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Biomedical subjects

F H Epstein

Publications and source records attributed to F H Epstein.

At least 91 records · Page 5Linked to original sources
PubMed1992

Determinants of intrarenal oxygenation: factors in acute renal failure.

Oxygen tension within the renal parenchyma is influenced by two factors: metabolic demand and oxygen supply. There are three regions within the kidney in which there is an anatomical basis for limited oxygen availability. The first is the inner stripe where oxygen diffusion between arterial and venous vasa recta reduces PO2. The other two are the outer stripe and medullary rays which are fed by O2-poor blood from venous vasa recta. The balance between oxygen demand and supply is most critical in the inner stripe where the PO2 is most influenced by transport activity. In contrast, altering transport activities in the outer stripe will not change the prevalence of hypoxic S3 injury but will alter its type (i.e., cell fragmentation related to high GFR and increased workload versus cell edema related to low GFR and minimal workload). The effect of transport activity on medullary ray PO2 has not been well defined. Using sensitive oxygen microelectrodes, cortical PO2 (52 +/- 2 mm Hg) in the rat was found to be higher than medullary PO2 (21 +/- 2 mm Hg, p less than 0.001). How are these observations reflected in current models of acute renal failure? The ischemia-reflow model affects proximal tubules with a predilection for S3 (located within the outer stripe of medulla) after short-term ischemia. With hyperfiltration (induced by glycine or renal hypertrophy) and the pursuant increase in transport related O2 demand, hypoxic mTAL inner stripe injury becomes prominent. Renal parenchymal hypertrophy exaggerates injury in the contrast nephropathy model, in which mTAL inner stripe injury is a predominant feature and medullary PO2 is very low.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1991

Toxicity of adenine nucleotides in the isolated perfused kidney: selective destruction of the S2 segment of the proximal tubule.

In an attempt to ameliorate the morphological abnormalities and decreased renal function produced by hypoxia in the isolated perfused rat kidney, adenosine triphosphate (ATP) was added to the perfusate medium. No improvement was noted in the histological changes or renal function. Paradoxically, however, in oxygenated control kidneys, ATP (2.5-10 mM), caused a severe injury remarkably limited to the S2 segments of proximal tubule. This injury was more destructive than that observed with complete ischemia for the same period of time or with inhibitors of glycolysis, intermediary metabolism, or respiratory chain function. Tubular damage produced by ATP was paradoxically prevented by hypoxia and mitochondrial inhibition. The mechanism of this selective toxic injury to the proximal tubule remains unclear and may depend upon intact transport metabolism of the cell.

Adenosine Diphosphate↗
PubMed1991

Protective action of glycine in cisplatin nephrotoxicity.

Because glycine is cytoprotective for kidney cells in vitro, we investigated its possible action in vivo to protect rats against cisplatin nephrotoxicity, a well-established experimental model of renal tubular injury. Glycine was infused at a dose of 1 mmol per 100 g body weight per hour for 75 minutes, starting 15 minutes before cisplatin, 5 mg per kg, was injected intravenously. Plasma concentration of glycine rose to 3.5 mmol per liter at the time cisplatin was injected. These rats were compared with cisplatin-treated animals treated with L-alanine or with isotonic saline. After five days plasma creatinine of saline-treated rats given cisplatin had risen threefold to 2.6 +/- 1.5 mg per 100 ml (mean +/- SD), as creatinine clearance fell to 25% of baseline (0.14 +/- 0.05 ml/min/100 g). Morphological evaluation disclosed extensive damage involving all S3 segments in the outer medulla as well as the medullary rays of the cortex. In contrast, in rats treated with glycine, plasma creatinine rose only to 1.2 +/- 0.2 mg/100 ml and creatinine clearance was maintained at 75% of baseline (0.35 +/- 0.05 ml/min/100 g). Glycine also attenuated the weight loss, polyuria, increased fractional excretion of sodium and potassium, decreased urinary osmolality, and renal glycosuria observed in control, saline-treated rats after cisplatin, while substantially decreasing the percentage of S3 tubules with evident morphological injury. Renal platinum content was unaffected by glycine. The administration of L-alanine or the delayed infusion of glycine, starting one hour after cisplatin was given, did not prevent cisplatin toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Early renal medullary hypoxic injury from radiocontrast and indomethacin.

