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Biomedical subjects

M Epstein

Publications and source records attributed to M Epstein.

At least 127 records · Page 7Linked to original sources
PubMed1995

Diabetes mellitus and associated hypertension, vascular disease, and nephropathy. An update.

Because considerable important information has been published since our previous review, this update concentrates on new findings with regard to cardiovascular and renal risk factors contributing to the striking morbidity and mortality of these coexisting diseases. For example, a large body of investigative data has recently emerged suggesting or delineating a pathogenic role for hyperglycemic-related glycosylation and oxidation of lipoproteins and vascular and renal tissues. Great strides have recently been made in the understanding of platelet, coagulation, lipoprotein, and endothelial abnormalities in the pathogenesis of cardiovascular and renal disease associated with diabetes mellitus and hypertension. Major progress has been made in clarifying the pathophysiology of glomerulosclerosis and other processes involved in the progression of diabetic nephropathy. Furthermore, accumulating data surveyed in this review address new and promising pharmacological interventions that specifically address these pathophysiological mechanisms.

Adrenergic alpha-Antagonists↗
PubMed1995

Effects of lysophosphatidic acid, a novel lipid mediator, on cytosolic Ca2+ and contractility in cultured rat mesangial cells.

Lysophosphatidic acid (LPA), the smallest and structurally simplest phospholipid, has the potential to modulate cellular signaling in diverse tissues and cell types, including fibroblasts. In the present study, we assessed the effects of LPA on cultured rat glomerular mesangial cells. Quantitative changes of [Ca2+]i in response to LPA were measured in monolayers of mesangial cells loaded with the fluorescent Ca2+ indicator fura 2. LPA (10 nmol/L to 100 mumol/L) increased [Ca2+]i in a dose-dependent manner and evoked inositol trisphosphate formation. LPA (1 mumol/L to 30 mumol/L) also elicited a marked, albeit transient, contractile response in mesangial cells cultured on collagen gel, as assessed by a decrease in cell surface area (CSA). The contraction persisted for 5 minutes (CSA decreased by 31%), whereupon the mesangial cells gradually relaxed with a consequent increase in CSA. Pretreatment of mesangial cells with isradipine (1 mumol/L), a dihydropyridine-sensitive Ca2+ channel blocker, completely blocked LPA-induced contraction. Isradipine also decreased resting [Ca2+]i levels as well as the peak and the subsequently sustained [Ca2+]i levels induced by LPA, suggesting that the contractile effects of LPA are dependent on Ca2+ entry through voltage-gated Ca2+ channels. Finally, LPA stimulated an increase in both prostaglandin E2 synthesis and cAMP accumulation, indicating that these mediators may modulate the contractile effects of LPA. Our study is the first demonstration that exogenous LPA induces mesangial cell contraction and suggests that the contraction is mediated by mobilization of intracellular Ca2+ by activation of the phosphoinositide cascade as well as by promotion of Ca2+ entry across the plasma membrane.

Analysis of Variance↗
PubMed1995

Release of kaliuretic peptide during immersion-induced central hypervolemia in healthy humans.

Kaliuretic peptide, a new peptide hormone consisting of amino acids 79-98 of the 126 amino acid atrial natriuretic factor (ANF) prohormone, is synthesized in the heart and is a potent stimulator of potassium excretion. The mechanism(s) controlling the release of kaliuretic peptide heretofore has not been defined. Because water immersion to the neck provides an acute central volume expansion identical to that produced by 2 liters of saline but without the plasma compositional change, immersion to the neck (NI) was utilized to assess kaliuretic peptide responses to acute central blood volume expansion in seven seated sodium-replete normal subjects. Since atrial natriuretic factor (ANF; amino acids 99-126 of the prohormone) originates from the amino acids adjacent to kaliuretic peptide in the ANF prohormone but is proteolytically cleaved from the rest of the prohormone before release, measurement of ANF was incorporated into this study to determine if there are differences with respect to release of these two portions of the ANF prohormone. Both kaliuretic peptide and ANF increased promptly with NI, with ANF peaking at 1 hr of immersion, whereas kaliuretic peptide peaked at the 3rd hr of immersion. With cessation of immersion, ANF decreased to preimmersion levels within 0.5 hr while kaliuretic peptide was still significantly (P < 0.05) elevated at 1 hr postimmersion. These findings indicate that kaliuretic peptide and ANF are released simultaneously but that kaliuretic peptide peak circulating concentration and its return to preimmersion values are prolonged compared with ANF. These last findings suggest a slower clearance from the circulation for kaliuretic peptide. The diuretic peak response to NI corresponded in a temporal manner to the peak circulating concentration of kaliuretic peptide, suggesting a possible physiologic role for kaliuretic peptide in modulating volume homeostasis in humans.

