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Biomedical subjects

M Epstein

Publications and source records attributed to M Epstein.

At least 91 records · Page 5Linked to original sources
PubMed1997

Lysophosphatidic acid and platelet-derived growth factor synergistically stimulate growth of cultured rat mesangial cells.

Lysophosphatidic acid (LPA) is a structurally simple, platelet-derived phospholipid, capable of eliciting a variety of physiological responses. We have demonstrated previously that LPA elicited a marked contractile response in rat mesangial cells (Inoue CN, Forster HG, Epstein M. Circ Res 77:888-896, 1995). In the present study, we examined the potential of this vasoactive substance to induce mesangial cell proliferation. Serum-starved quiescent rat mesangial cells were incubated with either LPA or in combination with platelet-derived growth factor (PDGF). DNA synthesis was assessed by [3H]thymidine incorporation after 24 hr, and cell numbers were determined at 0, 4, and 7 days. LPA- (1 nM-30 microM) stimulated mesangial cell DNA synthesis in a dose-dependent manner. The DNA synthesis stimulated by PDGF (1-100 ng/ml) was characterized by a bell-shaped response curve with a maximum at 40 ng/ml PDGF. The ability of LPA (30 microM) to synergize PDGF was observed over the entire range of PDGF concentrations (1-100 ng/ml). Under optimal concentrations of LPA/PDGF (30 microM40 ng/ml, respectively), mesangial cells displayed a 67-fold increase in [3H]thymidine incorporation, and a 1.9-fold (Day 4) and 2.5-fold (Day 7) increase in cell number as compared with that of quiescent mesangial cells. With an in vitro assay with myelin basic protein as the substrate, both LPA and PDGF induced stimulation of mitogen-activated protein (MAP) kinase activity. In addition, LPA augmented PDGF-induced increase in MAP kinase activity. In summary, these results demonstrate that LPA is mitogenic alone and also acts synergistically in combination with PDGF to promote mesangial cell proliferation. We postulate that these actions of LPA have the potential to play a crucial role in the mitogenic response of mesangial cells seen in a wide array of inflammatory and thrombotic glomerular disorders.

Animals↗
PubMed1997

Alcohol's impact on kidney function.

Both acute and chronic alcohol consumption can compromise kidney function, particularly in conjunction with established liver disease. Investigators have observed alcohol-related changes in the structure and function of the kidneys and impairment in their ability to regulate the volume and composition of fluid and electrolytes in the body. Chronic alcoholic patients may experience low blood concentrations of key electrolytes as well as potentially severe alterations in the body's acid-base balance. In addition, alcohol can disrupt the hormonal control mechanisms that govern kidney function. By promoting liver disease, chronic drinking has further detrimental effects on the kidneys, including impaired sodium and fluid handling and even acute kidney failure.

Acute Kidney Injury↗
PubMed1997

Video-microscopic assessment of the role of tissue angiotensin-converting enzyme in the control of the renal microcirculation.

In the present study, we assessed the role of tissue angiotensin-converting enzyme as a determinant of intrarenal hemodynamics by using the angiotensin-converting enzyme inhibitor trandolaprilat and the angiotensin II receptor antagonist losartan. Afferent and efferent arteriolar diameters were measured with computer-assisted vessel imaging in isolated perfused hydronephrotic rat kidneys. In response to the addition of 1.0 nM angiotensin I, afferent arterioles constricted by 27.3 +/- 2.4% and efferent arterioles by 20.9 +/- 2.4%. These constrictions were similar to those observed after the administration of 0.3 nM angiotensin 11 (33.7 +/- 2.3% and 20.9 +/- 2.4% in afferent and efferent arterioles, respectively). Pretreatment with the angiotensin-converting enzyme inhibitor trandolaprilat (0.1-10 microM) blunted the angiotensin I-induced constriction of afferent arterioles (12.7 +/- 1.4%) and completely abolished the angiotensin I-induced constriction of efferent arterioles. Subsequent addition of angiotensin II to the perfusate resulted in a marked decrease of afferent (39.9 +/- 1.8%) and efferent (27.8 +/- 3.3%) arteriolar diameters. Pretreatment with the angiotensin II receptor antagonist losartan completely blocked the angiotensin I-induced constriction of both afferent and efferent arterioles. Collectively, these data suggest that angiotensin I affects renal microvessels through its conversion to angiotensin II, mediated by locally available tissue angiotensin-converting enzyme, which subserves the local control of the renal microcirculation.

