Losartan -- Magic Bullet for Alzheimer's ???

[Mark Thorson]

Losartan (an angiotensin receptor blocker) and
atenolol (a beta blocker) compared for effect
on memory function in the elderly:

http://www.nature.com/jhh/journal/v17/n11/pdf/1001613a.pdf

When given at doses producing the same level of
lowering blood pressure, memory function declined
slightly in the atenolol group but significantly
increased in the losartan group. Whatever is
causing the improved memory, it is NOT blood
pressure.

Huge reduction in risk of diagnosed Alzheimer's
patients requiring going to a nursing home when
taking an angiotensin receptor blocker vs. an
ACE inhibitor:

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806632/pdf/bmj.b5465.pdf

I think that indicates the angiotensin receptor
blockers are doing something that ACE inhibitors
are not doing. What could that be? An ACE
inhibitor prevents angiotensin II from being
synthesized from the parent molecule angiotensin I.
An angiotensin receptor blocker occupies the
receptor for angiotensin II and prevents the
latter from binding to the receptor. One would
think both classes of drugs would have exactly
the same effect, but it turns out that losartan
does more than block the angiotensin receptor.

Rat study indicates that losartan up-regulates
GTPCH1 protein expression (enzyme that performs
the rate-limiting step in tetrahydrobiopterin
synthesis) but it does not up-regulate synthesis
of the messenger RNA for the GTPCH1 protein:

http://ndt.oxfordjournals.org/content/early/2008/07/02/ndt.gfn357.full.pdf

Enzyme expression is usually regulated at the
level of messenger RNA, so it's weird that there
would be more GTPCH1 without more mRNA for
making GTPCH1.

Tetrahydrobiopterin is an essential cofactor for
the enzymes that perform the rate-limiting steps
in the synthesis of several neurotransmitters,
including serotonin, melatonin, epinephrine,
norepinephrine, and nitric oxide. Long-term
potentiation experiments show nitric oxide is
essential for the memory effect probed by these
experiments, so this seems to be the mechanism
by which angiotensin receptor blockers like
losartan improve memory.

However, an alternative set of hypotheses for the
efficacy of angiotensin receptor blockers against
Alzheimer's Disease is presented here:

http://www.jraas.com/content/9/4/226.full.pdf

I don't believe that's the case, but there isn't
enough data to know for sure at this time.

[Mark Thorson]

Post by Mark Thorson
Tetrahydrobiopterin is an essential cofactor for
the enzymes that perform the rate-limiting steps
in the synthesis of several neurotransmitters,
including serotonin, melatonin, epinephrine,
norepinephrine, and nitric oxide.

I forget to include dopamine. Tetrahydrobiopterin
is an essential cofactor for dopamine synthesis.
Maybe I need some losartan, except I have low
blood pressure, which is the main contraindication
for prescribing losartan. No losartan for me.