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Effects of palmitoyl carnitine and a novel ester derivative on the isolated perfused rat heart
J Mol Cell Cardiol 22 (Supplement
III) (1990)
pS73 EPFECTS OF PALHtTOIL CAIUIRIEE AIID
A HOVEL ESTER DERIVATIVE OH THE IS(LAm PERFUSEDAAT HEART. David N Criddle, George H Dewar, William B Wathey, Brian Woodward. School of Pharmacy k Pharmacology, University of Ba_t+, Avon, UK. Using a constant flow system (lOml.min ) we have examined the effects of palmitoyl carnitine (PC), and an ester derivative isopropyl palmitoyl carnitine (PlPi) on developed tension CDT), perfusion pressure (PP) and heart rate (FIR) of Langendorff perfused rat hearts. Bolus injections of PC (I-300nmoles) produced increases in PP and an irreversible depression of DT. At the highest doses the increase in PP was follcwed by a small dilator component. There was no effect on heart rate. Constant perfusion of PC(0.3-l.OuM) had no effect on PP; 3uM produced a fall in PP of 36.3 ti.8 mu@ while 1OuW resulted in a rapid increase in PP (72.09.2mmHg) and complete inhibition of DT within 3.4~0.8 min. (n=Z). In contrast, bolus doses of PlPi (O.l-1Orrmoles.j caused a rapid dose dependent fall in PP which was sustained for upto 2Omin at the higher doses, this was associated with a small depression of DT. Constant perfusion of PlPi also decreased PP (maximal at O.luM, EC 16nM,n=4). A high concentration of PlPi( 10uM) produced a large increase in PP (5fs?5+1.5mrnHg) and inhibition of DT within 16.020.3min. Therefore, esterification of PC alters its profile of vascular activity. The vasodilation produced by PlPi was not affected by flurbiprofen (lOuM), SOD (2Ou.ml- ) or atropine (5OnM).
ps74
EFFECT OF ACUTE AND CHRONIC TREATllENT
PROPIONIL-L-CARNITINE
WITH
ON NECHANICAL PERFORNANCE Of
ISOLAIEI)
HEART Evasio
Pasini,
Chair
of We
Claudia
the
rabbit
acute
induced
i’s75
heart
a positive
inotropic
This
was
correlated
lhis
effect
effect
of
PLC
with
an
was
not
2
19).
(84 inotropic
effects
mg/Kg)
rate
(HR)
longer These
in
8-10
Condorelli.
myocardial after that
to
Roberto
no
beinq Nat
content 5
days PLC,
changes
HR
of
PLC
(from
treatment given
68 uhen
chronically
or
CPP
[err
i.
of
the
t
17
acutely
volumes
PLC
(SE)
to
content at
least
uf M,
it
2.;
medium, 141. ot
+
atO PlC
R ddvs),
tlk, :tr JL,:
3.' :,
rimas)g; iem> pxp-5
effect.
ACTIONS OF PALMITOYL CARNITINE IN EMBRYOMC CHICK MYOCYTES Leslie Patmore, Mandy 3. Anderson, Greig P. Duncan & Michael Spedding. Syntex Research Centre, Riccarton, Edinburgh, EH14 4AP, Scotland Palmitoyl carnitine and Bay K 8644 have been shown to increase contractility in embryonic chick myocyte aggregates. Bay K 8644 also increased the inward calcium channel current recorded from single myocytes. In contrast palmitoyl -d,l-camitine (PC) (1pM) did not increase the calcium channel currents but caused a reduction in the transient component of the current with a 17 mV shift of the conductance-voltage curve to more positive potentials. Pretmatmem of cells with PC (1pM) for 15 rnin - 3 hr had essentially similar effects on the calcium channel currents.These data indicate that although PC is positively inotropic it does not share the same mechanism of action on the calcium channel as Bay K 8644. PC had little effect on inward sodium currents activated by depolarization from -80 mV to test potentials of -40 to +4O mV. Pretreatment of aggregates with 5 pM ryanodine abolished the positive inotropic response to PC bur did not significantly affect the response to Bay K 8644. Treatment of myccytes with 1 p.M PC increased the outward potassium current, doubling the current evoked on depolarization from -80 to +30 mV. This is consistent with release of calcium from the SR potentiating Ca-activated potassium currents. These findings indicate that acyl camitines, lipid metabolites which accumulate in ischaemia, cause increased calcium mobilization by a selective effect on the SR. s.113
,,I "it
nmelioratvd from
or
haa'
chrgnicaliy
perfusion
tissue
funqt1o.i '> !O
to
added and
for
(For
IO
added When
evident
concentration of
uhen
When (CPP). in
mccha;gical
(from
animals.
maximally
on
perfusate
pressure
with
and
the
the
perfusIon
Ca
(PLC)
in
days
p
from
suggest
in-ice
prapionil-1-carnitine
inotropZ&sm
apparent
Cargnoni,
delivered
coronary
(30%.
indipendent
data
f or or
positive
increase
of
directly
effect
was
Rnna
Italy.
either
(250
relationship,
Curello,
Brescia,
chronic was
injected
ml.
positive
PLC
inotropism,
pressure-volume
unchanged
of and
heart.
