William Goldring

Exaggerated natriuresis in essential hypertension

P ATIENTS with essential hypertension excrete more sodium than do normotensive patients in response to the infusion of hypertonic saline solution [7-d]. The work reported in this paper attempts to assay the role of the renal tubule in the genesis of this exaggerated natriuresis. Our observations confirm the finding that exaggerated natriuresis occurs in hypertensive patients challenged with infusion of hypertonic saline solution, and we find that increased sodium excretion is also induced by infusion of hypotonic inulin and p-aminohippurate solution administered at low rates. However, the basal sodium excretion in hypertensive patients is comparable to that observed in normotensive patients, indicating that both groups are in sodium balance on the same diet; and the exaggerated natriuresis induced in hypertensive patients by infusion of hypertonic saline solution can be abolished by salt deprivation. This and other evidence indicates that the tendency to exaggerated natriuresis in hypertensive patients has an extrarenal basis.

HEMODYNAMIC ALTERATIONS IN NORMOTENSIVE AND HYPERTENSIVE SUBJECTS DURING THE PYROGENIC REACTION

It is well known that toxic substances, probably derivatives of bacterial protein (1), frequently appear in improperly distilled water. A dramatic and often potentially dangerous syndrome of chill and fever (pyrogenic reaction), occasionally complicated by peripheral circulatory collapse, follows the intravenous administration of solutions contaminated with these substances. A marked increase in renal blood flow (2), a reduction in arterial pressure (3) and an increase in cardiac output (4) have been observed during the pyro-genic reaction in normal man, indicating a marked reduction in overall peripheral resistance. Three stages of arterial pressure change have been described (3): namely, (a) a short period of elevated pressure during the chill and initial rise in temperature, (b) a phase characterized by a moderate fall in blood pressure, coinciding approximately with the appearance of renal hyperemia, and (c) a marked reduction in blood pressure with a narrowing of the pulse pressure some 4 or 5 hours after the administration of the pyrogen. Although antipyretics, such as amidopyrine, when given in adequate doses prior to injection of the pyrogen, will prevent chill and fever, they do not affect renal hyperemia or phases (b) and (c). The reduction of arterial pressure (c) is usually greater among hypertensive than among normal subjects and may be so profound as to result in a shocklike state, even in the absence of fever. It is not known whether the late reduction in blood pressure is a result of widespread vasodilation, reduced cardiac output or a combination of the two. Nor is it known whether there is any fundamental difference in response on the part of hy-pertensive as compared with normotensive individuals. The present study was undertaken to evaluate the hemodynamic factors involved in this reduction. METHODS Eight subjects, 6 of whom had essential hypertension, selected from the wards of the Third (New York University) Medical Division of Bellevue Hospital, and Evans Memorial Hospital (Boston University School of Medicine), were examined under basal conditions after several days of bed rest. All subjects were free of gross cardiac pathology. Amidopyrine in doses of 0.6 gram was given to each subject every 4 hours for 5 or 6 doses during the 24 hours immediately prior to the administration of pyrogen. Typhoid vaccine and contaminated inulin (Pfanstiehl inulin lot No. 268) were used as sources of pyrogen. Pyrogenic inulin, in doses of 100 to 200 mgm. dissolved in sterile saline and passed through a …

