, and platelet function when marine oil supplements (rich in n-3 fatty acids) or vegetable oil supplements (rich in n-6 fatty acids) were added to the usual diets of patients with mild essential hypertension. In a randomized, double-blind, parallel-group study, patients received 50 g of either marine oil (n = 8) or vegetable oil (n = 8) daily for 6 weeks following a baseline observation period. Diastolic blood pressure declined during treatment with fish oil (mean +/- SEM, 96 +/- 2 v 89 +/- 2 mm Hg, P = .02), but did not change with vegetable oil (92 +/- 1 v 94 +/- 1 mm Hg). Systolic blood pressure did not change significantly during either treatment. Serum triglycerides declined (by approximately 30%) in patients receiving only marine oil, but total cholesterol, LDL-, HDL-, HDL2-, and HDL3-cholesterol-subfractions and apolipoproteins A-I and B were unchanged in both treatment groups. Bleeding time increased by 33% during treatment with marine oil but did not change with vegetable oil supplements. Marine oil did not alter in vitro platelet aggregation thresholds. The lack of a significant correlation between blood pressure changes and platelet membrane fluidity, plasma renin activity, aldosterone, norepinephrine, or epinephrine suggests that these variables did not mediate the antihypertensive effect of the marine oil. We conclude that large doses of marine oil reduce diastolic blood pressure, lower triglycerides, and increase bleeding time in patients with mild hypertension.

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The purpose of this study was to determine the importance of various neurohormonal systems in mediating the sodium retention associated with glucose ingestion. Eight normotensive men were randomized to receive, after an overnight fast, glucose (1 mg/kg po) in water, and water alone, during two studies seven to ten days apart. Sodium excretion declined 38 +/- 5% from baseline one to two hours after glucose ingestion (P less than .005), but did not change significantly on the control day. Urinary norepinephrine and dopamine did not change during glucose or control studies. Peak serum insulin levels after glucose correlated inversely with the decline in sodium excretion (r = .67, P less than .10). Plasma renin activity (PRA) increased after glucose ingestion (P less than .01), but changes in PRA did not correlate with changes in sodium excretion. We conclude that the antinatriuresis following glucose ingestion does not result from alterations in noradrenergic-dopaminergic activity or changes in the renin-angiotensin-aldosterone axis. Insulin may modulate renal sodium metabolism directly, or through a yet unknown mechanism.

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1. We estimated the extent to which circulating dopa (3,4-dihydroxyphenylalanine) is the source of urinary dopamine (DA; 3,4-dihydroxyphenethylamine). Tritiated dopa ([3H]dopa) was infused for 90 min into the left renal artery of seven anaesthetized foxhounds, and levels of labelled and unlabelled dopa and DA were measured in the ureteral urine and in the femoral arterial and left renal venous plasma. 2. Only a small percentage of [3H]dopa delivered to the kidneys was excreted as [3H]DA (0.59% from the left kidney, 0.68% from the right); however, the arterial concentration of endogenous dopa (1220 pg/ml) and the renal plasma flows (144 and 141 ml/min by p-aminohippurate clearances) were such that all of the urinary excretion of endogenous DA (about 1 ng/min from each kidney) could be accounted for by uptake and decarboxylation of circulating endogenous dopa. 3. Plasma dopa is the main source of urinary DA.

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Ketanserin, a serotonin-2-receptor antagonist, was administered to 12 subjects with mild to moderate hypertension in a randomized, double-blind, placebo-controlled crossover trial. After 6 weeks of ketanserin (40 mg every 12 h), blood pressures measured 12 h after dosing were not significantly different from those obtained during the placebo period. However, 2 h after ketanserin administration, supine systolic and diastolic blood pressures declined 11 +/- 10 mm Hg (p less than 0.01) and 6 +/- 5 mm Hg (p less than 0.005) from predose values, whereas placebo caused no change in either systolic or diastolic blood pressure. At the time of peak antihypertensive activity, plasma renin activity, aldosterone, growth hormone, and prolactin levels were unchanged. Prolactin levels decreased slightly (4.1 +/- 3.0 vs. 3.7 +/- 2.9 ng/ml, p less than 0.05) during ketanserin therapy when measured 12 h after dosing. Other pituitary hormones, serum testosterone, plasma catecholamines, and plasma lipids showed no changes. Heart rate was also unchanged. Stroke volume, measured 2 h after dosing, increased (70 +/- 22 vs. 85 +/- 31 ml, p less than 0.05) with ketanserin therapy, but cardiac output did not change significantly. Ketanserin has a moderate antihypertensive effect and neutral metabolic-hormonal profile when used as monotherapy for the treatment of hypertension. However, further studies are needed to define the frequency of dosing that will provide 24-h antihypertensive activity.

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Ketanserin, a serotonin-2-receptor antagonist, was administered to 12 subjects with mild to moderate hypertension in a randomized, double-blind, placebo-controlled crossover trial. After 6 weeks of ketanserin (40 mg every 12 hours), blood pressures measured 12 hours after dosing were not significantly different from those obtained after placebo. However, 2 hours after ketanserin administration, supine systolic and diastolic blood pressures declined 11 +/- 10 mm Hg (P less than 0.01) and 6 +/- 5 mm Hg (P less than 0.005) from predose values, whereas placebo caused no change in either systolic or diastolic blood pressure. Except for a slight decline in serum prolactin levels 12 hours after dosing with ketanserin, no changes were observed in pituitary hormone levels, serum testosterone, plasma catecholamines, plasma renin activity, aldosterone, or lipoproteins. Stroke volume, measured 2 hours after dosing, increased with ketanserin therapy, but cardiac output, systemic resistance, and heart rate were unchanged. Ketanserin has a moderate antihypertensive effect and neutral metabolic-hormonal profile when used as monotherapy for the treatment of hypertension. However, further studies are needed to define the frequency of dosing that will provide 24 hours of antihypertensive activity.

