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1.
Basic Res Cardiol ; 116(1): 34, 2021 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-34018053

RESUMEN

Reducing infarct size (IS) by interfering with mechanisms for cardiomyocyte death remains an elusive goal. DMX-5804, a selective inhibitor of the stress-activated kinase MAP4K4, suppresses cell death in mouse myocardial infarction (MI), human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs), and 3D human engineered heart tissue, whose fidelity to human biology is hoped to strengthen the route to clinical success. Here, DMX-10001, a soluble, rapidly cleaved pro-drug of DMX-5804, was developed for i.v. testing in large-mammal MI. Following pharmacodynamic studies, a randomized, blinded efficacy study was performed in swine subjected to LAD balloon occlusion (60 min) and reperfusion (24 h). Thirty-six animals were enrolled; 12 were excluded by pre-defined criteria, death before infusion, or technical issues. DMX-10001 was begun 20 min before reperfusion (30 min, 60 mg/kg/h; 23.5 h, 17 mg/kg/h). At all times tested, beginning 30 min after the start of infusion, DMX-5804 concentrations exceeded > fivefold the levels that rescued hPSC-CMs and reduced IS in mice after oral dosing with DMX-5804 itself. No significant reduction occurred in IS or no-reflow corrected for the area at ischemic risk, even though DMX-10001 reduced IS, expressed in grams or % of LV mass, by 27%. In summary, a rapidly cleaved pro-drug of DMX-5804 failed to reduce IS in large-mammal MI, despite exceeding the concentrations for proven success in both mice and hPSC-CMs.


Asunto(s)
Células Madre Pluripotentes Inducidas/efectos de los fármacos , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Infarto del Miocardio/prevención & control , Miocitos Cardíacos/efectos de los fármacos , Profármacos/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Animales , Modelos Animales de Enfermedad , Femenino , Hemodinámica/efectos de los fármacos , Humanos , Células Madre Pluripotentes Inducidas/enzimología , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Ratones , Infarto del Miocardio/enzimología , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Miocitos Cardíacos/enzimología , Miocitos Cardíacos/patología , Profármacos/farmacocinética , Inhibidores de Proteínas Quinasas/farmacocinética , Proteínas Serina-Treonina Quinasas/metabolismo , Sus scrofa , Investigación Biomédica Traslacional , Función Ventricular Izquierda/efectos de los fármacos
2.
Arterioscler Thromb Vasc Biol ; 39(11): 2338-2352, 2019 11.
Artículo en Inglés | MEDLINE | ID: mdl-31554418

RESUMEN

OBJECTIVE: In an adult porcine model of familial hypercholesterolemia (FH), coronary plaque development was characterized. To elucidate the underlying mechanisms of the observed inter-individual variation in disease severity, detailed lipoprotein profiles were determined. Approach and Results: FH pigs (3 years old, homozygous LDLR R84C mutation) received an atherogenic diet for 12 months. Coronary atherosclerosis development was monitored using serial invasive imaging and histology. A pronounced difference was observed between mildly diseased pigs which exclusively developed early lesions (maximal plaque burden, 25% [23%-34%]; n=5) and advanced-diseased pigs (n=5) which developed human-like, lumen intruding plaques (maximal plaque burden, 69% [57%-77%]) with large necrotic cores, intraplaque hemorrhage, and calcifications. Advanced-diseased pigs and mildly diseased pigs displayed no differences in conventional risk factors. Additional plasma lipoprotein profiling by size-exclusion chromatography revealed 2 different LDL (low-density lipoprotein) subtypes: regular and larger LDL. Cholesterol, sphingosine-1-phosphate, ceramide, and sphingomyelin levels were determined in these LDL-subfractions using standard laboratory techniques and high-pressure liquid chromatography mass-spectrometry analyses, respectively. At 3 months of diet, regular LDL of advanced-diseased pigs contained relatively more cholesterol (LDL-C; regular/larger LDL-C ratio 1.7 [1.3-1.9] versus 0.8 [0.6-0.9]; P=0.008) than mildly diseased pigs, while larger LDL contained more sphingosine-1-phosphate, ceramides, and sphingomyelins. Larger and regular LDL was also found in plasma of 3 patients with homozygous FH with varying LDL-C ratios. CONCLUSIONS: In our adult FH pig model, inter-individual differences in atherosclerotic disease severity were directly related to the distribution of cholesterol and sphingolipids over a distinct LDL profile with regular and larger LDL shortly after the diet start. A similar LDL profile was detected in patients with homozygous FH.