Angiotensin I↗
PubMed1997

Diabetes and hypertension: the bad companions.

DIABETES AND HYPERTENSION: Diabetes mellitus and hypertension are interrelated diseases that strongly predispose people to atherosclerotic cardiovascular disease. Hypertension is about twice as frequent in individuals with diabetes as in those without. The prevalence of coexisting hypertension and diabetes appears to be increasing in industrialized nations because populations are aging, and both hypertension and non-insulin-dependent diabetes mellitus (NIDDM) increase with age. An estimated 35-75% of diabetic cardiovascular and renal complications can be attributed to hypertension. ESSENTIAL HYPERTENSION: Essential hypertension accounts for the majority of hypertension in individuals with diabetes, particularly those with NIDDM, who constitute over 90% of those with a dual diagnosis of diabetes and hypertension. Diabetic nephropathy, which occurs after 15 years of diabetes in one-third of those with insulin-dependent diabetes and 20% of those with NIDDM, is an important contributing factor to the development of hypertension in the diabetic. New investigations should focus increasingly on identifying appropriate antihypertensive agents that not only lower blood pressure but also reduce cardiovascular risk and retard the rate of progression of diabetic renal disease.

Diabetes Mellitus, Type 2↗
PubMed1997

Hepatorenal syndrome: emerging perspectives.

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 renal failure (ATN), hepatorenal syndrome patients manifest characteristic alterations of renal function including (1) relatively hyperosmolar urine; (2) high creatinine urine to plasma (U:P) ratio, and (3) a very low urine sodium concentration (< 10 mEq/L). During the past several years we have witnessed new insights into both the pathophysiology and the therapeutics of this syndrome. The application of new 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 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 use of transjugular intrahepatic porto-systemic shunt. 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.

Clinical Trials as Topic↗
PubMed1997

Extracorporeal blood purification in the management of patients with hepatic failure.

With the increasing success of orthotopic liver transplantation, the time has come for a reassessment of the role of extracorporeal blood purification in the management of patients with liver failure. In those patients with combined liver and kidney failure, both standard hemodialysis and the newer continuous renal replacement therapies have been found to be helpful in maintaining fluid, electrolyte, and acid base balance. In those patients with liver failure but without kidney dysfunction, extracorporeal purification techniques have been found useful for the removal of hepatic toxins and in facilitating the replacement of clotting factors. This review will outline the rationale and documented utility of a wide variety of blood purification modalities used in the management of patients with liver failure.

Blood Chemical Analysis↗
PubMed1997

Surrogate endpoints and renal protection: focus on microalbuminuria.

End-stage renal disease (ESRD) is a major public health problem worldwide. The past decade has witnessed increased interest and investigative attention on therapeutic manoeuvres to retard the progression of renal disease. Reduction of albuminuria is regarded as a surrogate endpoint, because this phenomenon seems to be associated with preservation of GFR (principal endpoint) in diabetic nephropathy. Studies from our laboratory suggest that reduction in albuminuria during ACE inhibition constitutes a predictor of an attenuated rate of decline in GFR in early diabetic nephropathy. Because the rate of decline in kidney function is used to assess prognosis and the efficacy of therapy on progression of renal disease, a valid method for the determination of GFR is essential. During the last two decades, several radioactive and non-radioactive filtration markers have been validated and found to be both accurate and precise compared to inulin. Plasma clearance of such filtration markers is frequently applied in clinical trials in diabetic nephropathy because patients suffering from this complication frequently also suffer from diabetic cystopathy, precluding measurements of urine volume. Measurements of serum creatinine, creatinine clearance, calculated creatinine clearance by use of the Cockroft-Gault formula must all be regarded as surrogate measurements for glomerular filtration rate. Consequently, care must be taken to select appropriate filtration markers in order to rigorously evaluate therapeutic trials in progressive renal disease.

