Table Of ContentGUANIDINES 2
Further Explorations of the Biological
and Clinical Significance of
Guanidino Compounds
GUANIDINES
2
Further Explorations of the Biological
and Clinical Significance of
Guanidino Compounds
Edited by
Akitane Mori
>,
Okayama University Medical School
Okayama, Japan
Burton D. Cohen
The Bronx Lebanon Hospital Center
Bronx, New York
and
Hikaru Koide
Juntendo University School of Medicine
Tokyo, Japan
PLENUM PRESS • NEW YORK AND LONDON
Library of Congress Cataloging in Publication Data
International Symposium on Guanidino Compounds in Biology and Medicine (2nd:
1987: Schizuoka-shi,Japan)
Guanidines 2: further explorations of the biological and clinical significance of
guanidino compounds I edited by Akitane Mori, Burton D. Cohen, and Hikaru
Koide.
p. cm.
"Proceedings of the Second International Symposium on Guanidino Compounds in
Biology and Medicine, held May 31-June 2, 1987, in Susono City, Schizuoka,
Japan" - T.p. verso.
Includes bibliographies and index.
ISBN-13:978-1-4612-8099-6 e-ISBN-13:978-1-4613-0821-8
DOl: 10.1007/978-1-4613-0821-8
l. Guanidino compounds-Physiological effect-Congresses. 2. Guanidino com
pounds - Pathophysiology - Congresses. 3. Guanidino compounds - Metabolism
Congresses. I. Mori, Akitane, 1930- . II. Cohen, B. D. (Burton D.) III. Koide,
Hikaru. IV. Title. V. Title: Guanidines two.
[DNLM: l. Guanidines-congresses. QU 60 16075g 1987]
QP80l.G83I59 1987
599'.01924-dc20
DNLM/DLC 89-8437
for Libraty of Congress CIP
Proceedings of the Second International Symposium on Guanidino
Compounds in Biology and Medicine, held May 31-June 2, 1987,
in Susono City, Shizuoka, Japan
© 1989 Plenum Press, New York
Softcover reprint of the hardcover 1st edition 1989
A Division of Plenum Publishing Corporation
233 Spring Street, New York, N.Y. 10013
All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted
.in any form or by any means, electromc, mechanical, photocopying, microfuming,
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FOREWORD
Guanidine is named for its similarity to the purine guanine which, in
turn, is named for its principal source guano, which comes from the Inca word,
huano, for dung. Guanidine, therefore, translates into dung-like, which is
hardly a genteel way to introduce a subject.
On the other hand, texts are seldom inspirational, "frequently crude and
rarely literary and should be judged on how successfully they assemble,
organize and present current data. I am impressed that the material which
fol]ows goes a long way toward successfully achieving those goals.
Tue International Guanidine Society is a synthesis of three groups of
investigators: biologists studying guanidines as phosphagens, neurologists
interested in guanidines as convulsants and nephrologists involved with
guanidines as toxins. As a member of the latter group. I am gratified by the
considerable progress this book represents.
To begin with. there now appears to be a common theme which unifies
current speculation concerning the metabolic origin of the guanidines in
uremia. At the First International Congress in 1983, evidence was presented
which supported the theory that certain guanidines were products of the mixed
function oxidation of urea. This year's meeting brings together overwhelming
data showing that methyl guanidine is an effect of active oxygen reacting
with creatinine. An idolatry, worshipped throughout biochemistry, that urea
and creatinine are inert byproducts of protein metabolism, is shown to have
feet of clay.
More important and practical. however, is the evidence that urinary
levels of guanidinoacetic acid (GAA) can be of clinical value as a highly
sensitive warning of impending renal failure under a variety of conditions.
Among the conditions reported are protein ingestion. renal transplantation.
malignant hypertension and a number of cytotoxic drugs including gentamicin.
tetracycline, cyclosporine and cisplatin. Additional SUPpQf~ is obviously
necessary before clinical chemistry laboratories rush o~t to purchase
guanidine analyzers, but the current data are especially :irqpressive since they
are arrived at by a series of investigators working inqep~~~ently to solve
different aspects of the same problem. It is an area to Watch.