Asunto(s)
LDL-Colesterol/sangre , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/patología , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/patología , Placa Aterosclerótica/sangre , Placa Aterosclerótica/patología , Animales , LDL-Colesterol/clasificación , Dieta Aterogénica , Modelos Animales de Enfermedad , Femenino , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico por imagen , Masculino , Placa Aterosclerótica/diagnóstico por imagen , Índice de Severidad de la Enfermedad , Esfingolípidos/sangre , Porcinos
3.
Catheter Cardiovasc Interv ; 93(5): 963-970, 2019 04 01.
Artículo en Inglés | MEDLINE | ID: mdl-30430723

RESUMEN

OBJECTIVES: To evaluate the in vivo feasibility of aortography with one accurately timed diastolic low-volume contrast injection for quantitative assessment of aortic regurgitation (AR) post transcatheter aortic valve replacement (TAVR). BACKGROUND: With the rise of a minimalistic approach for TAVR, aortography (re)emerges as a pragmatic tool for AR assessment. In a mock circulation system, we have validated the accuracy of a single diastolic injection triggered by electrocardiogram (ECG) with low-contrast volume. METHODS: Two-phase experiment: first, a series of aortograms were performed in a porcine model, with 8 mL of contrast using the synchronized (SYNC) and the conventional non-synchronized (NS) injections. In a second phase, we developed a model of AR by inserting partially unsheathed Wallstents of 6-10 mm of diameter across the pig's aortic valve, performing SYNC injections with 8 mL of contrast and NS injections with 8 mL and 15 mL (rate: 20 mL/sec). Respective accuracies of SYNC vs. NS were assessed using Passing-Bablock regression. An angiography core laboratory performed quantitative AR assessment with videodensitometry (VD-AR). RESULTS: The SYNC injections produced higher opacification of the aortic root compared with NS injections (P = 0.04 for density). In the second phase, a regression line for predicting VD-AR based on the SYNC injection resulted in a lower intercept and a slope closer to the line of identity (y = 11.9 + 0.79x, P < 0.001, r2 = 0.94) with the NS-8 mL than with the NS-15 mL injection (y = 26.5 + 0.55x, P < 0.001, r2 = 0.81). CONCLUSION: Synchronized diastolic injection with low contrast volume produced denser images in the aortic root and more accurate than the conventional injection; thus, may be an appealing alternative for assessment of AR post TAVR.


Asunto(s)
Insuficiencia de la Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/diagnóstico por imagen , Aortografía , Medios de Contraste/administración & dosificación , Hemodinámica , Yopamidol/administración & dosificación , Animales , Válvula Aórtica/fisiopatología , Insuficiencia de la Válvula Aórtica/fisiopatología , Diástole , Modelos Animales de Enfermedad , Electrocardiografía , Estudios de Factibilidad , Femenino , Frecuencia Cardíaca , Inyecciones , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Sus scrofa , Factores de Tiempo
4.
J Surg Res ; 217: 84-91, 2017 09.
Artículo en Inglés | MEDLINE | ID: mdl-28595813

