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Biomedical subjects

F H Epstein

Publications and source records attributed to F H Epstein.

At least 73 records · Page 4Linked to original sources
PubMed1993

Role of endothelin and prostaglandins in radiocontrast-induced renal artery constriction.

Infusion of radiocontrast agents in vivo results in renal artery constriction and subsequent renal hypoperfusion. To examine the role of endothelin and of prostaglandins in radiocontrast-mediated renal vasoconstriction, rats were treated with an endothelin receptor antagonist, CP170687, and with indomethacin. The dose of CP170687 utilized was sufficient to reverse endothelin1-mediated constriction of isolated aortic rings and of renal blood flow in intact rats. In normal rats there was a transient drop in renal blood flow to 80% of baseline following sodium iothalamate injection, an effect which was not prevented by CP170687. In rats first given indomethacin, the drop in renal blood flow was more pronounced (to 63% of baseline) and was sustained. In this instance, CP170687 fully reversed the sustained decrease of renal perfusion. CP170687 also diminished the rise in systemic blood pressure seen following iothalamate injection. In the absence of indomethacin, iothalamate increased urinary prostaglandin E2 to a maximum of sevenfold above baseline values. In summary, injection of radiocontrast results in an immediate decrease in renal blood flow that is counteracted by an increase in renal prostaglandin formation. When prostaglandin synthesis is inhibited, prolonged endothelin-mediated renal vasoconstriction is observed that is reversed by an endothelin receptor antagonist.

Animals↗
PubMed1993

Effects of ioversol versus iothalamate on endothelin release and radiocontrast nephropathy.

RATIONALE AND OBJECTIVES: Certain radiocontrast agents, including iothalamate, iohexol, and ioxaglate, release the renal vasoconstrictor peptide endothelin from vascular endothelium in a way that might contribute to radiocontrast nephropathy. The effects of the nonionic, low osmolar agent, ioversol, on endothelin release and renal function are investigated. METHODS: Effects of ioversol were compared with equi-iodine doses of iothalamate when applied to cultured bovine aortic endothelial cells or injected into normal rats and rats preconditioned by uninephrectomy, salt depletion, and indomethacin (USIC) to develop radiocontrast nephropathy. RESULTS: In comparison with iothalamate, ioversol had a greatly reduced propensity to stimulate the release of endothelin, from cultured cells and when injected into anesthetized rats. Ioversol produced less renal vasoconstriction than did iothalamate, in control and in USIC rats, and the development of radiocontrast nephropathy, assessed by creatinine clearance and morphologic damage to the renal medulla, was largely avoided. CONCLUSIONS: These results strengthen the hypothesis that endothelin release induced by radiocontrast agents is correlated with their renal toxicity and therefore, may play a role in radiocontrast nephropathy.

Animals↗
PubMed1993

Cellular mechanisms of acute ischemic injury in the kidney.

Hypoxic injury to tubular cells represents an early event in acute renal failure. Although important advances have been made in the understanding of hypoxic injury at the cellular level (e.g. loss of cell polarity, production of free radicals, calcium entry, and the activation of genes for protection or regeneration), the basic mechanisms responsible for organ failure remain elusive. The renal medulla, working on the brink of anoxia and being the site of concentration for many toxins, may be an important target for the synergistic events of hypoperfusion and nephrotoxic exposure that often precede human acute renal failure.

Acute Kidney Injury↗
PubMed1993

Neuropeptide Y inhibits chloride secretion in the shark rectal gland.

We studied the effects of the 36-amino acid peptide, neuropeptide Y (NPY), on salt secretion by the rectal gland of Squalus acanthias. We used three preparations: whole isolated perfused glands, freshly prepared separated rectal gland tubules, and confluent monolayers of cultured rectal gland cells. In perfused glands NPY inhibited secretion stimulated by vasoactive intestinal peptide (VIP), forskolin, or adenosine 3',5'-cyclic monophosphate (cAMP) and theophylline. Maximal inhibition of 63 +/- 3.4% was seen at 3 x 10(-8) M NPY, with half-maximal effect at 3 x 10(-9) M. NPY did not inhibit the basal activity of rectal gland adenylate cyclase or that stimulated by VIP. The inhibitory action of NPY was not prevented by procaine, nifedipine, or diltiazem, suggesting that it was not secondary to the release of somatostatin or other unknown neurotransmitters from rectal gland nerves. In confirmation, somatostatin was not detected in the venous effluent after administration of NPY. NPY also inhibited transport-related oxygen consumption in separated rectal gland tubules and inhibited short-circuit current generated by confluent monolayers of primary cultures of rectal gland cells. The results indicate that NPY inhibits chloride secretion by a direct action on cells of the shark rectal gland at a site distal to the generation of cAMP.