Albuminuria↗
PubMed1996

Calcium channel blockers and hypertension: 2. Safety issues.

As the safety of calcium channel blockers continues to be debated, it is important to realize that not all calcium channel blockers are alike. Safety, and efficacy, depend on the kinetic as well as the pharmacologic properties of the drug.

Antihypertensive Agents↗
PubMed1996

Newer approaches to antihypertensive therapy. Use of fixed-dose combination therapy.

Despite the availability of many newer antihypertensive agents, hypertensive patients remain at higher risk of premature death than the general population. This persistence of morbidity and mortality may be accounted for by the frequent failure to achieve adequate blood pressure reduction despite an extensive array of available antihypertensive agents. Such considerations have led to reassessment of the potential role of fixed-dose combination agents in the antihypertensive armamentarium. The rationale for combination therapy relates to the concept that antihypertensive efficacy may be enhanced when 2 classes of agents are combined. In addition, combination therapy enhances tolerability-1 drug of a fixed combination can antagonize some of the adverse effects of the second drug. Fixed-dose combination therapy simplifies the treatment regimen, preventing treatment failures that might result from missed doses. An additional novel concept is the possibility of enhancing salutary effects on target organs, including regressing left ventricular hypertension and retarding progression of renal disease, by combination therapy over and above the effects expected from the fall in arterial pressure alone. The recent approval by the Food and Drug Administration of 2 fixed-dose angiotensin-converting enzyme inhibitor/calcium antagonist combinations has focused attention on and prompted reexamination of this issue.

Antihypertensive Agents↗
PubMed1996

Renal Parenchymal Hypertension: current concepts of pathogenesis and management.

Renal parenchymal disease is a common but often unrecognized cause of hypertension. Chronic renal disease and systemic hypertension may coexist in two distinct settings. First, essential hypertension is an important cause of chronic renal disease. Second, renal parenchymal disease is a well-established cause of secondary hypertension. Renal parenchymal disease is the most common cause of secondary hypertension, accounting for 2.5% to 5.0% of all cases of systemic hypertension. Secondary hypertension may also accelerate the decline in renal function if inadequately controlled. Therefore, hypertension is both a cause and a consequence of renal disease, and it may be difficult to distinguish them clinically.

Humans↗
PubMed1996

Gamma knife pallidotomy in advanced Parkinson's disease.

Posteroventral pallidotomy as a treatment for Parkinson's disease (PD) has been the subject of increasing interest. We treated 4 nondemented patients with advanced PD, 2 with severe bradykinesia and a declining response to medication, and 2 with marked clinical fluctuations. All patients received 180 Gy delivered in one sitting to the right posteroventral pallidum site, used by Laitinen and colleagues, adjusted as needed, to avoid the optic tract. Only 1 patient changed significantly. Dyskinesia completely resolved on the side contralateral to the lesion in this patient. This same patient also became transiently demented and psychotic. The other 3 patients suffered no clearly identifiable beneficial or harmful effects. Follow-up magnetic resonance imaging scans of the brain at 1 year revealed lesions exactly where targeted although of unequal sizes. Our negative experience forces us to conclude that either larger volumes of tissue must be ablated, that physiologic monitoring is required for placing a lesion, that our subjects were poor candidates for the procedure, or that surgical ablation and radiation cause tissue damage of different types with different results.

