Robert L. Wolf

Simultaneous Urinary Assays for the Combined Metanephrines and 3-Methoxy-4-Hydroxyphenylglycol in Patients with Pheochromocytoma and Primary Hypertension

THE discovery, by Armstrong and McMillan,1 in 1957, of the presence of the catecholamine metabolite, 3-methoxy-4-hydroxymandelic acid (VMA), in human urine stimulated investigations that resulted i...

Metabolism of 14C‐labeled pyridostigmine in myasthenia gravis: Evidence for multiple metabolites

THE AIM of this investigation is to study the metabolism and excretion pattern of pyridostigmine in normal and myasthenic subjects. Approximately 10% of patients with myasthenia gravis develop resistance or insensitivity to anticholinesterase drug therapy. The reasons for this are only conjectural. Pyridostigmine is currently the most widely used drug. There is considerable variation among patients in the doses required for relief of symptoms. The varying doses required by different patients are related to several factors: duration and severity of the disease, as well as absorption, metabolism, and excretion of the drug. The factor of absorption can be eliminated by using a parenteral form of the drug. Previous investigations have demonstrated that, after oral administration of pyridostigmine, the urine excretion pattern per patient remains quite constant but considerable difference exists in the urine excretion pattern of different patients.1 Previous animal studies have dealt with pyridostigmine-14C metabolism in the rat.2~3 Following oral administration of the drug, about 42% of the dose is absorbed and excreted in urine.3 About 75% of excreted radioactivity represents intact pyridostigmine, while 25% is metabolite.3 Following intramuscular injection of pyridostigmine-14C in the rat, there is rapid elimination of the drug, chiefly by renal tubu-

The effect of spironolactone on digital vascular reactivity in essential hypertension

Abstract 1. 1. Spironolactone was administered (100 mg. daily) to 16 hypertensive patients for 2 weeks. 2. 2. Brachial and digital blood pressures and digital blood flow (calorimetric) were measured before and after vasodilatation by indirect heat supplemented by ganglion blockade, as well as during the intravenous administration of l-norepinephrine (NE). These measurements were made before and at the end of the drug period and from the data, changes in digital vascular caliber and work of vasoconstriction were calculated. 3. 3. The drug produced a statistically significant decrease in supine brachial and digital blood pressure and in digital vascular reactivity to NE. 4. 4. These decreases seem attributable to sodium depletion by the drug.

The effect of aldosterone on electrolytes and on digital vascular reactivity to I-norepinephrine in normotensive, hypertensive, and hypotensive subjects☆

Abstract 1. 1. Aldosterone was administered intramuscularly to 15 normotensive subjects and 15 patients with essential hypertension who were on a fixed intake of sodium chloride. Two patients with renal hypertension and 2 with postural hypotension were also studied. 2. 2. The excretion of sodium in the urine was significantly decreased in the normotensive group. The other electrolyte changes were inconclusive. 3. 3. Digital vascular responsiveness to 1-norepinephrine was significantly increased from an initially high level by the aldosterone in the subjects with essential hypertension but only slightly increased in the normotensive subjects. It was also found to increase from an initially normal level in the 2 patients with renal hypertension, and to decrease from an initially high level in the 2 patients with postural hypotension. 4. 4. The possible mechanisms involved in these changes are discussed.

Metabolism of Corticotropin in Man.

Summary Synthetic beta1-24 corticotropin has been labeled with I131 and intravenously administered to normal subjects. Analysis of the blood radioactivity following intravenous administration of beta1-24 corticotropin-I131 revealed that this substance has an apparent space of distribution of 43% of the body weight and a plasma half-life of 7 minutes.

Reactivity of the digital blood vessels to angiotensin II in normotensive and hypertensive subjects

Abstract 1. 1. Digital vascular reactivity to infused angiotensin II was measured in 15 normotensive subjects and 15 pateints with essential hypertension. 2. 2. This reactivity was found to be increased in the hypertensive group. 3. 3. The mechanisms involved are discussed.

Angiotensin II Studies in Hypertension

1. In primary hypertension, the digital blood vessels are more reactive than normal to angiotensin II as well as to l-norepinephrine. 2. In terms of weight, the potency of angiotensin II in constricting digital blood vessels is 10 times that of norepinephrine in both normotensive and hypertensive subjects. 3. The turnover of angiotensin II-I131 is slower than normal in patients with primary hypertension. 4. Digital vascular reactivity to both l-norepinephrine and angiotensin II is normal in “pure” renal hypertension. 5. Angiotensin II-I131 turnover, in contrast, in the case of renal hypertension studied, was slower than in the normal group and was similar to that in the case of primary hypertension.

Metabolism of Angiotensin II-I131 in Normotensive and Hypertensive Human Subjects

B IOLOGICAL ASSAYS of angiotensin in the blood of patients with normal blood pressures, patients with benign essential hypertension, and patients with malignant hypertension indicate that there are significantly greater quantities of angiotensin in the subjects with benign essential hypertension than in the normotensive group and that the greatest quantities of angiotensin are present in the patients with malignant hypertension. The present investigations were designed to determine the metabolism and rate of turnover of angiotensin in normotensive and hypertensive human subjects.

The Metabolism of Angiotensin II

1. I131-labeled angiotensin II has been employed to study the metabolism of this polypeptide. 2. Following the intravenous administration of angiotensin II-I131 to normotensive and untreated primary benign hypertensive subjects, a slower angiotensin II degradation rate and a larger final volume of distribution of angiotensin II-I131 was found in the hypertensive than in the normotensive patients. The slow rate of degradation of angiotensin II may be responsible for the increased quantity and concentration of this polypeptide in the body fluids. 3. Greater quantities of angiotensin II-I131 are degraded in vitro by sera from untreated primary benign hypertensive patients than from normotensive or secondary renal hypertensive patients. There is evidence for the presence of a serum factor or factors enhancing angiotensin II-I131 degradation and for the presence of a heat labile inhibitor.

Vascular reactivity in the patient with essential hypertension and hypertension of renal origin

Abstract 1. 1. It has been demonstrated that vascular reactivity of the blood vessels of digital skin and forearm muscle to such vasoactive substances as 1-norepinephrine or angiotensin II is increased in primary hypertension. This is best demonstrated after blockade of casual sympathetic nervous activity. In forearm muscle intraarterial infusion is necessary to avoid general reflex effects. In the digit, however, the effect can be demonstrated during the infusion of the vasoactive substance intravenously. 2. 2. Although structural changes occur in primary hypertension, these are probably not responsible for the increased reactivity. Reactivity is normal or only slightly elevated, for example, in renal hypertension and in Raynauds disease in which structural changes in the digital vessels are known to be present. 3. 3. Also, reactivity is increased by glucocorticosteroids in the normotensive but not in the primary hypertensive subject, whereas aldosterone increases reactivity more in the hypertensive than in the normotensive subject. Reactivity is decreased, moreover, by chlorothiazide and its congeners in the primary hypertensive but increased by these drugs, at least in the digit, in the normotensive subject. Increased reactivity, moreover, develops very early in the course of primary hypertension and can be demonstrated in the children of hypertensive patients prior to any elevation of blood pressure. 4. 4. These phenomena therefore probably have a chemical cause the exact nature of which is unclear. A decrease in the turnover of angiotensin II has been demonstrated in primary hypertension, but no such change has as yet been indicated for norepinephrine. Evaluation of the binding and metabolism of these substances in hypertension is necessary. The chemical defect may reside here or in smooth muscle metabolism itself and is probably the factor which is transmitted through the germ plasm and which initiates essential hypertension.