Adenylyl Cyclases↗
PubMed1993

Chronic amphotericin nephropathy: morphometric, electron microscopic, and functional studies.

The two major hypotheses for the pathogenesis of amphotericin nephrotoxicity are direct interaction with epithelial cell membranes and vasoconstriction. Studies indicating the special vulnerability of the medullary ray and medulla to hypoxia led to a reexamination of amphotericin nephrotoxicity. Twenty-four rats were divided into four groups: amphotericin injection (5 mg/kg daily for 3 wk), amphotericin plus salt depletion, vehicle, and salt depletion and vehicle. The amphotericin group had polyuria (P < 0.01) but normal serum creatinine. In contrast, amphotericin plus salt depletion rats exhibited renal failure (creatinine of 1.49 +/- 0.05 versus amphotericin alone 0.98 +/- 0.01; P < 0.01). Semiquantitative histologic analysis of cortical and medullary injury correlated with functional impairment. Cortical changes in the amphotericin group were largely restricted to the medullary ray, where focal rupture and calcification of thick ascending limbs were noted. The S2/S3 tubules in the medullary rays showed focally diminished cell complexity with histiocytic/lymphocytic infiltration. However, calcification was also seen in the area of the macula densa. Morphometry revealed that the thick ascending limbs in the medulla were hypertrophied (1,420 +/- 63 versus 1,195 +/- 48 microns 2 for vehicle; P < 0.05). In contrast, in the amphotericin and salt depletion group, the changes in the medullary ray extended to the labyrinth and the thick ascending limbs in the inner stripe showed atrophic changes (772 +/- 23 microns 2; P < 0.01 versus vehicle). Thus, changes as a result of amphotericin toxicity take place both in areas known to be most vulnerable to hypoxia (medullary ray and medulla), and in areas rich in oxygen (adjacent to glomerulus). Salt depletion potentiates the cortical changes and converts medullary hypertrophy to atrophy. These findings support a dual pathogenesis for amphotericin nephropathy (direct toxicity and vasoconstriction).

Amphotericin B↗
PubMed1993

Strategies for primary coronary heart disease prevention.

With increasing knowledge of coronary heart disease (CHD) epidemiology, it has become apparent that preventive treatment of high-risk individuals--the high-risk strategy--will reduce individual risk but is insufficient by itself to reduce the burden of CHD in the population as a whole because more than half of the future victims of CHD have risk factor levels below the high range, leaving these persons unprotected. Since the relationship between risk factors and clinical CHD risk is continuous in most instances, without a sharp dividing line between high and low risk, the aim of optimal preventive action must be to shift the entire risk factor distribution curves to the left, in order to reduce the number of persons in the upper end of the distribution on the right. The strategy designed to effect this shift is the community strategy which requires that the whole population adopts preventive measures, i.e. makes changes in lifestyles, especially as regards diet, smoking habits, daily exercise and patterns of stress which favour unhealthy habits or may be harmful in themselves. The two strategies are not alternatives but complementary and, for optimal effectiveness, must be carried out simultaneously in the community. It can be shown that the combined strategy is more effective than either strategy alone. Each of the strategies has on comparison its own particular strengths, adding up to create a community climate favourable for prevention. The practicing physician is primarily concerned with the high-risk strategy but also plays an essential role in providing active support for the community strategy through giving preventive advice on health-promoting living habits to all of his patients and their families.

Coronary Disease↗
PubMed1992

Shaping the signal response during the approach to steady state in three-dimensional magnetization-prepared rapid gradient-echo imaging using variable flip angles.

A theoretical algorithm for shaping the signal response during the approach to steady state in three-dimensional magnetization-prepared rapid gradient-echo (3D MP-RAGE) pulse sequences has been developed and implemented. This algorithm derives the flip angle series required to produce specifically chosen time evolutions of the signal intensities during the data acquisition segment of 3D MP-RAGE sequences. Theoretical predictions for the cases of unshaped, uniform, and mono-exponential decay signal responses were quantitatively validated with a doped-water phantom on a 1.5-T whole-body imager and in all cases there was excellent agreement between the theoretical and experimental values. The effects of RF inhomogeneities and eddy currents on the signal response shaping were also investigated. To demonstrate the potential utility of the technique, the signal response shaping algorithm was applied to a T1-weighted 3D MP-RAGE sequence to derive the acquisition flip angle series which theoretically yields the maximum white matter/gray matter signal difference (WGSD) consistent with the chosen response shape. Images obtained from a healthy volunteer using this variable flip angle sequence were compared with 3D RF-spoiled steady-state gradient-echo images obtained in the same total imaging time. The 3D MP-RAGE images demonstrated a 41% increase in the WGSD-to-noise ratio. These initial very promising results indicate that with further refinement to eliminate some intensity artifacts, the variable flip angle 3D MP-RAGE technique may, with respect to certain image properties, provide considerable improvements over currently available 3D gradient-echo imaging techniques.