Adult↗
PubMed1995

Case report: multiple myeloma presenting as a diastolic heart failure with no evidence of amyloidosis.

The development of severe right sided congestive heart failure led to a diagnosis of immunoglobulin G (lambda) myeloma with a predominance of light chains. Cardiac catheterization and endomyocardial biopsy showed a severe diastolic dysfunction of both right and left ventricles and extensive myocardial infiltration by intercellular fibrillar tissue, which was not amyloid. This is a rare presentation of immunoglobulin deposition disease associated with immunocytic dyscrasias.

Amyloidosis↗
PubMed1995

Effects of ACE inhibitors and calcium antagonists on progression of chronic renal disease.

The declining mortality due to coronary heart disease and stroke has been attributed in part to improved effectiveness and application of antihypertensive therapy and the successful identification and treatment of the population at risk. In striking contrast, end-stage renal disease (ESRD) attributed to hypertension has increased annually for the last decade and will probably worsen at least through the year 2000. Taken together, patients with diabetic nephropathy and patients with hypertensive renal disease account for the majority of new cases annually. The reasons for the striking dissociation between our success with coronary heart disease and stroke on the one hand and our inability to lessen the incidence of ESRD on the other remain to be clarified. Evidence reveals that all levels of untreated hypertension are associated with potentially declining renal function. Data from the Hypertension Detection and Follow-up Program and other studies suggest that antihypertensive treatment can prevent or retard development of progressive renal failure. Although the importance of blood pressure control is implicit, a theoretic framework based on data derived from experimental animal suggests that ACE-inhibitors and perhaps calcium antagonists may exert specific renoprotective effects beyond those achieved by blood pressure reduction per se. The results of recent long-term prospective studies are consistent with such a formulation. In view of the increasing importance of ACE-inhibitors and calcium antagonists in the antihypertensive armamentarium, additional prospective randomized studies are required to delineate further the effects of these agents on the progression of chronic renal insufficiency.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Renal parenchymal disease and hypertension.

Renal parenchymal disease is the most common cause of secondary hypertension, accounting for 2.5% to 5.0% of all cases. Hypertension associated with renal parenchymal disease occurs as a complication of a wide variety of glomerular and interstitial renal diseases and may accelerate the decline in renal function if inadequately controlled. Renal parenchymal hypertension most probably represents the combined interactions of multiple independent mechanisms: potential factors include impaired sodium handling leading to volume expansion, perturbations of the renin-angiotensin system, alterations in endogenous vasodepressor compounds, and possibly increased activity of vasoactive substances. The past several years have witnessed newer insights into both the pathophysiology and the therapeutics of this disorder. The characterization of endothelin and the nitric oxide (NO)-arginine pathway and their roles in biology and medicine has provided additional new insights with regard to the pathogenesis of hypertension in renal parenchymal disease. For example, methylated L-arginine derivatives that possess NO synthase inhibitor capabilities including NG-N-dimethylarginine and N-monomethyl-L-arginine are found in human plasma and in urine. Patients with chronic uremia have impaired elimination of these compounds, and circulating concentrations of these compounds may increase sufficiently to result in inhibition of NO production. Thus, accumulation of endogenous NO synthase inhibitors might contribute to the hypertension of advanced renal failure. Similarly, it has been proposed that increased endothelium-derived endothelin that results from hypertensive injury to vascular endothelium could lead to further vasoconstriction and worsening of hypertension. Additional insight into this fascinating problem must await further biochemical characterization of some of the mediators and a more precise delineation of their pathophysiological role.

Aldosterone↗
PubMed1994

Effects of calcium antagonists on renal hemodynamics and progression of nondiabetic chronic renal disease.