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Antecedent light flashes enhance the amplitude of the electroretinogram (ERG) oscillatory potentials, but do not modify other ERG responses nor dark-adaptation sensory thresholds. Metoclopramide infusion (i.v.) has a generally attenuating effect on the ERG, which is more evident under conditions of dark- than light-adaptation. Metoclopramide decreases the peak amplitude of the rod b-wave and the dark-adapted cone b-wave in a similar manner; it also significantly increases the implicit time of the rod b-wave, but not of the dark-adapted cone b-wave. In addition metoclopramide reverses the enhancement of the oscillatory potentials by the antecedent light flashes.

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Elements of a hypothesis that relate endogenous digitalis-like factors to both natriuretic hormone and hypertension are briefly reviewed. The stimulus for secretion of these factors appears to involve a tendency toward a state of extracellular fluid volume expansion as a consequence of an inherited or an acquired defect in renal function. Several studies implicate the brain and, in particular, the hypothalamus in the control of the secretion. The digitalis-like factors are thought to act by partial inhibition of active sodium transport, thereby promoting increased intracellular levels of Na+ and Ca2+ in a variety of cell types. In the kidney, inhibition of sodium transport leads to a compensatory natriuresis to correct the tendency for volume overload. In smooth muscle, the inhibition of sodium transport will indirectly increase intracellular calcium levels. The increased availability of Ca2+ will elevate muscle tone and increase peripheral vascular resistance. Also presented are criteria that may be used to characterize digitalis-like activity in samples and extracts obtained from purification procedures. Finally, we review our measurements of the 6-h integrated plasma levels of digitalis-like factors and other hormones for normotensive subjects and patients with essential hypertension. The data indicate the presence of two classes of digitalis-like factors with potentially different roles in electrolyte metabolism and hypertension.

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We describe here and validate an in vivo technique to measure the regional proportionate removal of norepinephrine (NE) by neuronal uptake (Uptake1) in man. The measurement is based on the steady-state arterial and venous concentrations of tritiated NE and tritiated isoproterenol (ISO) during simultaneous infusion of both. The validity of this technique depends on the removal of circulating NE, but not of ISO, by sympathetic nerve endings and on there being no other factor contributing to the net difference in the plasma disappearance of these catecholamines. To test these hypotheses, we compared the removal of NE in the arm with that of ISO in 14 people and the effects of pretreatment with the specific inhibitor of Uptake1, desipramine, in 8 people. In all the subjects a greater percent of NE than of ISO was removed during passage of blood through the forearm (54 vs. 46%, P less than 0.0001). Pretreatment with desipramine decreased significantly the removal of NE to virtually exactly that of ISO. The difference in NE and ISO clearances by arm tissues was therefore completely accounted for by Uptake1. About 15% of infused NE which is removed in the arm is removed by Uptake1. The ability to measure regional Uptake1 should contribute to better understanding of the relationship between circulating levels of plasma NE and sympathetic neural activity and may allow detection of abnormalities of neuronal norepinephrine removal in clinical disease states.

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The present study was performed to determine the hemodynamic, hormonal, and natriuretic responses to infusions of dopamine (DA) that reflect physiological as well as pharmacological levels in blood or tissue. In six normal men, DA was infused for 2 h at three fixed dosages (0.03 or 0.1, 0.3, and 3.0 micrograms/kg X min) on three separate occasions, which resulted in increases in mean plasma DA concentrations from basal levels of less than 0.03 ng/ml to 0.69 +/- 0.12, 3.73 +/- 0.40, and 38.4 +/- 3.80 (+/- SE) ng/ml. Mean plasma PRL decreased and DA excretion increased significantly from basal levels during all three DA infusions. Plasma LH decreased and norepinephrine (NE) excretion increased during both the middle and high dose infusions, while sodium excretion, plasma NE, and heart rate increased only during the high dose DA infusion. Basal plasma aldosterone values were low and did not change with DA treatment. PRA, TSH, and FSH also did not change. GH responses were difficult to assess because of the frequency of episodic secretions. Since DA concentrations in hypophysial-portal blood may equal or exceed 1 ng/ml, these results support a role for DA in the acute regulation of PRL, and possibly LH, in normal men. As a natriuretic response occurred only at supraphysiological concentrations of circulating DA, if DA has a physiological role in modulating sodium excretion during normal sodium intake, it must be released from dopaminergic neurons or otherwise locally produced in very high concentrations in the kidney.

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To assess the contribution of sympathetic outflow to blood pressure in patients with essential hypertension, we measured blood pressure and plasma norepinephrine responses to clonidine, an antihypertensive agent that decreases central sympathetic outflow, in 44 patients and in 41 normotensive control subjects of similar age. Among the hypertensive patients, the resting level of plasma norepinephrine was significantly related to the decrease in mean arterial pressure 3 hours after a single oral dose of clonidine 300 micrograms (r = 0.62, p less than 0.001). The magnitude of the depressor response in the patients also was correlated significantly with the decrease in plasma norepinephrine after clonidine (r = 0.60, p less than 0.001). These results suggest that increased sympathetic outflow plays a pathophysiologic role in some patients with essential hypertension.

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