Algorithms↗
PubMed1992

Plasma endothelin levels in preeclampsia: elevation and correlation with uric acid levels and renal impairment.

OBJECTIVE: The purpose of this study was to determine if endothelin levels are elevated in women with preeclampsia and if these levels correlated with other laboratory features of disease severity. STUDY DESIGN: Parameters were compared in four groups of women volunteers by means of analysis of variance: (1) 16 women with preeclamptic pregnancies, (2) 11 pregnant women without preeclampsia, of similar lengths of gestation, (3) six otherwise normal women with pregnancies at term or beyond (greater than 38 weeks), and (4) 22 normotensive young women. RESULTS: Endothelin levels were elevated in women with preeclampsia as compared with those of gestation-matched pregnant and nonpregnant controls (22.6 +/- 2.0 vs 12.0 +/- 1.0 vs 10.4 +/- 1.3 pmol/L, p less than 0.005, preeclampsia vs controls) and also were increased in late gestation (17.7 +/- 2.0 pmol/L). Endothelin correlated positively with plasma levels of uric acid (r = 0.698, p less than 0.005) and inversely with creatinine clearance (r = -0.659, p less than 0.05). CONCLUSION: Circulating endothelin levels are elevated in women with preeclampsia and correlate closely with serum uric acid levels and measures of renal dysfunction. These observations suggest that endothelin may contribute to renal vasoconstriction in preeclampsia.

Adult↗
PubMed1992

Low serum cholesterol, cancer and other noncardiovascular disorders.

There has been much concern and discussion whether reduction of serum cholesterol by diet or drugs, while preventing coronary heart disease, might cause an increase in the risk of dying from noncardiovascular disorders, in particular cancer. A review of the evidence from ecological, cross-cultural comparisons, prospective epidemiological cohort studies and intervention trials provides no indication for a cause-and-effect association between low serum cholesterol or serum cholesterol lowering and the risk of cancer, except possibly at very low levels. An inverse relationship between noncardiovascular-noncancer mortality and serum cholesterol level does exist but the link is unlikely to be causal; for better understanding, there is a need for studying the biological, lifestyle and social correlates of this association. Continuing observations should pay attention to the accuracy of information on specific causes of noncardiovascular deaths, especially mortality not due to disease. Further research needs to include investigations into the determinants of low serum cholesterol levels and their possible influence on biological functions. It is concluded that the current recommendations for coronary heart disease prevention, aimed at lowering elevated serum cholesterol levels in individuals (the 'high-risk strategy') and in populations at high risk (the 'population strategy') require no basic modification in the light of present knowledge on the relationships between cholesterol and noncardiovascular disease mortality.

Cholesterol↗
PubMed1992

The effect of mercury on chloride secretion in the shark (Squalus acanthias) rectal gland.

1. Mercuric chloride inhibited chloride secretion in a dose dependent way in isolated perfused rectal glands. The effect was readily apparent at a concentration of 10(-6) M and profound and irreversible at 10(-4) M. 2. The dithiol dithiothreitol (DTT) 10(-2) M completely prevented the effect of 10(-6) M mercuric chloride, reduced that at 10(-5) M and 10(-4) M, and made the inhibition at the latter concentration reversible. 3. Two organic mercurials, mersalyl and meralluride, that are effective diuretics in the mammalian kidney, and p-chloromercuribenzoyl sulfonic acid (PCMBS), that has no diuretic activity, had no effect on chloride secretion by the rectal gland. 4. The effect of mersalyl was not modified by lowering the pH of the solution perfusing the glands. 5. These results indicate that inorganic mercury and organic mercurials do not share the same mechanism of action. 6. The absence of an effect of organic mercurials on chloride transport in the rectal gland suggests that its effect on another chloride transporting epithelia, the thick ascending limb of the loop of Henle, is not mediated by inhibition of the chloride cotransporter or Na+, K(+)-ATPase, common to both epithelia.

4-Chloromercuribenzenesulfonate↗
PubMed1992

Effect of glycine and hypertrophy on renal outer medullary hypoxic injury in ischemia reflow and contrast nephropathy.

