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The effects of age and chronic caffeine use (approximately 300 mg/day) on the cardiovascular and humoral responses to 250 mg of oral caffeine (the equivalent of 2 to 3 cups of coffee) were examined. Older subjects had greater increases in blood pressure than younger subjects (p less than 0.03), and caffeine nonusers had greater blood pressure increases than caffeine users, regardless of age (p less than 0.05). Caffeine increased the product of systolic blood pressure and heart rate (an estimate of myocardial oxygen demand) in older caffeine nonusers, but this effect was absent in older caffeine users (p less than 0.01). Cardiovascular effects of caffeine could not be related temporally to changes in plasma epinephrine, which were greater in caffeine nonusers and younger subjects, or to plasma norepinephrine, renin activity or vasopressin, which did not change. Thus, age accentuates and moderate prior caffeine use attenuates the cardiovascular effects of oral caffeine; these effects are not mediated solely through the sympathoadrenal system.

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We studied 23 patients with renal functional deterioration after intravenous pyelography; 16 were nondiabetic. Nondiabetic patients at risk are often elderly and have preexisting renal disease. The course of acute renal failure is fairly characteristic; most patient recover, but some do not. Estimates suggest that the syndrome is not uncommon in susceptible nondiabetic subjects. Pyelography cannot be considered absolutely safe for this group, and alternative diagnostic procedures or caution with contrast dosage and patient preparation may be wise.

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The use of potent diuretics in acute renal failure remains controversial. Both beneficial and detrimental effects have been reported. In the present study, the effects of both low and high doses of furosemide administered in the developmental and established stages of mercuric chloride-induced acute renal failure were evaluated. Both low and high doses of furosemide produced a significant diuresis when given early in the course of experimental acute renal failure. Despite this diuresis, furosemide did not modify the development of the acute renal failure. Continued administration of a low dose of furosemide had no effect on renal function; however, prolonged administration of high doses of furosemide resulted in significantly lower creatinine clearances 48 hr after induction of acute renal failure. This detrimental effect was due to sodium depletion by the diuretic since it was prevented by continuous replacement of urinary sodium losses. In the absence of sodium depletion, high doses of furosemide produced a significant diuresis, both in the developmental and established phases of acute renal failure, but it had no effect on the degree of renal functional impairment.

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This study was designed to examine the pathogenesis of the excretory defect produced by bilateral ureteral obstruction in the rat. After release of obstruction of 24 hr duration glomerular filtration rate was reduced to 20% of normal. Free flow proximal tubular pressure was normal, excluding residual obstruction as a cause of depressed filtration, and indicating that an intrarenal hemodynamic abnormality was primarily responsible for the excretory defect. Total renal blood flow and cortical distribution of flow were normal. Clearance and micropuncture studies indicated the presence of marked heterogeneity of nephron function with residual excretory function residing primarily in vasodilated nephrons in which decreased postglomerular arteriolar resistance effected a reduction in glomerular filtration pressure. Heterogeneity of nephron function was evidenced by a wide scatter of values for single nephron filtration rate and from direct intratubular injection of dye which revealed that at least 28% of surface nephrons were either nonfiltering or had filtration rates too low to measure. The observed decrease in Hippuran extraction and increased ratio of Hippuran to inulin clearance ratio is characteristic of the vasodilated kidney. Further evidence of the vasodilated nature of residual functioning nephrons was demonstrated by the failure of intrarenal papaverine infusion to increase filtration rate in this lesion. The hemodynamic defect produced by bilateral obstruction is contrasted with that seen after release of unilateral ureteral ligation in which depression of filtration rate appears to result primarily from preglomerular vasoconstriction. This difference raises the possibility that a vasodilating substance accumulates during total suppression of renal excretory function. Diuresis and natriuresis were constant features of the postobstructive lesion. The present data support previously published studies which localize the defect in sodium transport to the distal nephron and indicate that this defect is a consequence of increased intraluminal pressure and tubular dilatation induced by bilateral ureteral ligation.