Once again we are deeply indebted to Professor A~itane Mori for pulling
all this together. Without his dedication to guanidines and the Guanidine
Society, this volume would not be possible. Professor Mori's unflagging
zeal in support of this arcane subject is solely responsible for this text
and the progress it represents:
B.D. Cohen
v
PREFACE
Guanidino compounds are known to be ubiquitous in both animal and plant
Kingdoms. Ever since the discovery of guanidine by Strecker in 1861, more
than 100 naturally occurring guanidino compounds have been identified. Some
of these substances play important biological roles in animal life, such as
the participation of arginine in ureagenesis, and of creatine in muscular
contraction. On the other hand, toxic effects of guanidino compounds have
also been observed. As early as 1886, Brieger identified methylguanidine in
stale horse meat and reported that creatine was decomposed by Vibrio cholerae
(Kommabacillen) to produce methylguanidine which could induce dyspnea, muscle
fibr'1;l.lation, and generalized convulsions. Although some other reports
concerning the toxicity of guanidino compounds such as methylguanidine or
guanidine were also made in the early 1900s, during the following more than
half a century, there appears to have been little interest in the subject.
The finding of guanidinosuccinic acid in uremic patients by Cohen's
group in 1963 has served as a major stimulus for the current wave of research
on guanidino compounds as uremic toxins. In recent years, considerable infor
mation about guanidino compounds has accumlated not only in the field of
nephrology, but also in other fields such as, analytical chemistry, biochem
istry, physiology and neurotoxicology. These subjects were discussed at the
first Symposium on Guanidino Compounds, held in Tokyo in 1983, (Guanidines:
Historical, Biological, Biochemical and Clinical Aspects of the Naturally
Occurring Guanidino Compounds, Plenum Press, New York and London, 1985).
The present monograph comprises the Proceedings of the Second Symposium
on Guanidino Compounds held in Susono City, at the foot of Mt. Fuji, June
1 - 2, 1987, and covers the following main topics.
1. Analytical methods for guanidino compounds and new guanidino compounds:
New developments in analytical methods for guanidino compounds utilizing
special enzymes or high performance liquid chromatography have been
introduced. Isolation of new guanidino compounds, such as y-guanidinooxy
propylamine, NG-methylagmatine, phascolamine and phascolasomine, is
reported in this section.
2. Metabolism of guanidino compounds:
A new idea for the existence of multiple forms of transamidinase has been
presented by Dr. J. Van Pilsum. The relationship of superoxide anions or
hydroxyl radicals to guanidino compounds has for the first time been high
lighted in this symposium. Effect of arginine-free diet on ureagenesis,
guanidino compounds in "sparse-fur" mutant mice with ornithine trans
carbamylase deficiency, and biosynthesis of guanidinoethanol, are also
discussed in this section.
vii
viii PREFACE
3. Physiological, pharmacological and toxicological aspects of guanidino
compounds:
Dr. B.D. Cohen presented a special lecture entitled "Guanidines as drugs",
and reviewed pharmacological and clinical effects of drugs, such as
cimetidine, amiloride, guanethidine, guanbenz and guanfacine, which
contain guanidino groups(s), on kidney, stomach and central nervous system
Alterations of guanidino compounds under unusual situations, such as anes
thesia, diabetes, hypertension, hemorrhagic shock and immersion stress are
discussed in this section. In addition, a digitalis like activity of
dimetqylarginine, inhibitory effect of adenosine and its potentiations on
methylguanidine synthesis, and effect of guanidino compounds on GABA
stimulated chloride channel, are also presented.
4. Involvement of guanidino compounds in seizure mechanisms:
Considerable information has been brought together concerning seizure
mechanisms and guanidino compounds. Studies involving compounds such as,
2-guanidinoethanol, and guanidinoethanesulfonate in epileptic patients as
well as in experimental animal models are reported. The involvement of
catecholamines in the mechanism of seizures induced by a-guanidinglutaric
acid is also discussed is this section.
5. Hyperargininemia:
Dr. A. Lowenthal, one of the first investigators to report hyperarginine
mia, overviews "Hyperargininemia". Recent findings in hyperargininemia
are reported by Dr. Lowenthal's colleagues and the Nagoya University
group.