We evaluated the acute changes in cortical and outer medullary oxygen tension and the alterations in renal function and morphology within the first 90 minutes after the administration of indomethacin and iothalamate to anesthetized Sprague-Dawley rats. Both agents were found to produce marked and protracted outer medullary hypoxia averaging 12 +/- 4 and 9 +/- 2 mm Hg, respectively (mean +/- SE). Given together to salt depleted uninephrectomized rats they produced an early hypoxic injury localized selectively in the outer medulla. This lesion progressed from 3 +/- 1% of medullary thick ascending limbs (mTALs) at 15 minutes to 22 +/- 7% at 24 hours. Condensed "dark" cells were observed at 15 minutes, probably representing a type of early injury. Residual red cell mass, quantified in the outer medullary vasculature of perfusion-fixed kidneys and presumably reflecting stasis, was substantially increased in iothalamate treated rats. Red cell mass in the interbundle zone correlated with mTAL necrosis. Taken together, these results show an early period of medullary hypoxia, accompanied by a selective injury to mTALs in the central interbundle zone with apparent stasis. These findings contrast sharply with the ischemia-reflow pattern of renal damage and emphasize the important role of medullary hypoxia in the genesis of acute renal failure in this model.

Animals↗
PubMed1991

Effect of glycine on medullary thick ascending limb injury in perfused kidneys.

The addition of 2 mM glycine to the recirculating perfusate of isolated perfused rat kidneys almost completely prevented the severe morphological injury to tubular cells lining the medullary thick ascending limb (mTAL) that normally develops in this preparation. Glycine was similarly effective in reducing mTAL injury associated with hypoxic perfusion, indomethacin and amphotericin. Fractional reabsorption of sodium was increased with glycine, without any change in perfusate flow to the whole kidney and without consistent improvement in GFR. L-alanine demonstrated a similar though less pronounced cytoprotective action, but glutamine, cysteine, glutamate, cysteine plus glutamate, 1-serine and 4-aminoisobutyric acid all had little or no effect in preventing severe mTAL injury. The protective effect of glycine was unimpaired by the arginine analogue NG-monomethyl-l-arginine (L-NMMA), suggesting that the endothelial-derived relaxing factor, NO, was not involved. The action of glycine was not reduced by the addition of a substrate (benzoate) or a product (hippurate) of the glycine N-acyltransferase reaction. Glycine did not depress the respiration of dispersed mTALs prepared from rat kidneys. The cytoprotective effect of glycine in the mTAL of perfused kidneys, shared with l-alanine, appears to be relatively specific for these amino acids and probably unrelated to a diminution in cell work.

Amino Acids↗
PubMed1991

Influence of age and dose on the end-organ responses to atrial natriuretic peptide in humans.

To test the hypothesis that age differentially affects the natriuretic, hemodynamic, and humoral response to exogenous ANP, we studied seven young (Y, 20 to 39 years) and five old (O, 65 to 83 years) healthy, normotensive, nonobese men during infusion of synthetic human ANP1,28 at two different rates: 1) 0.05 microgram/kg/min (high dose) for 1 h and 2) 0.005 microgram/kg/min (low dose) for 1 h. Compared to young, the old had higher basal ANP levels (O = 142 +/- 41 v Y = 29 +/- 4 pmol/L, P less than .025), achieved higher plasma levels with low-dose infusion (O = 327 +/- 24 v Y = 155 +/- 37 pmol/L, P less than .001) and had a longer ANP half-life (O = 7.8 +/- 0.6 v Y = 4.3 +/- 0.6 min, P less than .001), suggesting decreased catabolism in the old compared to the young. Despite these age-related differences in ANP levels, there was no difference in urinary sodium or cyclic GMP excretion. After termination of the low-dose infusion, plasma ANP and urinary cGMP promptly returned to baseline levels. Despite this, a sustained natriuresis (2-fold above control) was observed for 3 h in both groups. Low-dose infusion was associated with sustained suppression of aldosterone with minimal hemodynamic changes. During high-dose infusions there was no difference in natriuresis or peak ANP levels between the two groups (O = 1299 +/- 93 v Y = 1140 +/- 54 pmol/L). In contrast to the low-dose infusion, the high-dose infusion produced a transient natriuresis lasting only for the duration of the infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Atrial natriuretic peptide suppresses osmostimulated vasopressin release in young and elderly humans.

