3 research outputs found
Effects of Hypoxia and Acidosis on Cardiac Electrophysiology and Hemodynamics. Is NHE-Inhibition by Cariporide Still Advantageous?
Hypoxia often leads to severe cardiac malfunctions. It is assumed that intracellular
calcium overload is -inter alia- responsible for left ventricular (LV) deterioration. Inhibition of
the sodium-proton exchanger (NHE), which finally inhibits/slows calcium overload, may
ameliorate cardiac function. Our aim was to evaluate cariporide, an inhibitor of NHE1
in a Langendorff-perfused heart model. To discriminate a potentially different impact of
extracellular acidosis and hypoxia we examined 48 Chinchilla Bastard rabbits divided
into 8 experimental groups: control group (pH = 7.4, O2 = 100%) without or with
cariporide (1µM), acidosis group (pH = 7.0, O2 = 100%) without or with cariporide
(1µM), hypoxia group (pH = 7.4, O2 = 40%) without or with cariporide (1µM) and
hypoxia+acidosis group (pH = 7.0, O2 = 40%) without or with cariporide (1µM).
Hearts were subjected to acidotic/hypoxic conditions for 90 min followed by 60 min of
reperfusion. Hypoxia and hypoxia+acidosis led to a severe deterioration of LV function
with a decrease in LV pressure by about 70% and an increase of end-diastolic pressure
from 6.7 ± 0.6 to 36.8 ± 5.4 (hypoxia) or from 7.0 ± 0.2 to 18.6 ± 4.1 (hypoxia+acidosis).
Moreover, maximum contraction velocity decreased from about 1,800 mmHg/s to 600
mmHg/s during hypoxia ± acidosis and maximum relaxation velocity deteriorated from
−1,500 mmHg/s to about −600 mmHg/s. During reperfusion hearts subjected to
hypoxia+acidosis recovered faster than hearts subjected to hypoxia alone, reaching
control levels after 5 min of reperfusion. Electrophysiologic analysis revealed an 1.2
fold increase in both dispersion of activation-recovery interval and in total activation
time in the hypoxia ± acidosis group. Cariporide application significantly improved
LV hemodynamics and electrophysiology in the hypoxia group but not in the group
subjected to hypoxia+acidosis. Immunohistologic analysis of cardiac specimen revealed
a significant increase of factors involved in hypoxia/reperfusion injury like nitrotyrosine
and poly-ADP-ribose as well as apoptosis-inducing factors like AIF or cleaved-caspase
3 in LV after hypoxia ± acidosis. ATP was reduced by hypoxia but not by acidosis. Again,
cariporide mitigated these processes only in the hypoxia alone group, but not in the group
with additional acidosis. Acidosis without hypoxia only marginally disturbed LV function
and electrophysiology, and was not affected by cariporide. Thus, our study demonstrated
that several detrimental effects of hypoxia were mitigated or abrogated by acidosis and
that NHE-inhibition improved only hypoxia-induced cardiac dysfunction
Effects of Hypoxia and Acidosis on Cardiac Electrophysiology and Hemodynamics. Is NHE-Inhibition by Cariporide Still Advantageous?
Hypoxia often leads to severe cardiac malfunctions. It is assumed that intracellular
calcium overload is -inter alia- responsible for left ventricular (LV) deterioration. Inhibition of
the sodium-proton exchanger (NHE), which finally inhibits/slows calcium overload, may
ameliorate cardiac function. Our aim was to evaluate cariporide, an inhibitor of NHE1
in a Langendorff-perfused heart model. To discriminate a potentially different impact of
extracellular acidosis and hypoxia we examined 48 Chinchilla Bastard rabbits divided
into 8 experimental groups: control group (pH = 7.4, O2 = 100%) without or with
cariporide (1µM), acidosis group (pH = 7.0, O2 = 100%) without or with cariporide
(1µM), hypoxia group (pH = 7.4, O2 = 40%) without or with cariporide (1µM) and
hypoxia+acidosis group (pH = 7.0, O2 = 40%) without or with cariporide (1µM).
Hearts were subjected to acidotic/hypoxic conditions for 90 min followed by 60 min of
reperfusion. Hypoxia and hypoxia+acidosis led to a severe deterioration of LV function
with a decrease in LV pressure by about 70% and an increase of end-diastolic pressure
from 6.7 ± 0.6 to 36.8 ± 5.4 (hypoxia) or from 7.0 ± 0.2 to 18.6 ± 4.1 (hypoxia+acidosis).