Glycine preserves tubular cell integrity under hypoxic and toxic conditions in vitro. It also ameliorates cisplatin nephrotoxicity in vivo. We studied the effect of glycine on tubular necrosis from ischemia reflow and on inner stripe injury in an animal model of radiocontrast nephropathy. In all experiments, glycine (75 mg/100 g/h) increased tubular damage in the inner stripe. In the model of radiocontrast nephropathy, the percentage of medullary thick ascending limb (mTAL) necrosis at 24 hours increased from 22% +/- 6% to 41% +/- 9% or 55% +/- 7% with glycine infusion of 75 or 135 minutes, respectively (mean +/- SE, P less than 0.05, analysis of variance [ANOVA]). Renal function was not significantly affected. In rat kidneys subjected to ischemia reflow, mTAL injury following glycine increased from 1% +/- 0% to 12% +/- 6% (P less than 0.05) and from 8% +/- 5% to 49% +/- 8% (P less than 0.01) 24 hours after 30 minutes and 45 minutes ischemia, respectively. Tubular injury in the inner stripe was maximal in the deep interbundle zone, typical of hypoxic, rather than reperfusion, injury. Prior uninephrectomy increased inner stripe damage, but protected the proximal tubules. Both uninephrectomy and glycine infusion were found to contribute to mTAL necrosis. The infusion of glycine for 1 hour in intact rats increased renal blood flow by 44% and tripled urine volume (P less than 0.01). A parallel increase in glomerular filtration rate GFR; by 22% over 90 minutes) fell short of statistical significance.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Mechanism of glycine protection in hypoxic injury: analogies with glycine receptor.

Addition of glycine to the recirculating perfusate of isolated perfused rat kidneys protects against hypoxic injury to the medullary thick ascending limb and slows functional deterioration in the course of perfusion. This effect is dependent on dose; the earliest significant protection is seen at 0.25 mM, and the protective effects increase as glycine concentration is increased to 2 mM, the highest level tested. Two specific agonists of the strychnine-insensitive (NMDA) glycine receptor in neural membranes, 1-aminocyclopropane carboxylic acid (ACC) and d-serine, also exerted a cytoprotective effect at a concentration of 2 mM. On the other hand, 1-serine and taurine, ineffective agonists of the NMDA-glycine receptor but effective agonists of the strychnine-sensitive glycine receptor, had no protective effect in this system. Two antagonists to glycine at its binding site on the N-methyl-D-Aspartate (NMDA) receptor, 7-chlorokynurenic acid (2 mM) and indole-2-carboxylic acid (12.5 mM), did not reverse the cytoprotective action of 0.25 mM glycine. The data are consistent with a ligand-acceptor type of interaction to account for cytoprotection. The configuration of the glycine acceptor may resemble, but is not identical with, that of certain glycine receptors in the nervous system.

Animals↗
PubMed1992

In-vivo and in-vitro studies on the effect of amphotericin B on endothelin release.

Since amphotericin B nephrotoxicity is mediated, in part by hypoxic tubular injury, the role of endothelin in the renal vasoconstriction, characteristic of amphotericin toxicity has been studied. Intact and salt depleted rats were infused with amphotericin B (20 micrograms/kg per min) or 5% dextrose over 20 min. Plasma endothelin levels determined at the conclusion of the infusion period, did not differ between the experimental groups, despite a marked reduction in renal blood flow noted in rats infused with amphotericin B. Amphotericin B (10(-5)-10(-7) M) did not stimulate endothelin release from cultured bovine aortic endothelial cells. However, in a model of chronic amphotericin nephrotoxicity produced by repeated daily intraperitoneal injections of amphotericin B (5 mg/kg) to salt depleted rats, renal failure was associated with elevated plasma endothelin levels (29.3 +/- 4.4 fmol/mL, vs 10.8 +/- 1.2 fmol/mL in salt depleted controls, P less than 0.01). We conclude that while plasma endothelin may be increased in chronic amphotericin B nephropathy, this peptide does not mediate the acute renal vasoconstriction associated with the infusion of this drug.

Amphotericin B↗
PubMed1992

Altered dopaminergic responses in hypertension.