6. Involvement of guanidino compound in renal dysfunction:
Involvement af guanidino compounds, especially of guanidinoacetic acid,
methylguanidine and guanidinosuccinic acid, in renal dysfunction had been
demonstrated not only in patients with acute and chronic renal failure and
with kidney transplantation, but also in experimental animal models with
renal failure and in an in vitro model system for nephropathy. The role
of guanidine as an indicator of peroxidation in uremics, and of nonprotein
nitrogen in progressive renal failure, is also discussed in this section.
The pace of exploration of guanidino compounds has accelerated greatly
in the past decade. The proceedings of the 1987 Internat.ional Symposium on
Guanidino Compounds compile a major part of current topics in biological and
medical research as related to this group of substances. I hope that this
volume will become a significant milestone in the study of the 'guanidine
kingdom', and will serve as an important basis for futher research and
collaboratian in this area.
A. Mori
Okayama, June 1988
ACKNOWLEDGEMENTS
The editorial work was performed by Dr. I. Yokoi. the Department of
Neurochemistry, Institute for Neurobiology, Okayama University Medical
School. We wish to express our gratitude to Dr. I. Yokoi.
CONTENTS
I. ANALYTICAL METHOD FOR GUANIDINO COMPOUNDS
AND NEW GUANIDINO COMPOUNDS
Enzymic Determination of Methylguanidine in Serum and Plasma of
Hemodialysis Patients as a Marker for Hydroxyl Radicals 3
M. Nakajima, K. Nakamura, Y. Shirokane, Y. Hirasawa
Measurement of Creatine and Phosphocreatine in Muscle Tissue
Using HPLC 13
K. Haruki, S. Hatakeyama, M. Hirata, H. Muramoto,
Y. Tofuku, R. Takeda
y-Guanidinooxypropylamine and NG-Methylagmatine:
Novel Guanidinoamines Found in Seeds of Leguminous Plants 15
S. Matsuzaki, K. Hamana, K. Isobe
Phascoline and Phascolosomine:
New Catabolic Products of Pyrimidines in Sipunculid Worms 23
Y. Robin, Y. Guillou
II. METABOLISM OF GUANIDINO COMPOUNDS
Effects of A~inine-Free Diet on Ureagenesis in Young and
Adult Ferrets 35
D.R. Deshmukh
Serum and Urinary Guanidino Compounds in "Sparse-fur" Mutant
Mice with Ornithine Transcarbamylase Deficiency 45
I.A. Qureshi, B. Marescau, M. Levy, P.P. De Deyn,
J. Letarte, A. Lowenthal
Biosynthesis of 2-Guanidinoethanol 53
Y. Watanabe, I. Yokoi, A. Mori
The Existence of Multiple Forms of Rat Kidney Transamidinase 61
M.D. Gross, A.M. Simon, R.J. Jenny, E.D. Gray,
D.M. McGuire, J.F. Van Pilsum
Puromycin Aminonucleoside Stimulates the Synthesis of
Methylguanidine: A Possible Marker of Active Oxygen Generation
in Isolated Rat Hepatocytes 71
K. Aoyagi, S. Nagase, M. Sakamoto, M. Narita, S. Tojo
xi
xii CONTENTS
Active Oxygen in Methylguafiidine Synthesis by Isolated Rat
Hepatocytes 79
K. Aoyagi, S. Nagase, M. Sakamoto, M. Narita, S. Tojo
Effect of Active Oxygen on Guanidine Synthesis in vitro 87
M. Sakamoto, K. Aoyagi, S. Nagase, S. Ohba, M. Miyazaki,
M. Narita, S. Tojo
The Reactivity of Guanidino Compounds with Hydroxyl Radicals 97
M. Hiramatsu, R. Edamatsu, M. Kohno, A. Mori