In recent years, substantial investigative attention has focused on therapeutic regimens that could retard the progression of chronic renal insufficiency. Emphasis has been placed on the effects of antihypertensive treatment on renal hemodynamics and preservation of renal function. It has been suggested that some classes of antihypertensive agents may confer a greater renoprotective effect, especially agents that lower glomerular capillary pressure. Conversely, by virtue of their ability to preferentially dilate the afferent arteriole calcium antagonists theoretically could favor an increase in glomerular capillary pressure thereby accelerating the decline of renal function. In this review we survey the literature critically and conclude that in patients with essential hypertension and in patients with chronic renal insufficiency, calcium antagonists effectively reduce systemic blood pressure while maintaining glomerular filtration rate and effective renal plasma flow. Preliminary results from a few long-term studies suggest that calcium antagonists may even attenuate the decline in renal function of patients with chronic renal failure. The majority of studies in humans, however, have been nonrandomized, of too short duration, or confounded by investigative difficulties precluding definite conclusions whether calcium antagonists have renoprotective effects. Although the possibility that calcium antagonists may retard progression of renal disease remains to be ascertained, the available evidence indicates that calcium antagonists may be used in patients with renal functional impairment without further exacerbating renal function.

Animals↗
PubMed1994

Intrinsic and extrinsic characteristics of human tumors relevant to radiosurgery: comparative cellular radiosensitivity and hypoxic percentages.

UNLABELLED: We have collected the in vitro x-ray radiation survival characteristics of 181 lines from 12 different classes of exponentially growing human tumor cells (sarcomas, lung cancers, colo-rectal cancers, medulloblastomas, melanoma, breast cancers, prostate cancers, renal cell cancers, grades III and IV brain tumors, ovarian, and head and neck cancers). This information was used to intercompare survival after single high doses of 20-40 Gy for each tumor line. Radiosensitivities could roughly be divided into two groups. The more radiosensitive group included: sarcoma, small-cell lung cancer, non-small cell lung cancer, colorectal cancer, medulloblastoma and melanoma. The more radioresistant group included breast, prostate, renal cell, primary brain tumors, ovarian tumors, and head and neck cancers. Using a model of a 3 cm diameter brain lesion containing about 1.4 x 10(9) oxic cells, the single doses calculated to reduce survival to 1 cell were: sarcoma and small cell lung cancers-22-23 Gy; melanoma-25 Gy; non-small cell lung and colorectal cancer-26 Gy; medullo-blastoma-28 Gy; breast, prostate, renal cell, primary brain tumors, ovarian tumors, and head and neck cancers-30-36 Gy. If, however, tumors contained on average 20 percent hypoxic cells, the dose needed for equivalent cell killing increased by about a factor of 2.6-2.8. Also, there was no correlation between the ranking of relative radiosensitivities of the various classes of tumor cells at high doses (as in radiosurgery) to the sensitivity at low doses (as in conventional fractionated radiotherapy). CONCLUSION: available information on the intrinsic radiosensitivity of human tumor cells indicates that meaningful differences exist among different histological classes of neoplasm that are relevant to the single high doses used in radioneurosurgery, and which could constitute a basis for "tailoring" the administered dose to the particular neoplasm. However, if intracerebral lesions contain a large number of hypoxic cells (e.g., 20%), this may constitute a significant problem.

Cells, Cultured↗
PubMed1994

A prospective randomized clinical trial comparing a new oral sustained-release ritodrine with conventional tablets.

OBJECTIVES: Evaluation of maternal metabolic and cardiovascular responses to treatment with the new sustained-release oral ritodrine as compared with the conventional tablets. METHOD: Thirty-two pregnant patients who had successful intravenous tocolysis were randomly assigned to treatment with either ritodrine tablets or sustained-release capsules. After 5 days of the randomly determined first oral treatment each patient was shifted to the alternate ritodrine formulation for a further 5-day course. Each patient underwent metabolic and non-invasive hemodynamic evaluation. RESULTS: Echocardiographic parameters during treatment with ritodrine tablets were not significantly different from during sustained-release capsules. Mean systolic blood pressure increased significantly during peak drug activity in patients treated with ritodrine tablets and not during treatment with the sustained-release form. Fasting plasma glucose levels were higher in patients on conventional tablets therapy than in patients on sustained-release ritodrine therapy (88.9 +/- 9 mg/dl vs. 78.7 +/- 8 mg/dl, P < 0.05) while levels following a 50-g oral glucose challenge test did not differ significantly (135 +/- 32 mg/dl vs. 124.5 +/- 27 mg/dl) CONCLUSIONS: Because of fewer metabolic and cardiovascular side-effects, the new oral therapy offers some advantages over the presently available tablets.