Biogenic amine metabolism may be altered in hypertension and thus contribute to its pathophysiology. This report describes an abnormality in dopamine excretion in hypertensive subjects in the postabsorptive state that persists despite an increase in dietary precursors for dopamine supplied by a protein meal. We studied seven normotensive and six nonmedicated hypertensive men after two different meals: 60 g protein and a noncaloric electrolyte-equivalent broth. Overall mean sodium excretion was 56% higher in the hypertensive group throughout both meal studies (p less than 0.01), implying higher chronic dietary sodium intake. Despite this, overall urinary excretion of dopamine tended to be lower in hypertensive than in normotensive subjects (p = 0.06). Hypertensive also differed from normotensive subjects in their response to protein feeding. In the normotensive subjects there was a 23% increase in urinary dopamine excretion (p less than 0.05), which was not seen after the noncaloric meal. In the hypertensive subjects, there was no change in urinary dopamine after the protein meal. In the normotensive subjects there was a 74% increase in sodium excretion (p less than 0.01) after the protein meal, but no significant change was seen in the hypertensive subjects. There were no differences in baseline renal plasma flow or glomerular filtration rate between the groups and no statistically significant differences between the groups in their renal hemodynamic responses to the meals. In summary, hypertensive subjects have less renal dopamine production for the amount of sodium ingested and a decreased renal dopamine production in response to a protein load as compared with normotensive subjects, consistent with a renal defect in conversion of DOPA to dopamine.

Aged↗
PubMed1992

Effect of atrial natriuretic peptide on potassium-stimulated aldosterone secretion: potential relevance to hypoaldosteronism in man.

Atrial natriuretic peptide (ANP) has been shown to suppress aldosterone secretion under certain circumstances, although the physiological significance of this is uncertain. We wondered if ANP would suppress potassium-stimulated aldosterone secretion in man and, if so, whether we might find high circulating levels of ANP in patients with the syndrome of acquired hypoaldosteronism. We studied seven healthy young subjects under two conditions: 1) infusion of KCl (0.5 mmol/kg) over 45 min, and 2) KCl infused with ANP (0.01 microgram/kg.min) for 60 min. We also evaluated ANP levels in eight elderly subjects with the syndrome of acquired hypoaldosteronism, as defined by hyperkalemia (mean serum K+, 5.3 +/- 0.1 mmol/L) associated with inappropriately low aldosterone levels (216 +/- 50 pmol/L). In the normal subjects, ANP almost completely suppressed the aldosterone response to KCl infusion (P less than 0.001, by analysis of variance) despite a similar rise in the serum potassium level with KCl alone (0.70 +/- 0.07 mmol/L) and KCl plus ANP (0.75 +/- 0.09 mmol/L). PRA fell slightly during KCl plus ANP treatment, but did not change during the infusion of KCl alone. ANP levels were approximately 800 pmol/L during the ANP infusion studies. Endogenous ANP levels in the hyperkalemic patients with hypoaldosteronism were markedly elevated at 1186 +/- 340 pmol/L (compared to 93 +/- 10 pmol/L in healthy elderly controls), a level that would be capable of suppressing the potassium-mediated aldosterone response. Exogenous infusion of ANP suppressed the aldosterone response to hyperkalemia, and ANP levels were found to be markedly elevated in a group of patients with hyperkalemia and hypoaldosteronism. We suggest that ANP may contribute to clinically significant hypoaldosteronism and hyperkalemia in the syndrome of acquired hypoaldosteronism.

Adult↗
PubMed1992

cAMP activates the sodium pump in cultured cells of the elasmobranch rectal gland.

The inorganic ion content of rectal gland cells cultured from Squalus acanthias was studied by electron probe analysis in order to determine the effect of stimulation by cAMP. Cell sodium was reduced by 30% (P less than 0.01) at 8 min after exposure to dibutyryl cAMP and theophylline and remained low at 25 and 33 min. Chloride content also fell significantly with stimulation. Although cAMP may activate several transport sites, the results are consistent with a direct effect of stimulation to increase the activity of the sodium pump in shark rectal gland.

Animals↗
PubMed1992

Radiocontrast agents induce endothelin release in vivo and in vitro.

The intravascular administration of the ionic radiocontrast agent sodium iothalamate (2.9 g of iodine/kg body wt) to rats induced an increase in plasma concentration of immunoreactive endothelin from 21.3 +/- 1.2 to 36 +/- 3 fmol/mL, preceded by a transient rise in the plasma level of atrial natriuretic peptide and associated with a fall in RBF. Equi-iodine amounts of the nonionic agents ioxaglate and iohexol elicited similar or more marked changes in plasma endothelin, but hypertonic solutions of NaCl, mannitol, or glucose did not. Comparable levels of endothelin produced by infusions of endothelin-1 induced a reduction of up to 29% in RBF. Iothalamate and iohexol stimulated endothelin release from cultured bovine endothelial cells, suggesting a direct effect of ionic and nonionic agents on vascular endothelium. The data invite speculation that under some circumstances endothelin release might play a role in the circulatory changes caused by these compounds and in the pathogenesis of radiocontrast nephropathy.

Animals↗