excruciatingly specific details of tying up

[Susan Evans Garlinghouse <suendavid@worldnet.att.net>]

Lori & Roger Sumrall wrote:
> 
>         I would like one of you out there to detail for me the physiological
> details of tying up and its resulting effects on the kidneys, etc., not in
> layman's terms, but in biochemical and physiological terms.
>         I've heard some of the basics, but I have a lot of questions about the
> details.
> 
> Thanks so much, Lori Sumrall

Okay, here goes.  Details you want, details you got, brace yourself <g>:

The complete pathophysiology (Why It Happens) of tying up ("exertional
rhabdomyolysis") is still not completely understood.  Currently, the
conditions that are known to be factors in causing tying up are 1)
resting a conditioned horse on a full-grain diet, followed by exercise
("Monday morning disease"); 2) whole-body potassium depletion; 3)
selenium deficiency; 4) an unaccustomed level of exercise; 5) postviral
infections, particularly rhino; 6) intoxications with ionophores (a
substance which increases cellular permeability to a specific ion, which
would in turn disrupt the electrical potential of the cell), blister
beetle, mercury, coffee bean (cassia) or gossypol from raw cottonseed. 
Other factors which have been suggested as being contributory are
hypothyroidism, some high-performance lines of horses, nervous horses,
fillies, estrus, hyperestrogenism (resulting from possibly a granulosa
cell tumor), cold damp weather, heavy muscling, and low-sodium rations.

One of the current hypotheses is that when a conditioned horse is not
worked and kept on full feed high in soluble carbohydrates, the horse
will accumulate carbohydrates in the muscles.  If there is a sudden
demand for work, the cannot adequately remove the rapidly accumulating
lactic acid in the muscles.  This in turn causes vasospasms and
ischemia---which means essentially that the surrounding blood vessels
"clamp down" so that the lactic acid waste product cannot be removed,
intracellular pH drops, the muscle cell is disrupted and you get the
hard, crampy muscles you see when a horse ties up.  Other theories of
the biochemical mechanism is that there is a deficiency of the
high-energy phosphates in muscle cells following maximal, anaerobic
exertion, and/or a depletion of muscle glycogen after prolonged, slow
(endurance-type) exercise.  High body temperatures and electrolyte
imbalances/depletions are also probably contributing causes, and
certainly major factors in endurance horses that tie up during
competitions.

Unless you're a biochemist, all of these different theories essentially
boil down to the same net effect---the ion pumps (ie, sodium/potassium,
calcium/magnesium and calcium/ATPase) in the membrane surrounding the
muscle cell which move substrates in and out of the cell are disrupted,
and so the interior environment of the muscle cells either cannot get
rid of waste products of metabolism, OR has too much of a metabolic
substrate to be able to function, OR can't get enough of a metabolic
substrate to be able to function.  And so the muscle cell simply shuts
down.  When muscle cells shut down, they don't do so in the relaxed
position, they freeze up in the contracted position, which is why you
get those rock-hard muscles.  Biochemically, it's not all that different
from rigor mortis.

The effect on kidneys comes in when the connective tissue (the
sarcolemma) surrounding and enclosing the muscle cell is disrupted,
releasing the contents of the muscle cell into the bloodstream.  There
are lots of different proteins and substrates and whatnot in a muscle
cell, but the important one for this particular discussion is
myoglobin.  Myoglobin  is a protein pigment which is responsible for
oxygen transport in the muscle cell.  Hemoglobin transports oxygen in
the bloodstream, myoglobin transports oxygen in the muscle cell.  When
myoglobin is released from a disrupted muscle cell into the bloodstream,
it travels to the kidneys and is filtered out.  In being filtered out of
the bloodstream (and keep in mind, there's probably alot of it from the
kidney's point of view), it causes (or CAN cause) kidney damage or even
total renal failure by overwhelming and clogging up the kidney tubules
and restricting the blood (and therefore oxygen) supply to the kidneys. 
This effect will be worsened if the animal is hypovolemic, meaning he's
dehydrated and therefore his total blood volume is less, and the blood
is thicker and harder to circulate, meaning harder to circulate oxygen
and substrates, etc etc etc.  A vicious cycle sort of thing.  So while
myoglobin does not directly damage the kidneys, in great enough
concentration it will cause damage indirectly by clogging them up and
creating what is called myoglobinuric nephrosis and possibly renal
failure.  It's also the myoglobin being filtered out that shows up as
very dark urine.  The dark urine itself is not what you have to worry
about---what you DO have to worry about is the fact that myoglobin in
the urine means that significant muscle disruption and damage has
occurred in the system, and that the kidneys are being overwhelmed with
a whole lot of waste product to try and get rid of.  Needless to say,
this is serious s**t from the physiological point of view.  However, as
Heidi explained, dark urine doesn't neceesarily mean myoglobinuria, dark
urine can be caused by other things as well.  But if your horse is
dehydrated, won't move and is standing there hunched up and miserable
AND is peeing coffee, you've got problems.

OK, some of the other things a DVM will look for in a tying-up horse are
elevated enzymes in the blood plasma, specifically CK (creatinine
kinase) and AST (aspartate aminotransferase).  AST is also referred to
as SGOT, but both refer to the exact same enzyme.  There are other
things the vet will look for as well, like creatinine, urea,
electrolytes and so on, but enzyme levels are at the top of the list. 
CK and AST are both enzymes contained in the muscle cell (as well as
other types of cells) which are also released into the blood when the
muscle cell is disrupted.  Therefore, if the enzyme levels are elevated
in the blood panel, it must mean that tissue cells somewhere are being
(or were being) damaged.  The tricky part in diagnosis is figuring out
where tissue damage is occurring---AST occurs in both muscle and liver
cells, so elevated levels could mean problems in either muscle OR liver
(and for that matter, AST levels can also be elevated by certain drugs
or toxins).  CK levels will indicate muscle damage, while other elevated
enzymes in the blood panel will indicate liver damage.  And to make
things even more confusing, there are various isoforms of yet another
enzyme, LDH (lactate dehydrogenase) which will indicate whether muscle
damage occurring is from skeletal or cardiac (heart) muscle.  However,
while I assume LDH isoforms are a big deal in cardiac patients, I don't
know whether LDH is commonly included on a standard equine blood panel.

The elevation in CK will occur pretty rapidly and peak within about 24
hours, then decline fairly rapidly---the half-life for CK is six hours,
meaning that half of the remaining amount is removed within six hours. 
So 50% is gone within 6 hours, 75% is gone w/i 12 hrs, 87.5% is gone w/i
18 hrs, and 93.75% is removed w/i 24 hrs, and so on.  The concept of
"half-lifes" doesn't refer only to enzymes, by the way, the same general
idea applies to drug half-lifes, isotope half-life, etc etc (just a
little extra trivia for you)(I know, riveting.)  The levels of AST will
begin approximately 24 hours after the onset of the clinical signs of
tying up, and decline much more slowly---AST has a half-life of about 14
days, so with significant muscle damage, it'll be awhile before levels
are really back to normal.  The relative levels of these two enzymes,
among other things, are what a DVM will look at in determining the
extent of damage, whether damage is still occurring and how long ago the
initial damage occurred.  For example, if a horse transport company
delivers a tied-up horse to you and swears the horse must have injured
himself last week, but the blood analysis shows screaming CK levels
(indicating recent muscle damage) but relatively low AST levels (also
indicating recent damage), then it comes under the heading of I Don't
Think So Chuckles.  See?

I sure hope this answers your questions about the specifics of
tying-up.  I think I might have given myself an aneurysm typing it. <g>

Susan Garlinghouse