Atrial natriuretic peptide (ANP) may suppress vasopressin release, but the dynamics of this interaction as well as the influence of age have not been defined. We studied six or seven young (19-40 yr old) and seven elderly volunteers (65-83 yr old) under two circumstances: 1) after infusion of 5% saline (0.04 ml.kg-1.min-1) for 2 h and 2) after the same infusion given with simultaneous synthetic human ANP (0.05 micrograms.kg-1.min-1). Hypertonic saline alone produced a progressive rise in plasma vasopressin with increasing serum sodium. During hypertonic saline alone, vasopressin levels began to rise at an increment in serum sodium of 1.67 +/- 0.35 mM in the young and 1.43 +/- 0.32 mM in the elderly and rose linearly with increasing serum sodium. When ANP was infused with hypertonic saline (with peak ANP levels of approximately 1,000 pM), vasopressin levels began to rise at an increment in serum sodium of 4.43 +/- 0.67 mM in the young and 4.57 +/- 0.43 mM in the elderly (P less than 0.01 vs. saline alone). Furthermore, the vasopressin response for any given serum sodium was significantly reduced in both young and elderly subjects, resulting in a rightward displacement of the curve relating vasopressin response to sodium concentration (P less than 0.001). In conclusion, ANP not only suppresses vasopressin but raises the threshold for release of vasopressin in response to osmotic stimulation in both young and elderly individuals. High circulating ANP levels may be responsible in part for the suppression of vasopressin levels and water diuresis seen during states of volume expansion.

Adult↗
PubMed1991

Role of nitric oxide in renal medullary oxygenation. Studies in isolated and intact rat kidneys.

We investigated the role of the endothelial-derived relaxing factor nitric oxide (NO) in the homeostasis of O2 supply to the renal medulla, a region normally operating on the verge of hypoxia. Sensitive Clark-type O2 microelectrodes were inserted into renal cortex and medulla of anesthetized rats. The inhibitor of NO formation, L-NG-monomethylarginine (LNMMA), while increasing blood pressure and reducing renal blood flow, decreased medullary pO2 from 23 +/- 3 mmHg to 12 +/- 3 (P less than 0.001), with no change in the cortex. These responses were promptly reversed by L-arginine, which bypasses the LNMMA blockade. In isolated rat kidneys, LNMMA reduced perfusion flow without altering glomerular filtration rate, and augmented deep medullary hypoxic injury to thick ascending limbs from 68 to 90% of the tubules (P less than 0.02). These changes were prevented by L-arginine. Nitroprusside had a protective effect upon thick limb injury. Finally, in a previously reported model of radiocontrast nephropathy (1988. J. Clin. Invest. 82:401), LNMMA increased the severity of renal failure (final plasma creatinine from 2.3 +/- 2 mg% to 3.4 +/- 3, P less than 0.005) and the proportion of damaged thick limbs (from 24 +/- 6% to 53 +/- 9, P less than 0.01). Nitrovasodilatation may participate in the balance of renal medullary oxygenation and play an important role in the prevention of medullary hypoxic injury.

Acute Kidney Injury↗
PubMed1990

Effect of myo-inositol on renal Na-K-ATPase in experimental diabetes.

The activity of Na-K-ATPase in the kidney is increased by experimental diabetes. Because the kidney is rich in myo-inositol and abnormal inositol metabolism has been implicated in early neural complications of diabetes, we studied the effect of myo-inositol supplementation on Na-K-ATPase activity in renal medullary and cortical homogenates of Sprague-Dawley rats made diabetic with streptozotocin. Myo-inositol (650 mg/kg) was administered by gavage daily for 1 and 2 weeks after induction of diabetes. Medullary Na-K-ATPase (mumol/mg protein/h) was increased at 1 week by approximately 60% in diabetic rats versus control (25.9 +/- 0.07 vs 16.3 +/- 0.7; P less than .01). This increase was completely prevented by myo-inositol supplementation, despite persistent hyperglycemia. At 2 weeks, similar results were seen; medullary Na-K-ATPase activity was increased by 50% in diabetic rats compared with control, and once again myo-inositol prevented this increase. Sorbinil, the aldose reductase inhibitor, was also administered by gavage (20 mg/kg) for 2 weeks and partially prevented the increase in medullary Na-K-ATPase activity (20.0 +/- 0.9; P less than .05). At both 7 and 14 days, Na-K-ATPase activity in the cortex of untreated diabetic rats was also significantly increased compared with nondiabetic control rats and the increase was prevented by myo-inositol or Sorbinil. Myo-inositol or Sorbinil did not reduce Na-K-ATPase activity of nondiabetic control rats, nor did they prevent the increase in medullary Na-K-ATPase in compensatory hypertrophy following uninephrectomy. Myo-inositol content of outer medulla was about five to six times that of cortex, but was unaltered by the diabetic state.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