RESUMEN

BACKGROUND: Previous experimental studies on cyanoacrylate (CA) glue for the prevention of colorectal anastomotic leakage (AL) have shown promising results. The aim of this study was to investigate the effect of CA in prevention of leakage in a porcine model of ischemic colorectal AL. METHODS: Twenty-four animals were divided into four groups of six: (1)ischemic anastomosis with sufficient suture (ISCH), (2)ischemic anastomosis with sufficient suture and CA reinforcement (CA-ISCH), (3)ischemic anastomosis with insufficient suture (ISCH-AI), and (4)ischemic anastomosis with insufficient suture and CA reinforcement (CA-ISCH-AI). In CA groups, N-butyl-2-cyanoacrylate was applied between the colon ends. Anastomotic bursting pressure, abscess formation, and adhesion formation were evaluated on postoperative day 7. Tissue samples were obtained for histologic evaluation of foreign body reaction. RESULTS: The AL rate was 4 of 6 (67%) in the ISCH-AI group compared with none in the other three groups. The ISCH and ISCH-AI groups had significantly higher AL scores compared with the CA groups. The mean anastomotic bursting pressure was 167 ± 54 mm Hg in the ISCH-group versus 213 ± 43 mm Hg in the CA-ISCH-group (P = nonsignificant) and 145 ± 102 mm Hg in the ISCH-AI group versus 187 ± 19 mm Hg in the CA-ISCH-AI group (P = nonsignificant). The average adhesion score was significantly higher in the ISCH group than in the CA-ISCH group (4.2 ± 1.3 versus 1.7 ± 0.82; P = 0.019). Stricture of the anastomosis occurred only in the non-CA groups (3/12, 25%). CONCLUSIONS: Anastomotic reinforcement with CA is effective and safe to prevent leakage in a high-risk colorectal anastomosis in a porcine model.


Asunto(s)
Anastomosis Quirúrgica/métodos , Fuga Anastomótica/prevención & control , Colon/cirugía , Cianoacrilatos/uso terapéutico , Adhesivos Tisulares/uso terapéutico , Animales , Femenino , Distribución Aleatoria , Porcinos
5.
Basic Res Cardiol ; 110(5): 508, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26306761

RESUMEN

Vagal nerve stimulation (VNS) started prior to, or during, ischemia has been shown to reduce infarct size. Here, we investigated the effect of VNS when started just prior to, and continued during early, reperfusion on infarct size and no-reflow and studied the underlying mechanisms. For this purpose, swine (13 VNS, 10 sham) underwent 45 min mid-LAD occlusion followed by 120 min of reperfusion. VNS was started 5 min prior to reperfusion and continued until 15 min of reperfusion. Area at risk, area of no-reflow (% of infarct area) and infarct size (% of area at risk), circulating cytokines, and regional myocardial leukocyte influx were assessed after 120 min of reperfusion. VNS significantly reduced infarct size from 67 ± 2 % in sham to 54 ± 5 % and area of no-reflow from 54 ± 6 % in sham to 32 ± 6 %. These effects were accompanied by reductions in neutrophil (~40 %) and macrophage (~60 %) infiltration in the infarct area (all p < 0.05), whereas systemic circulating plasma levels of TNFα and IL6 were not affected. The degree of cardioprotection could not be explained by the VNS-induced bradycardia or the VNS-induced decrease in the double product of heart rate and left ventricular systolic pressure. In the presence of NO-synthase inhibitor LNNA, VNS no longer attenuated infarct size and area of no-reflow, which was paralleled by similarly unaffected regional leukocyte infiltration. In conclusion, VNS is a promising novel adjunctive therapy that limits reperfusion injury in a large animal model of acute myocardial infarction.


Asunto(s)
Infarto del Miocardio/fisiopatología , Daño por Reperfusión Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/fisiopatología , Estimulación del Nervio Vago/métodos , Animales , Modelos Animales de Enfermedad , Femenino , Masculino , Sus scrofa
6.
Am J Physiol Heart Circ Physiol ; 305(12): H1790-7, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24124184

