SUMMARYWe assessed the release of neuronal and adrenomedullary catecholamines in response to various stimuli of the sympathetic nervous system in normal subjects. Plasma catecholamines and their urinary metabolites, normetanephrine and metanephrine, were measured. Sodium restriction increased supine plasma norepinephrine by 37% and ambulatory plasma norepinephrine by 22%, with urinary normetanephrine excretion increased 29%. The sodium restriction did not elevate plasma epinephrine or urinary metanephrine. The most potent stimuli of norepinephrine were treadmill exercise, orthostasis, caffeine, the cold pressor test, sodium restriction and handgrip exercise, in descending order. Plasma epinephrine was increased by caffeine, treadmill exercise, the cold pressor test, handgrip exercise and the Valsalva maneuver, in that order. Syncope resulted in profound changes in plasma epinephrine but only modest changes in plasma norepinephrine. We conclude that in man, there is frequent dissociation between the effects of different stimuli on neuronal and adrenomedullary catecholamine release.LOW CONCENTRATIONS of catecholamines in blood and the poor sensitivity of fluorometric techniques for measuring them have prevented full assessment of the value of plasma norepinephrine (NE) as a marker of sympathetic nervous activity until the development of sensitive enzymatic assay methods.' The recent extension of these methods to epinephrine (E) and dopamine (D) permits better understanding of events at the neuronal and adrenomedullary levels.Many physiologic maneuvers have been used to elucidate the function of the autonomic nervous system, including the Valsalva maneuver,4 the cold pressor test,6 7 static8' 9 and dynamic exercise9' 10 and upright posture.5' 11 Other stimuli, too, result in sympathetic neuronal or adrenomedullary discharge: low sodium diet,2, 13 syncope,", 14 venepuncture 15 smoking'6 and caffeine.'7We compared the effects of these stimuli on plasma levels of NE, E and D in normal subjects by a sensitive enzymatic assay; we also assessed the effect of changes in sodium balance by measuring urinary normetanephrine and metanephrine with highly sensitive and specific stable isotope dilution assays. Because contradictory data in the literature may reflect different control conditions, we performed all our studies on patients in documented sodium balance who strictly avoided both tobacco16 and methylxanthine beverages.:" MethodsThe study subjects included one female and 14 male volunteers, 18-54 years old. Four were black and 11 were white. All subjects had a normal physical exam and no history of chronic or recent acute illness. No subject was on medication during the study. Volunteers abstained from methylxanthine and alcoholic beverages during the study, and the two who were smokers abstained from tobacco for 24 hours before and during the study. We excluded subjects who varied from their ideal weight by more than 10%. Serum creatinine, urea nitrogen, electrolytes, glucose, cholesterol and triglycerides were normal...

A BSTRA CT Human urine was analyzed by mass spectrometry for the presence of prostaglandins. Pros-taglandin E2 and F2. were detected in urine from females by selected ion monitoring of the prostaglandin E2-methylester-methoxime bis-acetate and the prostaglandin F2a-methyl ester-Tris-trimethylsilylether de-rivative. Additional evidence for the presence of prostaglandin F2. was obtained by isolating from female urine an amount of this prostaglandin sufficient to yield a complete mass spectrum. The methods utilized permitted quantitative analysis.The origin of urinary prostaglandin was determined by stimulating renal prostaglandin synthesis by arachidonic acid or angiotensin infusion. Arachidonic acid, the precursor of prostaglandin E2, when infused into one renal artery of a dog led to a significant increase in the excretion rate of this prostaglandin. Similarly, infusion of angiotensin II amide led to a significantly increased ipsilateral excretion rate of prostaglandin E2 and F2. in spite of a simultaneous decrease in the creatinine clearance. In man, i.v. infusion of angiotensin also led to an increased urinary elimination of prostaglandin E.These results show that urinary prostaglandins may originate from the kidney, indicating that renally synthesized prostaglandins diffuse or are excreted into the tubule. Thus, urinary prostaglandins are a reflection of renal prostaglandin synthesis and have potential as a tool to delineate renal prostaglandin physiology and pathology.

When human platelets are aggregated by thrombin, material is released that rapidly contracts strips of spirally cut porcine coronary artery. Prevention of the contraction by indomethacin suggested mediation by a prostaglandin. The contraction produced by aggregating platelets was unlike those produced by prostaglandins E2, F2alpha, G2, or H2, but resembled that evoked by thromboxane A2, which is formed by platelets during aggregation.

To investigate the relation between acetvlator phenotype and the development of procainamide-induced lupus, we determined the rate of development of antinuclear antibodies in 20 patients of known acetylator phenotype receiving chronic procainamide therapy. The duration of therapy required to induce antibodies in 50 per cent of slow (11) and rapid (nine) acetylators was 2.9 and 7.3 months respectively. The median total dose that produced ant;bodies was 1.5 g per kilogram and 6.1 g per kilogram respectively. After one year antibodies had developed in 18 patients. Retrospective studies of patients in whom procainamide lupus had developed revealed that the duration of therapy required for induction in 14 slow and seven rapid acetylators was 12 +/- 5 and 48 +/- 22 months respectively (P less than 0.002). We conclude that acetylator phenotype influences the rate at which procainamide induces antinuclear antibodies and probably the lupus syndrome. Antibody production is probably related to the parent compound or a non-acetylated metabolite.

A B S T R A C T Abrupt withdrawal after the chronic administration of propranolol has resulted in clinical syndromes that suggest adrenergic hypersensitivity. The effect of propranolol administration and withdrawal on ,-adrenergic receptors was studied in human lymphocyte membranes. Receptor density was quantitated by direct binding assays with the radioligand [1251]iodohydroxybenzylpindolol. Administration ofpropranolol (160 mg/d) for 8 d resulted in trough plasma levels of -35 ng/ml. By day 5 ofpropranolol administration the density of /3-adrenergic receptors had increased 43+4% (P < 0.01) above pretreatment levels. Abrupt withdrawal of propranolol was followed by the disappearance of propranolol from the plasma within 24 h. The density of f3-adrenergic receptors did not return to pretreatment level for several days. Physiologic supersensitivity of 8-adrenergic receptor-mediated responses was suggested by the appearance of significant increases in the orthostatic change in heart rate (P < 0.05) and the orthostatic change in the heart rate-systolic blood pressure product (P < 0.01) during the first 48 h after propranolol withdrawal. These data show that propranolol administration leads to an increase in the density of f3-adrenergic receptors in human tissue. The results are consistent with the hypothesis that some of the untoward effects observed after abrupt discontinuation of propranolol are caused by 8-receptor-mediated adrenergic hypersensitivity.