GLOMERULAR DYNAMICS IN THE NORMAL HUMAN KIDNEY

One of the most interesting facts about the renal circulation is that during marked changes in renal blood flow (adrenalin ischemia and pyrogenic hyperemia) the rate of glomerular filtration typically remains unchanged. This fact has been attributed to the circumstance that the changes in renal blood flow are mediated primarily by changes in the tonus of the efferent arterioles; consequently, any increase or decrease in blood flow is accompanied by a reciprocal change in glomerular filtration pressure, with the result that the filtration rate remains unchanged (3). Beyond the fact that this emphasis upon the efferent arteriole is to some extent contrary to the importance which has hitherto, chiefly for anatomical reasons, been attached to the afferent vessel, this description of the glomerular circulation presents several interesting implications. It assumes that the rate of glomerular filtration is determined solely by glomerular pressure factors, exclusive of any limitation imposed by the permeability of the glomerular membranes. There logically issues from this assumption the question whether or not filtration pressure equilibrium is normally reached in the glomerulus. The answer to this question is of practical importance in two respects. If filtration equilibrium is reached in the glomerular circulation, then this fact must set the upper limit to the hydrostatic pressure available to propel blood through the efferent arterioles and the postglomerular circulation. And in the face of a demonstration of filtration equilibrium in the normal kidney, a decrease in filtration rate in renal disease cannot logically be attributed to reduced permeability of the glomerular capillaries, in contradistinction to a decrease in filtration pressure or in total filtering

Effect of Febrile Plasma, Typhoid Vaccine and Nitrogen Mustard on Renal Manifestations of Human Glomerulonephritis

Summary Administration of plasma from patients acutely ill with pneumococcal and streptococcal infections failed to decrease proteinuria or induce diuresis in 2 patients with chronic diffuse glomerulonephritis. Induction of the pyrogenic reaction was accompanied by decrease in proteinuria on 2 occasions in one patient. We are inclined to attribute this result to the concomitant decrease in the rate of glomerular filtration. Therapeutic doses of HN2 reduced proteinuria but diuresis failed to occur in 2 patients with advanced chronic diffuse glomerulonephritis with marked renal functional impairment. However, in one patient with minimal renal functional impairment, administration of HN2 was followed on 2 separate occasions by diuresis, marked reduction in proteinuria and concomitant increase in filtration rate, a combination of effects consistent with a return of glomerular function towards normal.† Our observations indicate that reversal of renal manifestations of human glomerulonephritis can be induced by HN2. This study is being extended to include patients in earlier phases of glomerulonephritis.

Reassurance in the Management of Benign Hypertensive Disease

The therapeutic improvement achieved by administration of drugs in arterial hypertension and other disease states is widely recognized to be due to the potency of reassurance and suggestion as well as the possible pharmacologic action of the drugs employed. In this article Dr. Goldring and his associates evaluate the effectiveness of a calculated and deliberately dramatized regimen of reassurance on the blood pressure and on the symptoms in patients with benign hypertensive disease. These results help to explain why nonscientific treatment sometimes seems to be crowned with therapeutic success.

Inulin and its Suitability for Intravenous Administration in Man

After having administered dahlia inulin (lot 661-non-toxic) intravenously in large doses to dogs, and to man in 42 instances in doses ranging from 30 to 150 gm., without reaction, an unexplained transient reaction consisting of chills, fever, lumbar pain, nausea, vasomotor depression, herpes and anuria was encountered. The same reaction was encountered simultaneously in another laboratory where an independent sample of inulin was being used. The material that produced the reaction in our laboratory (lot 661-toxic) was a new shipment which had been purified separately by the manufacturer from the same batch of crude inulin as had supplied lot “661-non-toxic.” At our request the manufacturer supplied a fresh, highly purified sample (lot 681) prepared from a new batch of dahlia roots, which proved to be, if anything, more toxic than “661-toxic”, 1.0 gm. sufficing to produce either chill, fever, headache, nausea or lumbar pain. This reactive inulin appeared to be relatively innocuous for dogs, rabbits and guinea pigs, even when administered in very large doses. Boiling for 30 minutes in distilled water did not appreciably diminish the toxicity; partial hydrolysis with dilute acetic acid (sufficient to increase the reducing power from 0.9 to 13% by weight) diminished the toxicity somewhat, and complete hydrolysis with N/10 H2SO4 decreased the toxicity considerably. However, a fairly typical reaction was obtained after the administration of 20 gm. that had been hydrolyzed in the latter manner. Spectroscopic examination of the ash of both preparations revealed traces of numerous metals, but showed no Pb or Si, and no significant differences between the toxic and nontoxic preparations. Through the courtesy of Dr. Eaton M. Mackay and of the Bureau of Chemistry and Soils of the U. S. Department of Agriculture, we subsequently obtained a quantity of crude chicory inulin. This material was purified in the Department of Physiology, and with the exception noted below has proved to be innocuous to animals and to man. This material has, at the time of writing, been administered intravenously to man 28 times in doses of 30 to 40 gm. without reaction, and it produced no reaction in doses up to 80 gm.