Aged↗
PubMed1996

Impairment of afferent arteriolar myogenic responsiveness in the galactose-fed rat is prevented by tolrestat.

By permitting the separation of increased aldose reductase activity from hyperglycaemia and insulin deficiency, galactose-fed rats have constituted a useful model for investigating diabetic complications. Such rats manifest an impaired afferent arteriolar responsiveness to pressure similar to that of rats 4 to 6 weeks after induction of diabetes with streptozotocin. In the present study, we investigated whether treatment of galactose-fed rats with the aldose reductase inhibitor tolrestat prevent this autoregulatory defect and whether the blunted afferent arteriolar responsiveness to pressure is associated with impaired responsiveness to angiotensin II. Pressure-induced vasoconstriction of afferent arterioles was assessed in kidneys made hydronephrotic to allow direct visualization of renal microvessels by computer-assisted image processing. Vessel diameters were quantitated following stepwise increments of renal perfusion pressure (RAP; from 80 to 180 mm Hg) in kidneys of control rats and rats fed a diet for 2 weeks with 50% galactose with or without tolrestat. Subsequent to the pressure studies, angiotensin II (0.3 nmol/l) was added to the perfusate, and vessel diameters were reassessed. Control rats exhibited progressive afferent arteriolar vasoconstriction when RAP was increased from 80 to 180 mm Hg (-17.2 +/- 1.0%; p < 0.001). In contrast, myogenic responses to increases in pressure were absent in the arterioles of the galactose-fed rats (-4.1 +/- 1.9%; N.S.). Treatment with tolrestat completely prevented this impairment in afferent arteriolar responsiveness (-16.5 +/- 1.8%; p < 0.001). The angiotensin II-induced vasoconstriction did not differ between control rats and galactose-fed rats. We conclude that increased aldose reductase activity contributes to impaired renal auto-regulation in galactose-fed rats, a model of diabetic nephropathy, but is not involved in the loss of afferent arteriolar responsiveness to angiotensin II.

Aldehyde Reductase↗
PubMed1996

Stability of muscle fibers on the descending limb of the force-length relation. A theoretical consideration.

For the past 40 years it has generally been accepted that the descending limb of the force-length (F-L) relation of muscle fibers is unstable; strong sarcomeres are thought to shorten onto the ascending limb of the F-L relation at the expense of weak sarcomeres which are stretched beyond the thin-thick myofilament overlap. This unstable behavior has not been demonstrated by direct observation but has been inferred indirectly, based on the negative slope of the F-L relation. Intuitively, the idea that the sarcomere length within skeletal muscle is unstable at any length within the normal working range would not be advantageous. Therefore, the purpose of this study was to identify analytically the mechanical conditions for which sarcomeres in a muscle fiber are stable. It was found that the mechanical conditions required for sarcomere and fiber stability could be associated with known properties of skeletal muscle fibers. Furthermore, it could be demonstrated that a fiber composed of a large number of sarcomeres can be stable, and still exhibit an apparently unstable (negatively sloped) descending limb of the F-L curve.

Actin Cytoskeleton↗
PubMed1996

Force-length properties in stable skeletal muscle fibers--theoretical considerations.

Differences in the force-length (F-L) properties between sarcomeres and fibers have been associated with the supposed unstable nature of the sarcomere F-L relation on the descending limb (i.e. at sarcomere lengths greater than optimal length). Recently, it has been suggested that sarcomere behavior in a fiber is stable during contractions on the descending limb of the F-L relation; therefore, a factor other than sarcomere instability must be responsible for the observed differences in the F-L relations of sarcomeres and fibers. The purpose of this study was to determine theoretically the F-L relation of a muscle fiber when sarcomeres were at a stable, steady-state length. Three models of muscle fibers are presented; each model contains sarcomeres with different mechanical properties which have been observed experimentally. Results of these theoretical considerations demonstrate that sarcomeres with the classic F-L properties as measured by Gordon et al. (J. Physiol. 184, 170-192, 1966) cannot predict the F-L relation exhibited by fibers. The addition of cross-bridge stiffness properties to the classic sarcomere F-L relation still does not explain the differences between the sarcomere and fiber F-L relations. However, if history dependent sarcomere properties are used, the fiber F-L relation exhibits an elongated plateau and greater forces on the descending limb compared to the classic sarcomere F-L relation; and the fiber F-L relation corresponds qualitatively to experimental findings.