Administration, Oral↗
PubMed1994

Interactions between 4-HPR and diet in NMU-induced mammary tumorigenesis.

The present study was designed to determine whether the chemopreventive effect of the synthetic retinoid N(4-hydroxyphenyl)retinamide (4-HPR) on mammary tumorigenesis was influenced by diet. Three diets were used: the closed-formula grain-based Wayne Lab Blox, the open-formula grain-based NIH-07, and the casein-based semipurified AIN-76A. Groups of 25 virgin female F-344 rats were fed the experimental diets beginning one week before a single injection of N-methyl-N-nitrosourea (NMU, 45 mg/kg body wt i.v.) at 50 days of age. The experimental design was as follows: Group 1, unsupplemented AIN-76A; Group 2, AIN-76A supplemented with 4-HPR starting seven days before NMU until termination (-7); Group 3, AIN-76A supplemented with 4-HPR seven days after NMU until termination (+7); Group 4, Wayne (no 4-HPR); Group 5, Wayne (4-HPR, -7); Group 6, Wayne (4-HPR, +7); Group 7, NIH-07; Group 8, NIH-07 (4-HPR, -7). 4-HPR [782 mg/kg diet (2 mM)] was given to all supplemented groups. Termination was 25 weeks post-NMU. Analysis of tumor incidence, multiplicity, and latency indicated that 1) control rats fed the AIN-76A diet exhibited significantly higher mammary tumor yields than rats fed unsupplemented natural-ingredient diets (Wayne and NIH-07) and 2) 4-HPR inhibited mammary tumor development in the two grain-based diets but enhanced tumor development in the AIN-76A diet. Animals fed the AIN-76A diet gained weight to a greater extent than those fed the Wayne or NIH-07 diets and exhibited lower levels of circulating 4-HPR.

Animals↗
PubMed1994

A quantitative assessment of renal blood flow autoregulation in experimental diabetes.

Several approaches have been utilized to describe renal blood flow (RBF) autoregulation in normal and pathological conditions. When describing the relation between RBF and stepwise decrements in renal perfusion pressure (RPP), these methods have several limitations, including: the necessity for predetermining a pressure 'break-point', and establishing constraints on changes in flow. To circumvent these limitations, we successfully utilized a third order polynomial, the cubical parabola, to characterize the autoregulatory responses in untreated streptozotocin (STZ) diabetic and control rats. The nonlinear relationship occurring between RBF and RPP was estimated from individual observations using the equation RBF = a + b x 10(-6) (RPP-c)3. Variables a and c represent RBF and RPP at the inflection point of the curve, respectively; variable b represents the rate of fall of RBF as RPP decreases (shape factor). Variable c was significantly lower in the diabetic group than in the control group whereas variable b was greater in the diabetic group. RBF (a) did not differ between the two groups. In conclusion, we determined that the range of RBF autoregulation in untreated diabetic rats is reset to a lower RPP. Furthermore, the curve below the inflection point declines more rapidly in diabetic rats than in controls. We propose that the equation described herein constitutes a promising and reproducible method for describing RBF autoregulation in vivo.

Animals↗
PubMed1994

Multiple factors contribute to acetylcholine-induced renal afferent arteriolar vasodilation during myogenic and norepinephrine- and KCl-induced vasoconstriction. Studies in the isolated perfused hydronephrotic kidney.

Acetylcholine (ACh) elicits vasodilation by releasing a number of endothelium-derived relaxing factors (EDRFs). We used the isolated perfused hydronephrotic rat kidney to examine the characteristics of ACh-induced vasodilation of renal afferent arterioles during different types of underlying vasoconstriction. Basal arteriolar tone was increased by either elevating perfusion pressure to 180 mm Hg (myogenic), administering 0.3 mumol/L norepinephrine (NE), or elevating medium potassium concentration to 30 mmol/L (KCl). ACh (10 mumol/L) completely reversed myogenic and NE-induced vasoconstriction and reversed KCl-induced vasoconstriction by 80 +/- 5%. However, whereas ACh produced a sustained vasodilation during KCl- and NE-induced vasoconstriction, only a transient reversal of myogenic vasoconstriction was observed, and myogenic tone recovered within 5 to 10 minutes. ACh-induced vasodilation of arterioles preconstricted with KCl was markedly inhibited by either indomethacin (100 mumol/L) or nitro-L-arginine (100 mumol/L) and was completely abolished by pretreatment with both inhibitors. In contrast, indomethacin and nitro-L-arginine had no effect on the transient response to ACh observed during pressure-induced vasoconstriction. In vessels preconstricted with NE, nitro-L-arginine converted the normally sustained response to ACh to a transient vasodilation, which was refractory to both nitric oxide synthase and cyclooxygenase inhibition. Since this component was not observed during KCl-induced vasoconstriction, it may reflect the actions of an, as yet unidentified, endothelium-derived hyperpolarizing factor (EDHF). Our findings thus suggest that prostanoids, nitric oxide, and EDHF all contribute to ACh-induced renal afferent arteriolar vasodilation and that the relative contributions of these individual EDRFs depends on the nature of the underlying renal vascular tone.

