Duke University Medical Center

DURHAM, NORTH CAROLINA
27710

 

DEPARTMENT OF PHYSIOLOGY TELEPHONE (919) 684-2262

BOX 3709

March 27, 1981

Dr. Joshua Lederberg, President
The Rockefeller University

1230 York Avenue

New York, NY 10021

Dear Dr. Lederberg:

Many thanks for your enquiry about the effects of magnesium sulfate.
Although, as you remarked, my own work concerned its effects in the
central nervous system, not on peripheral tissues, I will try to give
you a reasonable opinion, even if unsupported by data.

A high concentration of a magnesium salt may well have a local
anesthetic effect, for divalent cations raise the threshold of excitation
of all excitable tissues. Soaking broken skin in a hypertonic solution
may raise the subcutaneous concentration sufficiently to block excitation
of nerve endings. It would not be too difficult to set up an experiment to
check whether this is true. In principle, I would not mind doing it
myself, except that at the moment I am committed to other projects. You
mention the supposed effect of hypertonicity per se. It is a time-honored,
though possibly not rigorously proven clinical tradition, that hypertonic
solutions reduce the oedema of inflammation. In Amsterdam we were taught
to use sodium bicarbonate or carbonate, because the alkalinity was believed
to help control infection. With the use of antibiotics, the latter may
not be important anymore. Since procaine and itS relatives are not always
tolerated, there may be some reason to use a magnesium salt for its com
bined hypertonic and local anesthetic effect. Whether it has an additional
specific anti-inflammatory action by some effect on capillary permeability,
or on reactive tissue cells, I am in no position to judge.

Then there is the use of intravenous magnesium sulfate in the treat-
ment of eclampsia of pregnancy. I have often wondered whether our work
make this therapy obsolete. For the following reasons I am not so sure:
(1) As you have read in our 1966 paper, when we received a rather
massive dose of this compound we did not go to sleep, but there was a
noticeable sedative effect. When we measured magnesium uptake in tissues
(Amer. J. Physiol. 214:406, 1968), we found that some did enter the brain
and spinal cord, although uptake in CNS was much less than in other organs.
However, in the light of our later work on cellular excitability changes
(J. Neurobiol. 1: 181 and 197, 1969), the small rise of magnesium ion con-
centration achieved by intravenous administration may be sufficient to becalm
the hyperexcitability of a preeclamptic brain. (2) It may be that in the
preeclamptic state, the blood-brain barrier is abnormally permeable to
magnesium, and thus the concentration achieved in brain may be higher than
Dr. Joshua Lederberg 2 March 27, 1981

expected. (3) Magnesium has additional effects, which include vaso-
dilatation (Viveros & Somjen, Experientia 24: 457, 1968) and diuresis,
both desirable in the treatment of eclampsia.

To answer your question, then, whether magnesium sulfate should be
removed from the Pharmacopeia , my advice would be to study it again,
after some decades of neglect, by modern methods, and in direct comparison
with more recent drugs. Such a simple compound could have advantages in
some cases, or it may be entirely obsolete. It would not be possible to
decide this without well-designed clinical trials. I am afraid that
few obstetricians are fully aware of the various points of view enumerated
in the previous paragraph. Renewed investigation followed by appropriate
publicity and entry into current textbooks could be beneficial.

I have left magnesium as a research topic about twelve years ago,
but after having been preoccupied with other matters, we recently began
a study of the permeability of the blood-brain barrier to calcium ions.
We intend to measure concurrently ion activity in circulating arterial
blood, and in the interstitial fluid of the central nervous system, with
ion-selective electrodes (for brain tissue we use microelectrodes). We
have made measurements in the two components (blood and brain) separately,
and will soon put them together in the same animal. From calcium it
should be a short step to magnesium, if and when magnesium-selective ion
exchanger will become available, and then we will be able to answer your
questions more directly. Meanwhile we will be kept busy solving the
equally puzzling and clinically important problems of calcium-deficiency
tetany, and of the central effects of hypercalcemia.

This letter grew excessively long, but I would also like to ask a
question myself. I have advance information that my NIH grant renewal
will probably end up in the bin marked “approved but not funded". Would
you know of an agency/foundation/fund that may be interested in sponsoring
our clinically relevant study of ion exchanges between blood and central
nervous system? If this is an inappropriate question to be addressed to
you, I must apologize, but I feel compelled to explore every possibility.

Yours very sincerely,

Yancy Yip} or

George G. Somjen, M.D.
Professor of Physiology

GGS/ma