RESUMEN

Recently, the ventilatory variation in pre-ejection period (ΔPEP) was found to be useful in the prediction of fluid-responsiveness of patients in shock. In the present study we investigated the behavior of the ventilation-induced variations in the systolic timing intervals in response to a graded hemorrhage protocol. The timing intervals studied included the ventilatory variation in ventricular electromechanical delay (ΔEMD), isovolumic contraction period (determined from the arterial pressure waveform, ΔAIC), pulse travel time (ΔPTT), and ΔPEP. ΔAIC and ΔPEP were evaluated in the aorta and carotid artery (annotated by subscripts Ao and CA) and were compared with the responses of pulse pressure variation (ΔPPAo) and stroke volume variation (ΔSV). The graded hemorrhage protocol, followed by resuscitation using norepinephrine and autologous blood transfusion, was performed in eight anesthetized Yorkshire X Landrace swine. ΔAICAo, ΔAICCA, ΔPEPAo, ΔPEPCA, ΔPPAo, ΔPPCA, and ΔSV showed significant increases during the graded hemorrhage and significant decreases during the subsequent resuscitation. ΔAICAo, ΔAICCA, ΔPEPAo, and ΔPEPCA all correlated well with ΔPPAo and ΔSV (all r ≥ 0.8, all P < 0.001). ΔEMD and ΔPTT did not significantly change throughout the protocol. In contrast with ΔPEPAo, which was significantly higher than ΔPEPCA (P < 0.01), ΔAICAo was not different from ΔAICCA. In conclusion, ventilation-induced preload variation principally affects the arterially determined isovolumic contraction period (AIC). Moreover, ΔAIC can be determined solely from the arterial pressure waveform, whereas ΔPEP also requires ECG measurement. Importantly, ΔAIC determined from either the carotid or aortic pressure waveform are interchangeable, suggesting that, in contrast with ΔPEP, ΔAIC may be site independent.


Asunto(s)
Presión Sanguínea/fisiología , Frecuencia Cardíaca/fisiología , Contracción Miocárdica/fisiología , Choque Hemorrágico/diagnóstico , Volumen Sistólico/fisiología , Animales , Femenino , Resucitación , Índice de Severidad de la Enfermedad , Choque Hemorrágico/fisiopatología , Porcinos
7.
Ultrasound Med Biol ; 49(12): 2476-2482, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37704558

RESUMEN

OBJECTIVE: The aim of this study was to assess the feasibility and imaging options of contrast-enhanced volumetric ultrasound kidney vasculature imaging in a porcine model using a prototype sparse spiral array. METHODS: Transcutaneous freehand in vivo imaging of two healthy porcine kidneys was performed according to three protocols with different microbubble concentrations and transmission sequences. Combining high-frame-rate transmission sequences with our previously described spatial coherence beamformer, we determined the ability to produce detailed volumetric images of the vasculature. We also determined power, color and spectral Doppler, as well as super-resolved microvasculature in a volume. The results were compared against a clinical 2-D ultrasound machine. RESULTS: Three-dimensional visualization of the kidney vasculature structure and blood flow was possible with our method. Good structural agreement was found between the visualized vasculature structure and the 2-D reference. Microvasculature patterns in the kidney cortex were visible with super-resolution processing. Blood flow velocity estimations were within a physiological range and pattern, also in agreement with the 2-D reference results. CONCLUSION: Volumetric imaging of the kidney vasculature was possible using a prototype sparse spiral array. Reliable structural and temporal information could be extracted from these imaging results.


Asunto(s)
Riñón , Microvasos , Animales , Porcinos , Riñón/diagnóstico por imagen , Riñón/irrigación sanguínea , Ultrasonografía/métodos , Microvasos/diagnóstico por imagen , Fantasmas de Imagen , Microburbujas
8.
Aging Cell ; 22(3): e13768, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36756698

RESUMEN

Heart failure has reached epidemic proportions in a progressively ageing population. The molecular mechanisms underlying heart failure remain elusive, but evidence indicates that DNA damage is enhanced in failing hearts. Here, we tested the hypothesis that endogenous DNA repair in cardiomyocytes is critical for maintaining normal cardiac function, so that perturbed repair of spontaneous DNA damage drives early onset of heart failure. To increase the burden of spontaneous DNA damage, we knocked out the DNA repair endonucleases xeroderma pigmentosum complementation group G (XPG) and excision repair cross-complementation group 1 (ERCC1), either systemically or cardiomyocyte-restricted, and studied the effects on cardiac function and structure. Loss of DNA repair permitted normal heart development but subsequently caused progressive deterioration of cardiac function, resulting in overt congestive heart failure and premature death within 6 months. Cardiac biopsies revealed increased oxidative stress associated with increased fibrosis and apoptosis. Moreover, gene set enrichment analysis showed enrichment of pathways associated with impaired DNA repair and apoptosis, and identified TP53 as one of the top active upstream transcription regulators. In support of the observed cardiac phenotype in mutant mice, several genetic variants in the ERCC1 and XPG gene in human GWAS data were found to be associated with cardiac remodelling and dysfunction. In conclusion, unrepaired spontaneous DNA damage in differentiated cardiomyocytes drives early onset of cardiac failure. These observations implicate DNA damage as a potential novel therapeutic target and highlight systemic and cardiomyocyte-restricted DNA repair-deficient mouse mutants as bona fide models of heart failure.