Acetylcholine↗
PubMed1994

Hepatorenal syndrome: emerging perspectives of pathophysiology and therapy.

Progressive oliguric renal failure (designated "hepatorenal syndrome") commonly complicates the course of patients with advanced hepatic disease. Despite the severe derangement of renal function and ominous prognosis when renal failure develops, minimal and inconsistent pathologic abnormalities of the kidneys are found at autopsy. Furthermore, the kidneys, if transplanted, are capable of normal function, which supports the concept that the renal failure is functional and potentially reversible. In contrast to patients with classical acute failure (ATN), hepatorenal syndrome patients manifest characteristic alterations of renal function including (1) relatively hyperosmolar urine; (2) high creatinine urine:plasma ratio, and (3) a very low urine sodium concentration (< 10 mEq/L). The past several years have witnessed newer insights into both the pathophysiology and the therapeutics of this syndrome. The application of newer methodology such as tracer kinetics has more rigorously delineated the role of a number of pathogenic mechanisms including activation of the sympathetic nervous system. The characterization of endothelin and the nitric oxide-arginine pathway and their roles in biology and medicine has provided additional new insights with regard to the pathogenesis of hepatorenal syndrome. For example, nitric oxide has been proposed to constitute a mediator of both the hyperdynamic circulation and renal failure. Finally, recently initiated therapeutic approaches lend a note of optimism to the future management of a syndrome that is so often incompatible with recovery. These include the acceptance of orthotopic liver transplantation as definitive treatment for patients with end-stage liver disease and attempts to improve renal function by countervailing the decreases in systemic vascular resistance while minimizing concomitant increments in renal vascular resistance. Hopefully, ongoing and future clinical trials will establish the precise contribution of each of these treatment modalities and their respective roles in the therapeutic armamentarium.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1994

Impairment of afferent arteriolar myogenic responsiveness in the galactose-fed rat.

Previous studies from our laboratory have demonstrated impaired afferent arteriolar responsiveness to pressure in rats 4-6 weeks after the induction of diabetes mellitus. Although the responsible mechanisms mediating this renal autoregulatory defect have not been fully defined, increased polyol metabolism has been implicated as a possible factor involved in the pathogenesis of diabetic complications. We therefore investigated the possible role of this metabolic disturbance in renal autoregulation using the galactose-fed rat, a model characterized by increased polyol pathway activity independent of hyperglycemia or insulin deficiency. Hydronephrosis was induced to permit direct visualization of renal microvessels. Pressure-induced vasoconstriction of afferent arterioles was assessed by quantitating vessel diameter following stepwise increments of renal perfusion pressure (RAP; from 80 to 180 mm Hg) in the hydronephrotic kidneys from control rats and rats fed a 50% galactose diet for 2 or 4 weeks. Vessel diameters were measured from video images by computer-assisted image processing. Control rats exhibited progressive afferent arteriolar vasoconstriction when RAP was increased from 80 to 180 mm Hg (-17.3% +/- 1.0%; P < 0.001). In contrast, myogenic responses to increases in pressure were absent in the afferent arterioles of rats fed a 50% galactose diet for either 2 (-4.1% +/- 1.9%; not significant) or 4 weeks (-2.9 +/- 3.4%; not significant). Our demonstration that the impairment of afferent arteriolar responsiveness to increasing RAP in the normoglycemic galactose-fed rat was identical to that observed in the STZ-diabetic rat suggests that increased polyol accumulation may contribute to the impairment of renal autoregulation in the diabetic rat.

Animals↗