Page 99 - 79_02

Long-­-life
supplementation
with
atenolol…

can
increase
sudden
cardiac
death
and
thus
mortality.
It
seems
that
the
most

important
secondary
effect
of
atenolol
is
the
strongly
decrease
in
heart
rate
that
it

induces
(62,
63).
The
meta
analyses
recently
performed
in
humans
agree
with
our

results
in
mice,
because
we
did
not
see
any
differences
in
blood
pressure
or
heart

rate
when
measured
at
18
months
of
age,
whereas
heart
rate
was
strongly
and

significantly
decreased
in
the
atenolol
group
at
35
months
of
age
(499
mmHg
in
Old

AT
compared
to
674
mmHg
in
Old
controls).
We
believe
that
our
results
are
most

important
concerning
future
cardiologic
treatments
in
humans
since
there
are

available
antihypertensive
drugs
alternative
to
atenolol,
and
they
constitute
the
first

study
of
the
long-­-life
effects
of
atenolol
in
a
large
population
of
healthy
mammal.

5.
CONCLUSION

1.-­-
The
long-­-life
treatment
with
the
ß-­-blocker
atenolol
in
drinking
water
of
a

large
population
of
mice
strongly
decreases
the
degree
of
fatty
acid
unsaturation
of

skeletal
muscle
and
mitochondrial
membranes,
the
only
parameter
known,
apart

from
a
low
rate
of
mitochondrial
ROS
generation,
that
correlates
with
longevity
in
the

right
way.

2.-­-
That
change
seems
to
be
due
to
a
large
extent
to
a
decrease
in

desaturase/elongase/peroxisomal
ß-­-oxidation
activities,
which
are
rate
limiting
for

the
synthesis
of
the
highly
unsaturated
docosahexahenoic
acid
(22:6n-­-3).
This
fatty

acid
is
universally
avoided
in
the
tissue
cellular
membranes
of
long-­-lived
mammalian

and
bird
species.

3.-­-
Those
decreases
are
due
to
ß-­-adrenergic
blockade-­-induced
increases
in
p-­-
ERK
signaling
to
the
nucleus,
and
lead
to
strong
decreases
in
oxidation,
glycoxidation

and
lipoperoxidation
of
mitochondrial
proteins,
as
well
as
in
oxidative
damage
to

mtDNA
(in
the
case
of
heart
tissue).

4.-­-
These
beneficial
changes
were
not
translated
into
increased
(maximum)

longevity
most
likely
due
to
a
secondary
detrimental
effect
of
the
drug
on
heart

frequency,
and
likely
eventual
falls
in
arterial
pressure,
only
evident
in
very
old

animals,
whereas
the
mean
life
span
was
not
altered.
These
effects
are
most
relevant

for
consideration
of
possible
detrimental
effects
of
atenolol,
recently
detected
(meta-­-
analyses
from
2008
on)
only
in
old
hypertensive
human
subjects.

6.
ACKNOWLEDGMENTS

This
investigation
was
supported
in
part
by
I+D
grants
from
the
Spanish

Ministry
of
Science
and
Innovation
(BFU2008-­-00335/BFI)
to
G.Barja.

269