Asunto(s)
Proteínas de Unión al ADN , Insuficiencia Cardíaca , Ratones , Animales , Humanos , Proteínas de Unión al ADN/metabolismo , Miocitos Cardíacos/metabolismo , Reparación del ADN/genética , Daño del ADN/genética , Insuficiencia Cardíaca/genética , Endonucleasas
9.
Am J Physiol Heart Circ Physiol ; 298(3): H1103-13, 2010 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-20061545

RESUMEN

Because of their ability to perfuse remote regions and deliver oxygen, hemoglobin-based oxygen carriers (HBOCs) may be considered in the treatment of several ischemic conditions such as acute coronary syndromes or high-risk percutaneous intervention. Here we studied the effects of intracoronary infusion of ex vivo preoxygenated HBOC-201 during brief total coronary artery occlusion (CAOs) on myocardial oxygenation and left ventricular (LV) function in a large animal model and investigated the influence of HBOC-201 temperature and infusion rate on these effects. Thirteen open-chest anesthetized swine were instrumented for measurement of global and regional LV function and metabolism. CAOs were induced by inflating an intracoronary balloon catheter; preoxygenated HBOC-201 (12 g/dL) was infused distally through the central lumen of the balloon catheter. Animals underwent consecutive 3-min CAOs interspersed by 30 min of reperfusion, accompanied by different HBOC-201 infusion rates (0, 15, 23, 30, 40, and 50 ml/min) and/or two infusion temperatures (18 degrees C or 37 degrees C) in random order. CAO elicited immediate loss of systolic shortening (SS) in the ischemic region (19 +/- 1% at baseline vs. -3 +/- 2% at end of CAO), resulting in decreases in maximum rate of rise in LV pressure (15 +/- 5%) and stroke volume (12 +/- 4%; all P < 0.05). Balloon deflation resulted in marked coronary reactive hyperemia (to 472 +/- 74% of baseline), increases in coronary venous concentrations of adenosine + inosine (to 218 +/- 26% of baseline; both P < 0.05) and rapid restoration of SS toward baseline. HBOC-201 ameliorated the CAO-induced changes in SS, stroke volume, reactive hyperemia, and coronary venous adenosine + inosine. The effects were temperature and flow dependent with full preservation of SS at 50 ml/min HBOC-201 of 37 degrees C. In conclusion, intracoronary preoxygenated HBOC-201 preserved myocardial oxygenation and LV function in swine during CAO in a dose- and temperature-dependent manner. In our study setting, preoxygenated HBOC-201 can match the oxygen delivery role of endogenous blood in the heart on an almost equivalent-volume basis.


Asunto(s)
Sustitutos Sanguíneos/uso terapéutico , Estenosis Coronaria/complicaciones , Hemoglobinas/uso terapéutico , Daño por Reperfusión Miocárdica/etiología , Daño por Reperfusión Miocárdica/prevención & control , Animales , Sustitutos Sanguíneos/administración & dosificación , Sustitutos Sanguíneos/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Hemodinámica/efectos de los fármacos , Hemodinámica/fisiología , Hemoglobinas/administración & dosificación , Hemoglobinas/farmacología , Infusiones Intravenosas , Masculino , Daño por Reperfusión Miocárdica/fisiopatología , Miocardio/metabolismo , Oxígeno/metabolismo , Porcinos , Temperatura , Función Ventricular Izquierda/efectos de los fármacos , Función Ventricular Izquierda/fisiología
10.
EuroIntervention ; 15(5): 452-456, 2019 Aug 29.
Artículo en Inglés | MEDLINE | ID: mdl-31113762

RESUMEN

Prospective identification of lipid-rich vulnerable plaque has remained an elusive goal. Intravascular photoacoustics, a hybrid optical and ultrasonic technology, was developed as a tool for lipid-rich plaque imaging. Here, we present the first in vivo images of lipid-rich coronary atherosclerosis acquired with this new technology in a large animal model, and relate them to independent catheter-based imaging and histology.


