-
[show abstract]
[hide abstract]
ABSTRACT: Ischemic heart disease is the leading cause of morbi-mortality in developed countries. Both ischemia-reperfusion injury and mechanisms of cardioprotection have been studied for more than 50 years. It is known that the physiopathological mechanism of myocardial ischemia involves several factors that are closely related to its development, of which hypercholesterolemia is one of the main ones. Therefore, the objective of this review was to elucidate the effects of a high-cholesterol diet on normal ventricular function and ischemia-reperfusion injury associated phenomenon such as post-ischemic ventricular dysfunction (stunned myocardium). Although there exist many studies considering several aspects of this physiopathological entity, the majority were carried out on normal animals. Thus, experiments carried out on hypercholesterolemic models are controversial, in particular those evaluating different mechanisms of cardioprotection such as ischemic preconditioning and postconditioning, and cardioprotection granted by drugs such as statins, which apart from exerting a lipid-lowering effect, exert pleiotropic effects providing cardioprotection against ischemia-reperfusion injury. These controversial results concerning the mechanisms of cardioprotection vary according to quality, composition, and time of administration of the high-cholesterol diet, as well as the species used in each experiment. Thus, to compare the results it is necessary to take all of these variables into account, since they can change the obtained results.
Canadian Journal of Physiology and Pharmacology 08/2012; 90(9):1185-96. · 1.95 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This investigation was designed to determine the participation of the vagus nerve and muscarinic receptors in the remote ischemic preconditioning (rIPC) mechanism. New Zealand rabbits were anesthetized, and the femoral artery was dissected. After 30 min of monitoring, the hearts were isolated and subjected to 30 min of global no-flow ischemia and 180 min of reperfusion (non-rIPC group). The ventricular function was evaluated considering the left ventricular developed pressure and the left ventricular end diastolic pressure. In rIPC group, the rabbits were subjected to a three-cycle hind limb ischemia (5 min) and reperfusion (5 min) and the same protocol used in non-rIPC group was then repeated. In order to evaluate the afferent neural pathway during the rIPC protocol, we performed two different groups: one in which the femoral and sciatic nerves were sectioned and the other in which the spinal cord was sectioned (T9-T10 level). To study the efferent neural pathway during rIPC protocol, the vagus nerve was sectioned and, in a separated group, atropine was administered. The effect of vagal stimulation was also evaluated. An infarct size of 40.8±3.1% was obtained in non-rIPC group whereas in rIPC group, the infarct size decreased to 16.4±3.5% (p<0.05). During preconditioning protocol, the vagus nerve section and the atropine administration each abolished the effect of rIPC on infarct size. Vagal stimulation mimicked the effect of rIPC, decreasing infarct size to 15.2±4.7% (p<0.05). Decreases in infarct size were accompanied by improved left ventricular function. We demonstrated the presence of a neural afferent pathway since the spinal cord section completely abolished the effect of rIPC on infarct size. In conclusion, rIPC activates a neural afferent pathway and the cardioprotective signal reaches the heart through the vagus nerve (efferent pathway) and acetylcholine activates the IPC phenomenon when acting on the muscarinic receptors.
Experimental physiology 08/2012; · 3.17 Impact Factor
-
International journal of cardiology 03/2012; 155(3):490-1. · 7.08 Impact Factor
-
Verónica D'Annunzio,
Martín Donato,
Andrea Fellet, Bruno Buchholz,
Valeria G Antico Arciuch,
María C Carreras,
Laura B Valdez,
Tamara Zaobornyj,
Celina Morales,
Alberto Boveris,
Juan J Poderoso,
Ana M Balaszczuk,
Ricardo J Gelpi
[show abstract]
[hide abstract]
ABSTRACT: Hemorrhage (H) is associated with a left ventricular (LV) dysfunction. However, the diastolic function has not been studied in detail. The main goal was to assess the diastolic function both during and 120 min after bleeding, in the absence and in the presence of L-NAME. Also, the changes in mRNA and protein expression of nitric oxide synthase (NOS) isoforms were determined. New Zealand rabbits were divided into three groups: Sham group, H group (hemorrhage 20% blood volume), and H L-NAME group (hemorrhage treated with L-NAME). We evaluated systolic and diastolic ventricular functions in vivo and in vitro (Langendorff technique). Hemodynamic parameters and LV function were measured before, during, and at 120 min after bleeding. We analyzed the isovolumic relaxation using t ½ in vivo (closed chest). After that, hearts were excised and perfused in vitro to measure myocardial stiffness. Samples were frozen to measure NOS mRNA and protein expression. The t½ increased during bleeding and returned to basal values 120 min after bleeding. L-NAME blunted this effect. Data from the H group revealed a shift to the left in the LV end diastolic pressure-volume curve at 120 min after bleeding, which was blocked by L-NAME. iNOS and nNOS protein expression and mRNA levels increased at 120 min after the hemorrhage. Acute hemorrhage induces early and transient isovolumic relaxation impairment and an increase in myocardial stiffness 120 min after bleeding. L-NAME blunted the LV dysfunction, suggesting that NO modulates ventricular function through iNOS and nNOS isoforms.