The renal concentrating defect associated with potassium depletion is independent of prostaglandin E2.

Prostaglandin E2 (PGE2) impairs the hydrosmotic effect of vasopressin in toad bladder and mammalian kidney. Because some studies in animals have suggested that potassium depletion enhances renal PGE2 production, the present study examined whether the renal concentrating defect of potassium depletion in humans is mediated by PGE2. Five normal volunteers were studied before and after moderate potassium depletion achieved by 10 days of dietary potassium restriction and administration of a polystyrene sulfonate potassium exchange resin (Kayexalate). Maximal urinary osmolality (Umax) decreased from 1,094 +/- 58 (mean +/- SEM) to 820 +/- 26 mmol/kg (mOsm/kg) (P less than 0.01) following potassium depletion, but urinary PGE2 excretion did not change (496 +/- 145 and 435 +/- 186 ng/d, respectively). Indomethacin suppressed PGE2 excretion significantly, but failed to increase Umax in either the normal or the potassium-depleted state (1,094 +/- 34 and 825 +/- 56 mmol/kg, respectively). It is concluded that the renal concentrating defect produced by moderate potassium restriction in humans is not mediated by PGE2.

Adult↗
PubMed1990

Somatostatin mediates bombesin inhibition of chloride secretion by rectal gland.

The function of bombesin-like peptide, a neurotransmitter present in nerve fibers of elasmobranch rectal glands, is unknown. Since the principal activity of the rectal gland is to secrete chloride, the effects of bombesin on chloride secretion and the role of somatostatin in this response was studied. Bombesin failed to stimulate secretion in rectal glands perfused in the basal state. When added to glands stimulated by a constant infusion of vasoactive intestinal peptide (VIP), bombesin (8 x 10(-7) M) reversibly inhibited chloride secretion by 56 +/- 9.7% and at the same time evoked a 10-fold increase in the liberation of somatostatin into the venous effluent. Inactivation of somatostatin by the addition of cysteamine partially suppressed the inhibitory effect of bombesin on glandular secretion. The effect of bombesin to reduce chloride secretion was completely prevented by the calcium channel blocker nifedipine, which inhibits neurotransmitter release. These results suggest that bombesin inhibits the effect of VIP to stimulate chloride secretion by releasing somatostatin from neurosecretory nerve terminals within the rectal gland.

Animals↗
PubMed1990

Prostaglandin E2 inhibits oxygen consumption in rabbit medullary thick ascending limb.

The effect of prostaglandin (PG) E2 on transport-dependent oxygen consumption (QO2) of rabbit medullary thick ascending limb (MTAL) cells was studied. Exogenous PGE2, at a concentration of 30 microM, inhibited ouabain-sensitive QO2 by 70%. Addition of either ouabain or bumetanide, after PGE2, further depressed QO2, whereas PGE2 had no effect when added after these transport inhibitors. There was no significant inhibition of QO2 by PGE2 in the absence of either Na or Cl. The QO2 of amphotericin-treated cells was inhibited by the addition of PGE2. Therefore the inhibitory effect of PGE2 was on the transport-dependent moiety of QO2 and was independent of Na entry. Other prostanoids had no significant effect on MTAL QO2. Suspensions of isolated MTAL cells accumulated PGE2 at about one-fifth the rate of outer medullary collecting duct cells. Finally, PGE2 caused an increase in intracellular adenosine 3',5'-cyclic monophosphate levels by approximately 100%. Although the precise mechanism of action is unclear, PGE2, which is synthesized by several cell types in the renal medulla, exerts an inhibitory effect on transport in rabbit MTAL.