Animals↗
PubMed1996

Altered myogenic responsiveness of the renal microvasculature in experimental hypertension.

Recent investigations have delineated the renal microvascular responsiveness to pressure, by using isolated afferent arterioles, juxtamedullary nephrons, and isolated perfused hydronephrotic kidneys. Both afferent arterioles and interlobular arteries (ILA) manifest pressure-dependent vasoconstrictor responses to elevated renal arterial pressure. Several recent studies have indicated that the afferent arteriole adjacent to the glomerulus constricts primarily in response to tubuloglomerular feedback signals, whereas the afferent arteriole near the ILA is under the dominant influence of myogenic tone. Furthermore, the responsiveness of the ILA to pressure is dependent on the basal diameter, with the smaller diameter (distal) segments demonstrating more marked responses than do the larger (proximal) segments. The myogenic afferent arteriolar response is shifted to higher perfusion pressure in spontaneously hypertensive rat (SHR) kidneys, and blunted both in Dahl salt-sensitive rats and in Goldblatt renal hypertensive rats. This altered responsiveness of the afferent arteriole may account for the alterations in renal blood flow autoregulation, namely, resetting toward higher pressures in SHR, and impairment in Dahl salt-sensitive rats and Goldblatt hypertensive rats Distal ILA segments vasoconstricted similarly in response to pressure both in SHR and in Wistar-Kyoto rats (WKY), whereas proximal ILA segments did not exhibit vasoconstriction in either strain. The intermediate ILA segment from SHR kidneys manifests more prominent myogenic vasoconstriction than does that from WKY rat kidneys. The enhanced myogenic responsiveness of the intermediate ILA segment may act in concert with afferent arteriolar vasoconstriction to prevent glomerular hypertension in superficial nephrons. Finally, the myogenic vasoconstriction of renal microvessels is mediated in part by voltage-dependent calcium channels, and the altered myogenic response may be associated with modified activity of voltage-dependent calcium channels. Thus, the myogenic preglomerular tone constitutes a pivotal determinant of renal autoregulation, and teleologically may also play an important role in protecting glomeruli from barotrauma in hypertension, whereas the functional myogenic element is soon reinforced by an element of "structural autoregulation' of preglomerular resistance vessels.

Animals↗
PubMed1996

Predictive diagnosis of multiple endocrine neoplasia (MEN 1) in four Australian kindreds.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN 1) is a tumour predisposition syndrome that usually manifests in the first four decades of life. It has an autosomal dominant mode of inheritance which means that any new member of a MEN1 kindred has roughly a 50% chance of developing the disorder during their lifetime. The localisation of the MEN1 gene to a small region of chromosome band 11q13 has led to the development of DNA-based predictive diagnosis for this disease. AIMS: To establish a polymerase chain reaction (PCR)-based system, using simple tandem repeat polymorphisms (STRPs), to predict gene carriers in four Australian MEN 1 kindreds. METHODS: Six STRP markers flanking the MEN1 region of chromosome band 11q13 were used to screen individuals for a common haplotype in order to determine carrier status. RESULTS: The accuracy of prediction was calculated to be > 95% in informative individuals. CONCLUSIONS: DNA-based presymptomatic detection of affected members of MEN 1 kindreds could facilitate their care and reduce the inconvenience and expense of repeated testing of unaffected members. However, due to occasional recombination events or uninformativeness of markers in certain individuals, carrier status cannot always be predicted.

Adult↗