Asunto(s)
Enfermedad de la Arteria Coronaria , Técnicas Fotoacústicas , Placa Aterosclerótica , Animales , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Lípidos , Placa Aterosclerótica/diagnóstico por imagen , Estudios Prospectivos , Ultrasonografía Intervencional
11.
Sci Rep ; 8(1): 792, 2018 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-29335617

RESUMEN

Growing concerns have been expressed regarding cardiovascular performance in modern farm pigs, which has been proposed as a critical factor contributing to the reduced adaptability of modern pigs to stress. Here we tested the hypothesis that cardiac dimensions and pump function in modern heavy farm pigs are disproportionally low for their body weight, and investigated potential underlying mechanisms. The results from the present study indeed demonstrate disproportionally low values for stroke volume and cardiac output in pigs with bodyweights over 150 kg. Importantly, these low values were not the result of impaired left ventricular (LV) systolic contractile function, but were due to a disproportionally small LV end-diastolic volume. The latter was associated with changes in determinants of LV passive stiffness, including (i) an increase in LV myocardial collagen, (ii) a shift from the compliant N2BA titin isoform towards the stiff N2B, and (iii) a marked elevation of aortic blood pressure. Taken together, these results demonstrate reduced pumping capacity of the hearts of heavy modern pigs, due to structural abnormalities in the LV myocardium.


Asunto(s)
Ventrículos Cardíacos/fisiopatología , Función Ventricular Izquierda/fisiología , Animales , Presión Sanguínea , Peso Corporal , Colágeno/metabolismo , Conectina/metabolismo , Ventrículos Cardíacos/anatomía & histología , Miocardio/metabolismo , Isoformas de Proteínas/metabolismo , Porcinos
12.
J Appl Physiol (1985) ; 122(5): 1227-1237, 2017 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-28183818

RESUMEN

Hemoglobin-based oxygen carrier (HBOC)-201 is a cell-free modified hemoglobin solution potentially facilitating oxygen uptake and delivery in cardiovascular disorders and hemorrhagic shock. Clinical use has been hampered by vasoconstriction in the systemic and pulmonary beds. Therefore, we aimed to 1) determine the possibility of counteracting HBOC-201-induced pressor effects with either adenosine (ADO) or nitroglycerin (NTG); 2) assess the potential roles of nitric oxide (NO) scavenging, reactive oxygen species (ROS), and endothelin (ET) in mediating the observed vasoconstriction; and 3) compare these effects in resting and exercising swine. Chronically instrumented swine were studied at rest and during exercise after administration of HBOC-201 alone or in combination with ADO. The role of NO was assessed by supplementation with NTG or administration of the eNOS inhibitor Nω-nitro-l-arginine. Alternative vasoactive pathways were investigated via intravenous administration of the ETA/ETB receptor blocker tezosentan or a mixture of ROS scavengers. The systemic and to a lesser extent the pulmonary pressor effects of HBOC-201 could be counteracted by ADO; however, dosage titration was very important to avoid systemic hypotension. Similarly, supplementation of NO with NTG negated the pressor effects but also required titration of the dose. The pressor response to HBOC-201 was reduced after eNOS inhibition and abolished by simultaneous ETA/ETB receptor blockade, while ROS scavenging had no effect. In conclusion, the pressor response to HBOC-201 is mediated by vasoconstriction due to NO scavenging and production of ET. Further research should explore the effect of longer-acting ET receptor blockers to counteract the side effect of hemoglobin-based oxygen carriers.NEW & NOTEWORTHY Hemoglobin-based oxygen carrier (HBOC)-201 can disrupt hemodynamic homeostasis, mimicking some aspects of endothelial dysfunction, resulting in elevated systemic and pulmonary blood pressures. HBOC-201-induced vasoconstriction is mediated by scavenging nitric oxide (NO) and by upregulating endothelin (ET) production. Pressor effects can be prevented by adjuvant treatment with NO donors or direct vasodilators, such as nitroglycerin or adenosine, but dosages must be carefully monitored to avoid hypotension. However, hemodynamic normalization is more easily achieved via administration of an ET receptor blocker.