III. PHYSIOLOGICAL, PHARMACOLOGICAL AND TOXICOLOGICAL ASPECTS
OF GUANIDINO COMPOUNDS
Guanidines as Drugs 109
B.D. Cohen
Dimethylarginine Has Digitalis Like Activity 115
K. Nagai, A. Hashida, H. Nakagawa
Adenosine, Adenosine Analogues and Their Potentiators Inhibit
Methylguanidine Synthesis, a Possible Marker of Active Oxygen
in Isolated Rat Hepatocyte~ 123
K. Aoyagi, S. Nagase, M. Sakamoto, M. Narita, S. Tojo
The Alteration of Guanidino Compounds in the Liver, Kidney
and Blood Following Halothane Inhalation in Rats 129
M. Kitaura, Y. Ochiai, S. Sugimoto, K. Kabutan,
Y. Kosogabe, C. Tsuji, F. Kosaka
Amelioration of Guanidinoacetic Acid Metabolism in
Streptozotocin-Induced Diabetic Rats by Insulin Treatment 135
M. Hirata, S. Hatakeyama, K. Haruki, H. Muramoto,
T. Tofuku, R. Takeda
Urinary Excretion Rate of Guanidinoacetic Acid in Essential
Hypertension 137
Y. Takano, F. Gejyo, Y. Shirokane, M. Nakajima, M. Arakawa
Guanidino Compounds in Hemorrhagic Shock 147
S. Sugimoto, Y. Ochiai, M. Kitaura, K. Kabutan,
C. Tsuji, Y. Kosogabe. F. Kosaka
Effect of Guanidino Compounds on GABA-Stimulated Chloride
Influx into Membrane Vesicles from Rat Cerebral Cortex 153
T. Obata, A. Mori, H.I. Yamamura
Effect of Immersion Stress on Guanidino Compounds in Rat
Organs and Urine 159
H. Sugi, I. Yokoi, Y. Watanabe, A. Mori
CONTENTS xiii
IV. INVOLVEMENT OF SEIZURE MECHANISM
Effects of Anticonvulsants on Convulsive Activity Induced
by 2-Guanidinoethanol 169
I. Yokoi, A. Edaki, Y. Watanabe, Y. Shimizu,
H. Toda, A. Mori
Effect of Guanidinoethane Sulfonate on the Genetically
Seizure Susceptible Rat 183
S. Shindo, D.W: Bonhaus, R.J. Huxtable
Guanidinoethane Sulfonate and the Investigation of Taurine
and Other Neuroactive Amino Acids 189
R.J. Huxtable, A. Lehmann, M. Sandberg, S. Shindo
Guanidino Compounds in Audiogenic Sensitive Rats 199
P. Wiechert, B. Marescau, P.P. De Deyn, L. Van Gorp,
W.P. De Potter, A. Lowenthal
Guanidino Compounds in Serum and Cerebrospinal Fluid of
Epileptic and Some Other Neurological Patients 203
B. Marescau, P.P. De Deyn, P. Wiechert. M. Hiramatsll,
L. Van Gorp. W.P. De Potter, A. Lowenthal
The Involvement of Catecholamines in the Seizure Mechanism
Induced by a-Guanidinoglutaric Acid in Rats 213
H. Shiraga, M. Hiramatsu. A. Mori
V. HYPERARGININEMIA
Hyperargininemia 225
A. Lowenthal. B. Marescau
Neurotoxicity of Guanidino Compounds in Hyperargininemia 233
N. Mizutani, C. Hayakawa, Y. Oya, K. ~-latanabe,
Y. Watanabe, A. Mori
Serum Guanidinosuccinic Acid Levels in Urea Cycle Diseases 245
B. Marescau, I.A. Qureshi, P.P. De Deyn, J. Letarte,
N. Chamoles, M. Yoshino, W.P. De Potter, A. Lowenthal
a-Keto-o-guanidinovaleric Acid, a Compound Isolated from
Hyperargininemic Patients, Displays Epileptogenic Activities 251
P.P. De Deyn, L.R. Macdonald, B. Marescau, A. Lowenthal
VI. INVOLVEMENT OF GIUANIDINO COMPOUNDS IN RENAL DYSFUNCTION
Serum Levels of Guanidino Compounds in Acute Renal Failure 261
Y. Suzuki, F. Gejyo, M. Arakawa
Is Guanidine a Marker of Peroxidation in Uremics? 267
S. Nagase, K. Aoyagi, M. Sakamoto, M. Miyazaki, S. Ohba,
M. Narita, S. Tojo
