Measurement of regional neuronal removal of norepinephrine in man.

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.

Presence of rhinovirus in the respiratory tract of adolescents and young adults with asthma without symptoms of infection.

BACKGROUND: Viral respiratory infections have been associated with up to 80% of wheezing episodes and asthma exacerbations. However, studies on the role of these viruses in asthmatic patients in the interval between exacerbations are sparse. This study aimed to determine the presence of respiratory viruses, without symptoms of infection, in the airways of young asthmatics as compared to healthy controls. MATERIAL AND METHODS: Patients 10-35 years of age with stable asthma and a group of healthy controls were analyzed regarding the presence of RNA from common respiratory viruses in nasopharyngeal aspirates by PCR. Self-reported asthma control and quality of life, fraction of exhaled nitric oxide (FeNO), spirometry, and bronchial responsiveness to methacholine were recorded. Blood samples were collected to assess IgE sensitisation and eosinophil cationic protein (ECP) levels. RESULTS: In 354 patients with asthma and 108 healthy controls, human rhinovirus (HRV) was the only virus detected (4.5% of asthmatics vs. 0.9% of controls; p = 0.08). HRV(+) asthma patients had a higher degree of aeroallergen IgE sensitisation (median 37.7 vs. 10.4 kUA/L, p = 0.04), and a tendency for higher levels of serum ECP (median 17.2 vs. 12.6 µg/L, p = 0.07), as compared to their HRV(-) counterparts. CONCLUSIONS: Absence of symptoms of respiratory tract infection notwithstanding, HRV seems to be more prevalent in the airways of adolescents and young adults with asthma and a high degree of aeroallergen IgE sensitisation than in controls. The presence of HRV seems also to be related to systemic eosinophilic inflammation despite ongoing treatment with inhaled corticosteroids.

Causes and consequences of blood pressure alterations in obstructive sleep apnea.

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.

Persistence of normal BP after withdrawal of drug treatment in mild hypertension.

Antihypertensive therapy was discontinued in 24 patients with mild hypertension whose BPs had been well controlled with diuretics alone. Eleven patients (46%) maintained normal diastolic BPs (less than or equal to 90 mm Hg) for six months after stopping treatment and five patients (21%) for 12 months. All patients who remained normotensive for six to 12 months had mean diastolic BPs of 82 mm Hg or less during treatment. There was no significant correlation between maintenance of normotension and any of the following: pretreatment BP, presence of target-organ damage, duration of known hypertension, family history of hypertension, heart rate, body weight, weight gain after stopping diuretic therapy, 24-hour urinary sodium and potassium excretion, serum electrolyte values or renin profile. This study demonstrates that hypertension may be favorably modified, sometimes for many months, by effective antihypertensive treatment.

Endocrine, renal, and hemodynamic responses to graded dopamine infusions in normal men.

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.

Withdrawal phenomena in subjects with essential hypertension on clonidine or tiamenidine.

The incidence and pathogenesis of withdrawal phenomena with the centrally acting drugs clonidine (CLON) and tiamenidine (TIAM) were evaluated. Thirty subjects with hypertension on hydrochlorothiazide (HCTZ) were randomized to TIAM or CLON. Blood pressure and integrated plasma catecholamine levels fell equally in response to both drugs. On withdrawal, blood pressure and pulse rose in both groups with no difference between them. Three subjects had symptoms of withdrawal, four had blood pressure overshoot above pretreatment levels of 10 mm Hg or more, and eight had a rise in blood pressure of 30 mm Hg systolic or 20 mm Hg diastolic. There was no difference between TIAM and CLON in these effects. There was a direct correlation between blood pressure rise and increase in integrated plasma norepinephrine levels. We conclude that the incidence of withdrawal phenomena in subjects on TIAM or CLON is infrequent and that there is a direct relationship between the rise in blood pressure and the loss of suppression of catecholamines by these drugs.

Obstacles in the treatment of dying patients.

Theory and practice in the management of the dying patient have moved forward in the past two decades. However, the author believes the benefits of this progress have not reached a large segment of the population of dying patients--those individuals who have a higher level of psychopathology or are from a lower socioeconomic group. Obstacles in the treatment of such patients are described and illustrated by case histories; the author makes specific recommendations related to the care of these more difficult cases.

Psychological factors in susceptibility to drug-induced extrapyramidal symptoms.

In an effort to identify nonneurobiologic factors in the susceptibility to neuroleptic-induced extrapyramidal symptoms (EPS), the EPS response in 20 patients was correlated with field dependence, self-object differentiation, and premorbid social competence. Only the last proved to be a good predictor, which suggests that psychosocial factors play a role in a patient's EPS response.