Asunto(s)
Endotelinas/metabolismo , Hemoglobinas/farmacología , Óxido Nítrico/metabolismo , Vasoconstricción/efectos de los fármacos , Vasoconstrictores/farmacología , Adenosina/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Sustitutos Sanguíneos/farmacología , Femenino , Hipotensión/metabolismo , Masculino , Nitroglicerina/metabolismo , Condicionamiento Físico Animal/fisiología , Especies Reactivas de Oxígeno/metabolismo , Receptores de Endotelina/metabolismo , Porcinos
13.
Br J Pharmacol ; 145(6): 703-11, 2005 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15895104

RESUMEN

Endogenous adenosine is a trigger for ischemic myocardial preconditioning (IPC). Although intravascular administration of adenosine has been used to further unravel the mechanism of protection by IPC, it is questionable whether adenosine and IPC employ the same signaling pathways to exert cardioprotection. We therefore investigated whether the active metabolic barrier of the endothelium prevents an increase in myocardial interstitial adenosine concentrations by intravenous adenosine, using microdialysis, and also the role of NO and activation of a neurogenic pathway in the cardioprotection by adenosine. In pentobarbital-anesthetized rats, area at risk and infarct size (IS) were determined 120 min after a 60-min coronary artery occlusion (CAO), using trypan blue and nitro-blue-tetrazolium staining, respectively. IPC with a single 15-min CAO and a 15-min adenosine infusion (ADO, 200 microg min(-1) i.v.) limited IS to the same extent (IS = 41 +/- 6% and IS = 40 +/- 4%, respectively) compared to control rats (IS = 63 +/- 3%, both P < 0.05). However, IPC increased myocardial interstitial adenosine levels seven-fold from 4.3 +/- 0.7 to 27.1 +/- 10.0 microM (P < 0.05), while ADO had no effect on interstitial adenosine (4.1 +/- 1.2 microM), or any of the other purines. The NO synthase inhibitor N(omega)-nitro-L-arginine (LNNA), which did not affect IS (IS = 62 +/- 3%), attenuated the protection by ADO (IS = 56 +/- 3%; P < 0.05 vs ADO, P = NS vs LNNA). The ganglion blocker hexamethonium, which had also no effect on IS (IS = 66 +/- 3%), blunted the protection by ADO (IS = 55 +/- 4%; P < 0.05 vs ADO and vs hexamethonium). These observations demonstrate that cardioprotection by ADO is dependent on NO, and is primarily mediated by activation of a neurogenic pathway.


Asunto(s)
Adenosina/farmacología , Cardiotónicos/farmacología , Infarto del Miocardio/prevención & control , Óxido Nítrico/metabolismo , Animales , Bloqueadores Ganglionares/farmacología , Hexametonio/farmacología , Infusiones Intravenosas , Precondicionamiento Isquémico , Masculino , Microdiálisis , Miocardio/metabolismo , Óxido Nítrico Sintasa/antagonistas & inhibidores , Nitroarginina/farmacología , Ratas , Ratas Wistar
14.
JACC Cardiovasc Interv ; 8(15): 1990-1999, 2015 Dec 28.
Artículo en Inglés | MEDLINE | ID: mdl-26738671