Moreover, maximum contraction velocity decreased from about 1,800 mmHg/s to 600
mmHg/s during hypoxia ± acidosis and maximum relaxation velocity deteriorated from
−1,500 mmHg/s to about −600 mmHg/s. During reperfusion hearts subjected to
hypoxia+acidosis recovered faster than hearts subjected to hypoxia alone, reaching
control levels after 5 min of reperfusion. Electrophysiologic analysis revealed an 1.2
fold increase in both dispersion of activation-recovery interval and in total activation
time in the hypoxia ± acidosis group. Cariporide application significantly improved
LV hemodynamics and electrophysiology in the hypoxia group but not in the group
subjected to hypoxia+acidosis. Immunohistologic analysis of cardiac specimen revealed
a significant increase of factors involved in hypoxia/reperfusion injury like nitrotyrosine
and poly-ADP-ribose as well as apoptosis-inducing factors like AIF or cleaved-caspase
3 in LV after hypoxia ± acidosis. ATP was reduced by hypoxia but not by acidosis. Again,
cariporide mitigated these processes only in the hypoxia alone group, but not in the group
with additional acidosis. Acidosis without hypoxia only marginally disturbed LV function
and electrophysiology, and was not affected by cariporide. Thus, our study demonstrated
that several detrimental effects of hypoxia were mitigated or abrogated by acidosis and
that NHE-inhibition improved only hypoxia-induced cardiac dysfunction
Effects of Hypoxia and Acidosis on Cardiac Electrophysiology and Hemodynamics. Is NHE-Inhibition by Cariporide Still Advantageous?
Hypoxia often leads to severe cardiac malfunctions. It is assumed that intracellular
calcium overload is -inter alia- responsible for left ventricular (LV) deterioration. Inhibition of
the sodium-proton exchanger (NHE), which finally inhibits/slows calcium overload, may
ameliorate cardiac function. Our aim was to evaluate cariporide, an inhibitor of NHE1
in a Langendorff-perfused heart model. To discriminate a potentially different impact of
extracellular acidosis and hypoxia we examined 48 Chinchilla Bastard rabbits divided
into 8 experimental groups: control group (pH = 7.4, O2 = 100%) without or with
cariporide (1µM), acidosis group (pH = 7.0, O2 = 100%) without or with cariporide
(1µM), hypoxia group (pH = 7.4, O2 = 40%) without or with cariporide (1µM) and
hypoxia+acidosis group (pH = 7.0, O2 = 40%) without or with cariporide (1µM).
Hearts were subjected to acidotic/hypoxic conditions for 90 min followed by 60 min of
reperfusion. Hypoxia and hypoxia+acidosis led to a severe deterioration of LV function
with a decrease in LV pressure by about 70% and an increase of end-diastolic pressure
from 6.7 ± 0.6 to 36.8 ± 5.4 (hypoxia) or from 7.0 ± 0.2 to 18.6 ± 4.1 (hypoxia+acidosis).
Moreover, maximum contraction velocity decreased from about 1,800 mmHg/s to 600
mmHg/s during hypoxia ± acidosis and maximum relaxation velocity deteriorated from
−1,500 mmHg/s to about −600 mmHg/s. During reperfusion hearts subjected to
hypoxia+acidosis recovered faster than hearts subjected to hypoxia alone, reaching
control levels after 5 min of reperfusion. Electrophysiologic analysis revealed an 1.2
fold increase in both dispersion of activation-recovery interval and in total activation
time in the hypoxia ± acidosis group. Cariporide application significantly improved
LV hemodynamics and electrophysiology in the hypoxia group but not in the group
subjected to hypoxia+acidosis. Immunohistologic analysis of cardiac specimen revealed
a significant increase of factors involved in hypoxia/reperfusion injury like nitrotyrosine
and poly-ADP-ribose as well as apoptosis-inducing factors like AIF or cleaved-caspase
3 in LV after hypoxia ± acidosis. ATP was reduced by hypoxia but not by acidosis. Again,
cariporide mitigated these processes only in the hypoxia alone group, but not in the group
with additional acidosis. Acidosis without hypoxia only marginally disturbed LV function
and electrophysiology, and was not affected by cariporide. Thus, our study demonstrated
that several detrimental effects of hypoxia were mitigated or abrogated by acidosis and
that NHE-inhibition improved only hypoxia-induced cardiac dysfunction