Differentiation of Glomerular and Tubular Function in Glomerular Nephritis

It was recently shown that at low plasma levels about 94% of the phenol red clearance in the normal human kidney is accomplished by tubular activity. 1 In view of this fact this clearance is a sensitive index of tubular excretion, and when observed simultaneously with the inulin clearance, affords evidence of the respective functional activities of the tubules and of the glomeruli. The present investigation concerns the study of these clearances together with the urea clearance in 21 subjects with glomerular nephritis either during a first attack, during an exacerbation, or in the chronic stage. We have endeavored to maintain the urine flow above the augmentation limit wherever possible so that the urea clearances would be physiologically comparable. The urea clearance has ranged from 64.6 to 5.4, the inulin clearance from 131 to 6.2 cc. per minute; the urea/inulin clearance ratio has ranged from its normal value of 0.55 to a value of 0.88. In no case has the urea/inulin clearance ratio been observed to fall significantly below the normal value in any stage of the disease. In general it tends to rise, so that in advanced chronic glomerular nephritis it has a value of 0.85 or higher. Our observations do not bear out the belief that in renal disease there is increased back-diffusion of urea, or that the elevation of the blood urea is due to such back-diffusion. A full discussion of the behavior of the phenol red clearance and its relation to the inulin clearance in various stages of disease must be deferred to a later time, but a few interesting features may be noted here. In general, in those individuals in whom renal impairment is not too far advanced, the phenol red/inulin clearance ratia tends to maintain its normal value (above 3.0), suggesting that injury of glomeruli and tubules progresses in a parallel manner, as might be expected from the anatomical structure of the nephron.

Phenol Red Clearances in Man

Although phenol red, introduced by Rowntree and Geraghty in 1912, has been widely used as an empirical renal function test in man, there is no information on the excretion of this substance in relation to the simultaneous excretion of other urine constituents.∗ With knowledge available concerning the order of magnitude of glomerular filtration in man, 1 a determination of phenol red clearance is of particular interest in indicating the relative rôle played by filtration and secretion in the excretion of this substance. Preliminary observations following oral, intramuscular and intravenous administration of phenol red indicate that the latter is most suitable for investigative purposes. In the observations reported here, a sterile 10% solution of the dye, prepared for us by Hynson, Westcott and Dunning, was administered intravenously following the intravenous administration of inulin, and the experiments were so conducted that the simultaneous clearances of inulin and phenol red could be determined at various plasma levels of the latter, standard (basal) physiological conditions being maintained throughout. The dose of phenol red was varied from 300 mg. to 5 gm. per man, and observations were made at plasma concentrations ranging from 0.1 to 28.2 mg. %. At plasma levels of the dye below 1.5 mg. %, the phenol red clearance is essentially constant, having an average value of about 400 cc. per minute, when calculated upon the total dye in the plasma. The phenol red/inulin clearance ratio averages about 3.2 under these conditions. A series of such observations on several individuals are recorded in the upper right hand corner of Fig. 1. As the plasma level of the dye is increased, the phenol red clearance is lowered both absolutely and relative to the inulin clearance, until the phenol red/inulin clearance ratio may be less than 1.00. This depression of the phenol red clearance appears to be reversible, the same results being obtained, whether an intermediate plasma concentration is reached by the administration of a small dose, or on a falling plasma curve after the administration of a large dose. Results obtained in two series of observations on one individual (L.R.) are recorded in the figure.