Causes for the premature interruption of psychotherapy by private practice patients.

Thirty patients who discontinued private psychotherapy prematurely were evaluated. Factors stemming from the dynamic interaction between the patient and the treatment process were the most common reasons for dropping out, followed by chronic character traits such as impulsivity and masochism. It is hoped that this assessment of variables in the premature termination of therapy will serve to alert the therapist to the probability that treatment will be aborted, suggest which mechanisms will cause interruption, and enable the therapist to use preventive measures sooner.

Initial and long-term effects of prazosin on sympathetic vasopressor responses in essential hypertension.

In 10 untreated hypertensive patients who received an initial dose of 3 to 5 mg prazosin, supine blood pressure (BP) decreased significantly, from an average of 171 +/- 24/96 +/- 10 to 157 +/- 22/90 +/- 10 mm Hg (p less than 0.025). The Valsalva overshoot, response to cold pressor test and digital vasoconstrictor response to a deep breath were not inhibited. However, during 55 degrees passive headup tilt there was a significant decrease in BP. Seven patients received prazosin for a period of 3 months. After long-term therapy BP returned to baseline levels and a dose of prazosin similar to that given initially produced an average decrease in BP from 174 +/- 20/101 +/- 8 to 167 +/- 23/99 +/- 7 mm Hg. Upright tilting no longer resulted in a decrease in BP. The Valsalva overshoot, cold pressor test and digital vasoconstrictor responses remained unchanged. Orthostatic hypotension after the first dose of prazosin without blockade of the other sympathetic reflex responses suggests that the drug has a greater blocking effect on capacitance vessels than on resistance vessels. Prazosin showed a loss of antihypertensive effectiveness during long-term treatment.

Daytime hypertension in obstructive sleep apnea. Prevalence and contributing risk factors.

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.

Body fat distribution and sleep apnea severity in women.

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.

Adiposity and cardiovascular risk factors in men with obstructive sleep apnea.

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.

Hormone and catecholamine responses accompanying the antinatriuresis of glucose ingestion.

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.

Effects of n-3 fatty acids in essential hypertension.

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.

Metabolic and hemodynamic effects of antihypertensive treatment with ketanserin.

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.

Plasma norepinephrine and epinephrine responses to glucagon in patients with suspected pheochromocytomas.

Plasma norepinephrine and epinephrine levels were measured before and after glucagon administration in 28 patients suspected of having a pheochromocytoma: three patients were subsequently found to have tumors. The norepinephrine response predicted the presence or absence of a tumor in 27 of the 28 patients. Epinephrine levels doubled, on the average, in patients who did not have pheochromocytomas, and were not useful in distinguishing the patients with or without tumors. A comparison of the response to glucagon and a placebo indicated that changes in plasma catecholamine levels were hormone-related and not the result of side-effects accompanying injection. The glucagon provocation test, with measurement of plasma norepinephrine and epinephrine levels, may be a useful adjunctive tool for evaluating patients suspected of having a pheochromocytoma when performed according to a standardized protocol and interpreted in relation to appropriate controls.

The effect of metoclopramide on the Ganzfeld electroretinogram.

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.

Inhibitors of 11 beta-hydroxysteroid dehydrogenase and 5 beta-steroid reductase in urine from patients with congestive heart failure.

Recently, the current authors reported the presence in normotensive male and female urines of reproducibly measurable levels of naturally occurring substances in partially purified extracts of urine with inhibitory activity like glycyrrhetic acid (GA) towards both 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) and steroid 5 beta-reductase (5 beta-SR) in vitro. Since these substances mimic two known inhibitory activities of GA, they have been named 'Glycyrrhetic Acid-Like Factors', abbreviated as 'GALFs' or, more specifically 11 beta-GALF for substance(s) active against 11 beta-OHSD, and 5 beta-GALF for those inhibitory to 5 beta-SR. Administration of glycyrrhetic acid in man leads to cortisol-dependent mineralocorticoid hypertension, owing to impaired inactivation of cortisol by 11 beta-OHSD, and may be associated with increased sensitivity to mineralocorticoids owing to impaired 5 beta-SR. In this preliminary report, the results are described of a study on the presence of GALF factors in urines collected from patients with congestive heart failure (CHF) and mild essential hypertension. The results show that in such patients there are increased amounts of both 11 beta- and 5 beta- GALFs compared to normotensive. The possible physiological significance of these results is discussed.