intraperitoneally on
Salvatore
University
studied
isolated
effect
Cecooi,
Cardiology,
"91
III) (1990)
pS73 EPFECTS OF PALHtTOIL CAIUIRIEE AIID
A HOVEL ESTER DERIVATIVE OH THE IS(LAm PERFUSEDAAT HEART. David N Criddle, George H Dewar, William B Wathey, Brian Woodward. School of Pharmacy k Pharmacology, University of Ba_t+, Avon, UK. Using a constant flow system (lOml.min ) we have examined the effects of palmitoyl carnitine (PC), and an ester derivative isopropyl palmitoyl carnitine (PlPi) on developed tension CDT), perfusion pressure (PP) and heart rate (FIR) of Langendorff perfused rat hearts. Bolus injections of PC (I-300nmoles) produced increases in PP and an irreversible depression of DT. At the highest doses the increase in PP was follcwed by a small dilator component. There was no effect on heart rate. Constant perfusion of PC(0.3-l.OuM) had no effect on PP; 3uM produced a fall in PP of 36.3 ti.8 mu@ while 1OuW resulted in a rapid increase in PP (72.09.2mmHg) and complete inhibition of DT within 3.4~0.8 min. (n=Z). In contrast, bolus doses of PlPi (O.l-1Orrmoles.j caused a rapid dose dependent fall in PP which was sustained for upto 2Omin at the higher doses, this was associated with a small depression of DT. Constant perfusion of PlPi also decreased PP (maximal at O.luM, EC 16nM,n=4). A high concentration of PlPi( 10uM) produced a large increase in PP (5fs?5+1.5mrnHg) and inhibition of DT within 16.020.3min. Therefore, esterification of PC alters its profile of vascular activity. The vasodilation produced by PlPi was not affected by flurbiprofen (lOuM), SOD (2Ou.ml- ) or atropine (5OnM).
ps74
EFFECT OF ACUTE AND CHRONIC TREATllENT
PROPIONIL-L-CARNITINE
WITH
ON NECHANICAL PERFORNANCE Of
ISOLAIEI)
HEART Evasio
Pasini,
Chair
of We
Claudia
the
rabbit
acute
induced
i’s75
heart
a positive
inotropic
This
was
correlated
lhis
effect
effect
of
PLC
with
an
was
not
2
19).
(84 inotropic
effects
mg/Kg)
rate
(HR)
longer These
in
8-10
Condorelli.
myocardial after that
to
Roberto
no
beinq Nat
content 5
days PLC,
changes
HR
of
PLC
(from
treatment given
68 uhen
chronically
or
CPP
[err
i.
of
the
t
17
acutely
volumes
PLC
(SE)
to
content at
least
uf M,
it
2.;
medium, 141. ot
+
atO PlC
R ddvs),
tlk, :tr JL,:
3.' :,
rimas)g; iem> pxp-5
effect.
ACTIONS OF PALMITOYL CARNITINE IN EMBRYOMC CHICK MYOCYTES Leslie Patmore, Mandy 3. Anderson, Greig P. Duncan & Michael Spedding. Syntex Research Centre, Riccarton, Edinburgh, EH14 4AP, Scotland Palmitoyl carnitine and Bay K 8644 have been shown to increase contractility in embryonic chick myocyte aggregates. Bay K 8644 also increased the inward calcium channel current recorded from single myocytes. In contrast palmitoyl -d,l-camitine (PC) (1pM) did not increase the calcium channel currents but caused a reduction in the transient component of the current with a 17 mV shift of the conductance-voltage curve to more positive potentials. Pretmatmem of cells with PC (1pM) for 15 rnin - 3 hr had essentially similar effects on the calcium channel currents.These data indicate that although PC is positively inotropic it does not share the same mechanism of action on the calcium channel as Bay K 8644. PC had little effect on inward sodium currents activated by depolarization from -80 mV to test potentials of -40 to +4O mV. Pretreatment of aggregates with 5 pM ryanodine abolished the positive inotropic response to PC bur did not significantly affect the response to Bay K 8644. Treatment of myccytes with 1 p.M PC increased the outward potassium current, doubling the current evoked on depolarization from -80 to +30 mV. This is consistent with release of calcium from the SR potentiating Ca-activated potassium currents. These findings indicate that acyl camitines, lipid metabolites which accumulate in ischaemia, cause increased calcium mobilization by a selective effect on the SR. s.113
,,I "it
nmelioratvd from
or
haa'
chrgnicaliy
perfusion
tissue
funqt1o.i '> !O
to
added and
for
(For
IO
added When
evident
concentration of
uhen
When (CPP). in
mccha;gical
(from
animals.
maximally
on
perfusate
pressure
with
and
the
the
perfusIon
Ca
(PLC)
in
days
p
from
suggest
in-ice
prapionil-1-carnitine
inotropZ&sm
apparent
Cargnoni,
delivered
coronary
(30%.
indipendent
data
f or or
positive
increase
of
directly
effect
was
Rnna
Italy.
either
(250
relationship,
Curello,
Brescia,
chronic was
injected
ml.
positive
PLC
inotropism,
pressure-volume
unchanged
of and
heart.
intraperitoneally on
Salvatore
University
studied
isolated
effect
Cecooi,
Cardiology,
"91