Mechanism of Experimental Uremia

Mason, Merle

doi:10.1001/archinte.1937.00180020136010

Cited by 53 publications

(6 citation statements)

References 22 publications

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“…A few in vitro studies on the problem o f 'uremic cardio myopathy' have been reported and are in agreement with our findings: exposition of frog hearts to the serum of acutely uremic dogs results in a systolic cardiac arrest [28], Ultrafiltrates of sera withdrawn from uremic patients affect the beating frequency of atrial fragments derived from embryonic chick hearts. This effect is concentration de pendent ranging from tachycardia to complete cessation of contractions [29].…”

Section: Discussionsupporting

confidence: 90%

In vitro Approach to ‘Uremic Cardiomyopathy’

Weisensee¹,

Löw-Friedrich

Riehle³

et al. 1993

Nephron

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Cardiovascular complications determine the prognosis of patients with chronic renal failure. The contribution of compounds retained during uremia to specific myocardial lesions is controversal. We investigated the contractility of spontaneously beating mouse cardiac myocytes in culture under perfusion with sera derived from patients on maintenance hemodialysis and test solutions containing possible toxins. Cellular contractility under defined environmental conditions is determined by a computer-assisted digital image analysis. ‘Uremic sera’, creatinine, urea, and combinations of these compounds reduce inotropy of the cultured heart cells, induce arrhythmias or asynchronies in a concentration-dependent manner. We propose the myocyte perfusion technique as an in vitro approach to identify cardiotoxins in the body fluids of chronically uremic patients.

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Section: Discussionsupporting

confidence: 90%

In vitro Approach to ‘Uremic Cardiomyopathy’

Weisensee¹,

Löw-Friedrich

Riehle³

et al. 1993

Nephron

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“…This is suggested not only by the fact that phenobarbital is the most effective of the barbiturates but by the work that Dr. Tinsley Harrison has done on the mechanism of uremia which makes it evident that phenol compounds in general have exactly the sort of motor depressant effect that we should like. [Cobb et al, 19381 He was referring to a paper by Hamson, Mason, and Resnik presented at the American Society for Clinical Investigation on May 5, 1936-in other words, just two weeks before the remarks he made regarding Cobb's presentation (Hamson et al, 1936;Mason et al, 1937). Hamson and his co-workers pointed out that the administration of "free phenols" prevented the muscular twitching produced in animals by intracisternal injection of phosphorus during the terminal stages of uremia.…”

Section: The Next Hurdle Facing Memtt and Putnam Was Dis-mentioning

confidence: 99%

Putnam, Merritt, and the Discovery of Dilantin®

Friedlander

1986

Epilepsia

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In the first part of this essay, the "common wisdom" about Putnam and Merritt's contributions to the treatment of epilepsy was summarized (Rowland, 1982). Based on the history that has been presented here, how true are these "wisdoms"? Putnam and Merritt did devise "a simple and reliable method to test drugs of anticonvulsant effect" and they did show "that anticonvulsant effects in cats accurately predicted effects in humans," but others before them had done these same things. Dilantin, contrary to common wisdom, was not the first anticonvulsant drug to be tested in animals before it was given to human subjects; at least a year before, Cobb and his co-workers had done the same thing using vital dyes. However, Dilantin did represent the first time an anticonvulsant tested in animals was subsequently studied in a large series of patients. Nor were Putnam and Merritt the first to show that "anticonvulsant and sedative effects of drugs could be separated." Potassium borotartrate, ketogenic diet, ketone bodies, and vital dyes were anticonvulsive without necessarily being sedative. However, Putnam and Merritt were probably the first to make so explicit a statement to this effect. It may well have been this particular statement--and the fact that it was so well heard by other researchers--that represented their greatest achievement. In Kuhn's theory of scientific revolutions, the great step forward may not be so much the accumulation of evidence that the existing paradigm is not a feasible one, but rather the use of this evidence to form a new model or paradigm which is then accepted by normal science in such a fashion that the results prove to be productive. This, it would seem, is what Putnam and Merritt did. From it came their own major discovery, Dilantin, which, in Rowland's words, remains "a mainstay of treatment" for epilepsy up to the present time, and which "opened the way to the development of other anticonvulsant drugs."

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“…It has been claimed (Yatzidis, Oreopoulos, Tsaparas, Voudiclari, Stavroulaki & Zestanakis, 1966;Giovanetti, Biagini & Cioni, 1968a) that this substance is present in the serum of uraemic subjects in much higher concentrations than in normal subjects. Methylguanidine is known to have high acute toxicity (Mason, Resnik, Minot, Rainey, Pilcher & Harrison, 1937) and its chronic subcutaneous administration to normal dogs in amounts sufficient to produce methylguanidine concentrations similar to those reported in humans with severe renal failure (Yatzidis et al, 1966;Giovanetti et al, 1968a), induces a hypercatabolic state, impaired erythrocyte production and haemolysis, a decrease in platelet count, neuropathy, anorexia, vomiting, diarrhoea, gastrointestinal ulceration and haemorrhages, pulmonary oedema, tachycardia and arrhythmias (Giovanetti, Biagini, Balestri, Navalesi, Giagnoni, de Matteis, Ferro-Milone & Perfetti, 1969) (Balestri, Biagini, Rindi & Giovanetti, 1970). In such concentrations methylguanidine in vitro produces as much haemolysis as is produced by creatinine in concentrations typical of severe renal failure (Giovanetti, Cioni, Balestri & Biagini, 1968b).…”

mentioning

confidence: 99%

A Reinvestigation of Methylguanidine Concentrations in Sera from Normal and Uraemic Subjects

Baker

Marshall

1971

Clinical Science

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1.A cation-exchange-chromatographic method for the determination of methylguanidine in serum is described.2. In ten normal subjects, the mean serum methylguanidine concentration was 0·055 (SE 0'019) mg/ 100 ml and in ten uraemic patients it was 0·175 (SE 0,038) mg/ 100 ml. This difference is significant (P<0·02).3. Recent claims that methylguanidine is present in uraemic serum in much higher concentrations are shown to be due to artifactual conversion of creatinine when methods involving charcoal chromatography are employed.4. The results of intoxication experiments, in which blood concentrations of methylguanidine similar to those found by charcoal-chromatographic methods have been reproduced, must be interpreted with caution.

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Mechanism of Experimental Uremia

Cited by 53 publications

References 22 publications

In vitro Approach to ‘Uremic Cardiomyopathy’

In vitro Approach to ‘Uremic Cardiomyopathy’

Putnam, Merritt, and the Discovery of Dilantin®

A Reinvestigation of Methylguanidine Concentrations in Sera from Normal and Uraemic Subjects

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