Molecular and Cellular Biochemistry 08/2011; 359(1-2):169-76. · 2.06 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Isolated rabbit hearts were exposed to ischemia (I; 15 min) and reperfusion (R; 5-30 min) in a model of stunned myocardium. I/R decreased left-ventricle O(2) consumption (46%) and malate-glutamate-supported mitochondrial state 3 respiration (32%). Activity of complex I was 28% lower after I/R. The pattern observed for the decline in complex I activity was also observed for the reduction in mitochondrial nitric oxide synthase (mtNOS) biochemical (28%) and functional (50%) activities, in accordance with the reported physical and functional interactions between complex I and mtNOS. Malate-glutamate-supported state 4 H(2)O(2) production was increased by 78% after I/R. Rabbit heart Mn-SOD concentration in the mitochondrial matrix (7.4±0.7 μM) was not modified by I/R. Mitochondrial phospholipid oxidation products were increased by 42%, whereas protein oxidation was only slightly increased. I/R produced a marked (70%) enhancement in tyrosine nitration of the mitochondrial proteins. Adenosine attenuated postischemic ventricular dysfunction and protected the heart from the declines in O(2) consumption and in complex I and mtNOS activities and from the enhancement of mitochondrial phospholipid oxidation. Rabbit myocardial stunning is associated with a condition of dysfunctional mitochondria named "complex I syndrome." The beneficial effect of adenosine could be attributed to a better regulation of intracellular cardiomyocyte Ca(2+) concentration.
Free radical biology & medicine 06/2011; 51(6):1203-12. · 5.42 Impact Factor
-
Martín Donato,
Verónica D'Annunzio, Bruno Buchholz,
Verónica Miksztowicz,
Cristina Lorenzo Carrión,
Laura B Valdez,
Tamara Zaobornyj,
Laura Schreier,
Regina Wikinski,
Alberto Boveris,
Gabriela Berg,
Ricardo J Gelpi
[show abstract]
[hide abstract]
ABSTRACT: The activation of matrix metalloproteinases (MMPs) contributes to myocardial injury at the onset of reperfusion; however, their role in ischaemic postconditioning is unknown. The aim of the present study was to examine the effects of ischaemic postconditioning on MMP activity in isolated rabbit hearts. The isolated rabbit hearts were subjected to 30 min of global ischaemia followed by 180 min of reperfusion (I/R group; n = 8). In the ischaemic postconditioning group (n = 8), a postconditioning protocol was performed (2 cycles of 30 s reperfusion-ischaemia). In other experiments, we added doxycycline, an MMP inhibitor, at 25 (n = 7) or 50 micromol l(1) (n = 8) during the first 2 min of reperfusion. Coronary effluent and left ventricular tissue were collected during pre-ischaemic conditions and at different times during the reperfusion period to measure MMP-2 activity and cardiac protein nitration. We evaluated ventricular function and infarct size. In the I/R group, infarct size was 32.1 +/- 5.2%; Postcon reduced infarct size to 9.5 +/- 3.8% (P < 0.05) and inhibited MMP-2 activity during reperfusion. The administration of doxycycline at 50 micromol l(1) inhibited MMP-2 activity and cardiac protein nitration and reduced the infarct size to 9.7 +/- 2.8% (P < 0.05). A lower dose of doxycycline (25 micromol l(1)) failed to inhibit MMP-2 activity and did not modify the infarct size. Our results strongly suggest that ischaemic postconditioning may exert part of its cardioprotective effects through the inhibition of MMP-2 activity.
Experimental physiology 10/2009; 95(2):274-81. · 3.17 Impact Factor
-
Verónica D'Annunzio,
Martín Donato,
Lukas Erni,
Verónica Miksztowicz, Bruno Buchholz,
Cristina Lorenzo Carrión,
Laura Schreier,
Regina Wikinski,
Ricardo J Gelpi,
Gabriela Berg,
Nidia Basso
[show abstract]
[hide abstract]
ABSTRACT: There is evidence that statin treatment before ischemia protects myocardium from ischemia/reperfusion injury. The objective is to determine whether rosuvastatin administered during reperfusion modifies infarct size and the recovery of postischemic ventricular dysfunction in normocholesterolemic and hypercholesterolemic rabbits. In addition, we also evaluated the role of matrix metalloproteinase type 2 (MMP)-2 activation. Langendorff-perfused rabbit hearts were subjected to 30 minutes of ischemia and 120 minutes of reperfusion. In group 2, we added rosuvastatin after 30 minutes of ischemia and from the beginning of reperfusion. In group 3, an MMP inhibitor (doxycycline) was administered during the first 2 minutes of reperfusion. Finally, we repeated these groups but in hypercholesterolemic rabbits (groups 4, 5, and 6). The infarct size was 16.6% +/- 3.9% in group 1 and 25.6% +/- 2.7% in group 4. Rosuvastatin reduced infarct size to 4.5% +/- 1.1% and 6.1% +/- 1.5% in groups 2 and 5, respectively (P < 0.05). Rosuvastatin significantly decreased MMP-2 activity during reperfusion, and doxycycline induced an inhibition of MMP-2 activity and a reduction of infarct size in normocholesterolemic (4.9% +/- 0.9%) and hypercholesterolemic animals (8.3% +/- 1.6%) (P < 0.05). Rosuvastatin reduces infarct size and attenuates MMP-2 activity. These data and the correlation between MMP-2 and infarct size suggest that MMP-2 plays an important role in the mechanisms of cardioprotection afforded by rosuvastatin.
Journal of cardiovascular pharmacology 01/2009; 53(2):137-44. · 2.83 Impact Factor