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The role of renal ischemia in the pathogenesis of the renal failure produced by hemoglobin injection in the rat is evaluated. The data indicate that in the initial hours of this lesion renal blood flow is consistently reduced and that during its subsequent evolution blood flow rises towards normal levels, in some animals, while inulin clearance remains severely depressed. Volume expansion during the initial stage of the lesion may effect a rise in renal blood flow to normal levels with little effect on inulin clearance rate, further demonstrating the relative lack of dependence of the excretory defect on concomitant renal ischemia. These observations indicate that renal ischemia is probably a necessary factor in the initial production of the lesion; that it persists during its initial phase, up to 24 hours in most rats; and that, although it may contribute to the observed excretory defect, it is not the predominant etiologic factor. Other functional data indicate that renal blood is perfusing nephrons in which the excretory capacity is impaired but which retain the ability to extract Diodrast from the peritubular capillaries. This functional pattern indicates an excretory defect secondary either to intratubular obstruction or to a primary reduction of glomerular filtration rate of undefined etiology. The morphological findings of numerous dense intratubular hemoglobin casts and, in the well-perfused kidney, dilatation of proximal tubules, are suggestive of an obstructive lesion. However, the data do not conclusively distinguish between these two pathogenetic mechanisms.

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A method is presented for the production of a reproducible and reversible renal lesion in the rat by the intravenous injection of a relatively small amount of homologous hemoglobin (40 mg/100 g body weight). Production of the lesion is dependent on prior water deprivation and its severity is related to the degree of dehydration. Ether anesthesia, at the time of hemoglobin injection, predisposes to a severe and reproducible functional defect in the dehydrated rat. In contrast, injection of hemoglobin during pentobarbital anesthesia results in a significant lesion only sporadically. The functional evolution of the lesion has been characterized by inulin clearance measurements. Functional impairment occurs abruptly, within 1 hr after hemoglobin injection, and persists unchanged over the ensuing several hours. Some increase in inulin clearance rate is usually observed at 24 hr after injection, but severe functional impairment persists. Between 24 and 72 hr, a considerable increase in inulin clearance rate occurs, so that only moderate restriction of excretory function is present at the latter time. A further moderate increase in inulin clearance rate is apparent at 7 days after hemoglobin injection, but some reduction in function. persisted in all rats studied at this time. Hemoglobinuria is slight or inapparent in animals manifesting the most marked depression of excretory function, indicating that a severe renal lesion may exist in the absence of visible urinary pigment. Hemoglobinemia is evanescent at the dosage used in this study. These observations suggest that clinical acute renal failure secondary to hemoglobinemia may readily go unrecognized and that this may be a more frequent association than is now appreciated.

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Histological studies have been performed on experimental acute renal failure induced by intravenous injection of hemoglobin in rats. These have been correlated with alterations in renal excretory function, assessed by the measurement of inulin clearance, at various stages of the lesion. The most prominent morphological changes during the first 24 hr after hemoglobin injection, when inulin clearance is most markedly suppressed, are: the presence of hemoglobin within the lumen of small intrarenal vessels, particularly the vasa recta; hemoglobin cast formation involving predominantly the thick ascending limbs of the loops of Henle; and evidence of injury of the epithelium of the proximal tubules and thick ascending limbs. Notably absent during this stage of the lesion are marked tubular dilatation, interstitial edema, and cast formation in the distal collecting ducts. The considerable recovery of function which occurs at 72 hr is accompanied by a marked reduction in involvement of the vasa recta. Standard sections and microdissection reveal many markedly dilated proximal tubules at this stage of the lesion, suggesting obstruction of filtering nephrons. These data have led to a tentative hypothesis regarding the pathogenesis of renal failure in this experimental lesion. It is suggested that renal ischemia and failure of glomerular filtration are the primary factors responsible for the early and severe impairment of renal function, and that these are related to intravascular aggregation of hemoglobin pigment. As this defect recedes, tubular obstruction by hemoglobin casts prevents restitution of excretory function in a variable fraction of the nephrons. The latter accounts for the relatively prolonged, moderate reduction in inulin clearance associated with the late stages of this lesion. These hypotheses form the basis for a continuing study of this renal lesion.

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