Animals↗
PubMed1990

The influence of gender, age, and the menstrual cycle on plasma atrial natriuretic peptide.

To examine the influence of gender, age, and the menstrual cycle on atrial natriuretic peptide (ANP) levels, we measured daily levels of ANP, aldosterone, estrogen, and progesterone in 13 young women (ages 25-35 yr) during the luteal phase of the menstrual cycle and daily ANP and aldosterone levels in 9 young men (ages 25-43 yr) for 10 consecutive days. In addition, fasting plasma ANP levels were assayed in 12 elderly male (ages 62-86 yr) and 9 elderly female subjects (ages 64-80 yr) on at least two separate occasions. The average daily ANP levels in the young women were much higher than those in the men (68.1 +/- 5.5 vs. 39.8 +/- 3.4 pmol/L; P less than 0.001), although no cyclical changes in ANP levels were observed. ANP levels were 94.0 +/- 17.9 pmol/L in elderly men and 78.3 +/- 19.4 pmol/L in elderly women. Aldosterone levels were higher in women than men during the luteal phase of the menstrual cycle (1154 +/- 125 vs 488 +/- 42 pmol/L; P less than 0.001), but not during the periovulatory period (580 +/- 103 pmol/L) or during menses (563 +/- 61 pmol/L). In conclusion, ANP levels in young women average approximately twice those in young men, but do not fluctuate with the cyclical changes in estrogen, progesterone, and aldosterone seen during the menstrual cycle. However, ANP levels in postmenopausal women are not greater than those in age-matched elderly men. Thus, gender appears to affect the secretion or metabolism of ANP during the premenopausal years of life.

Adult↗
PubMed1990

Influence of endogenous prostaglandins on mTAL injury.

We altered renal prostaglandin production by isolated rat kidneys in several ways to see if this would influence the susceptibility of cells lining the medullary thick ascending limb to injury. Rats were fed a diet containing either safflower oil (high in linoleic acid) or fish oil (low in arachidonate precursors) as a source of fat. After 90 min of perfusion, the kidneys of rats fed safflower oil showed only 32.7 +/- 6.7% of medullary thick ascending limb cells near the inner medulla with severe damage, whereas the same zone in perfused kidneys of rats fed fish oil showed 96.6 +/- 1.3% severely damaged cells (P less than 0.01). The protection afforded by safflower oil was accompanied by a doubling of urinary excretion of PGE2 and 6-keto-PGF1 alpha, and was eliminated by indomethacin, which suppressed prostaglandin synthesis. Perfusion with bradykinin also greatly increased prostaglandin excretion and reduced severe medullary thick ascending limb damage in the deepest zone of the outer medulla from 51.3 +/- 6.6% in controls to 28.5 +/- 5.9% (P less than 0.02). The protection provided by bradykinin was also completely reversed by indomethacin. The results suggest that endogenous prostaglandins serve a protective function against hypoxic injury for cells of the medullary thick ascending limb.

Animals↗
PubMed1990

[Historical development of the cholesterol-atherosclerosis concept].

The development of the cholesterol hypothesis to the cholesterol theory, as related to atherogenesis, is followed in chronological sequence. The major milestones in terms of chemical pathology of the lesions, clinical observations on serum cholesterol levels in patients with coronary heart disease, lipoprotein research, epidemiological investigations and prevention of diseases due to atherosclerosis are described within three time periods: from the 19th till the beginning of the 20th century, the years between the two World Wars and the last 40 years. A total picture emerges which assigns to cholesterol and its lipoprotein carriers a key role in the origins and progression of atherosclerosis. These causal relationships have opened the way to the prevention of the disease, supported by intervention studies aimed at reduction of serum cholesterol levels.

Arteriosclerosis↗
PubMed1990

[From theory to practice: on the history of cardiovascular epidemiology].

The road of research from analytical epidemiology which led to the description of coronary heart disease risk factors, to experimental epidemiology (intervention studies) which brought evidence for the effectiveness of prevention through risk factor reduction, is delineated in historical sequence. This knowledge serves as the basis for the two strategies of preventive cardiology: the individual (high risk) and the population strategy; the first is mainly in the domain of the practicing physician while the second requires his support within the framework of health planning in the community.

Clinical Trials as Topic↗