RESUMEN

OBJECTIVES: In the absence of effective clinical pharmacotherapy for prevention of reperfusion-mediated injury, this study re-evaluated the effects of intracoronary adenosine on infarct size and no-reflow in a porcine model of acute myocardial infarction using clinical bolus and experimental high-dose infusion regimens. BACKGROUND: Despite the clear cardioprotective effects of adenosine, when administered prior to ischemia, studies on cardioprotection by adenosine when administered at reperfusion have yielded contradictory results in both pre-clinical and clinical settings. METHODS: Swine (54 ± 1 kg) were subjected to a 45-min mid-left anterior descending artery occlusion followed by 2 h of reperfusion. In protocol A, an intracoronary bolus of 3 mg adenosine injected over 1 min (n = 5) or saline (n = 10) was administered at reperfusion. In protocol B, an intracoronary infusion of 50 µg/kg/min adenosine (n = 15) or saline (n = 21) was administered starting 5 min prior to reperfusion and continued throughout the 2-h reperfusion period. RESULTS: In protocol A, area-at-risk, infarct size, and no-reflow were similar between groups. In protocol B, risk zones were similar, but administration of adenosine resulted in significant reductions in infarct size from 59 ± 3% of the area-at-risk in control swine to 46 ± 4% (p = 0.02), and no-reflow from 49 ± 6% of the infarct area to 26 ± 6% (p = 0.03). CONCLUSIONS: During reperfusion, intracoronary adenosine can limit infarct size and no-reflow in a porcine model of acute myocardial infarction. However, protection was only observed when adenosine was administered via prolonged high-dose infusion, and not via short-acting bolus injection. These findings warrant reconsideration of adenosine as an adjuvant therapy during early reperfusion.


Asunto(s)
Adenosina/administración & dosificación , Oclusión Coronaria/terapia , Infarto del Miocardio/prevención & control , Daño por Reperfusión Miocárdica/prevención & control , Reperfusión Miocárdica/efectos adversos , Miocardio/patología , Fenómeno de no Reflujo/prevención & control , Animales , Circulación Coronaria , Oclusión Coronaria/fisiopatología , Modelos Animales de Enfermedad , Esquema de Medicación , Femenino , Hemodinámica , Infusiones Parenterales , Masculino , Infarto del Miocardio/etiología , Infarto del Miocardio/patología , Infarto del Miocardio/fisiopatología , Daño por Reperfusión Miocárdica/etiología , Daño por Reperfusión Miocárdica/patología , Daño por Reperfusión Miocárdica/fisiopatología , Fenómeno de no Reflujo/etiología , Fenómeno de no Reflujo/patología , Fenómeno de no Reflujo/fisiopatología , Porcinos , Factores de Tiempo
15.
Physiol Meas ; 33(4): 557-69, 2012 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-22415053

RESUMEN

Prior to aortic valve opening, aortic pressure is perturbed by ventricular contraction. The onset of this pressure perturbation coincides with the onset of the left ventricular (LV) isovolumic contraction, and hence will be referred to as the start of the arterially detected isovolumic contraction (AIC(start)). In the present study we test the hypothesis that the pressure perturbation indeed has a cardiac origin. In ten Yorkshire-Landrace swine, waveform intensity analysis demonstrated that AIC(start) was followed by a positive intensity wave (0.3 × 10(5) ± 0.3 × 10(5) W (m(2) s(2))(-1)). Timing analysis of LV and aortic pressure waveform showed that AIC(start) was preceded by a LV pressure perturbation (3.8 ± 1.8 ms, p < 0.001). These novel cardiac timing and aortic wave intensity findings reveal the cardiac origin of the pressure perturbation. In 15 Yorkshire-Landrace swine, myocardial motion analysis showed a significantly higher rate of segment shortening during the first part of the LV pressure perturbation. Therefore, both the LV and aortic pressure perturbation are most likely caused by the early phase of myocardial contraction, which also causes mitral valve closure. Consequently, AIC(start) is useful in the determination of the isovolumic contraction period, a well-known marker to quantify cardiac dysfunction.


Asunto(s)
Aorta/fisiología , Presión Sanguínea/fisiología , Contracción Miocárdica/fisiología , Función Ventricular Izquierda/fisiología , Análisis de Ondículas , Animales , Velocidad del Flujo Sanguíneo/fisiología , Electrocardiografía , Femenino , Frecuencia Cardíaca/fisiología , Humanos , Porcinos , Factores de Tiempo
16.
Med Biol Eng Comput ; 49(8): 917-24, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21487819

RESUMEN

In earlier work, we suggested that the start of the isovolumic contraction period could be detected in arterial pressure waveforms as the start of a temporary pre-systolic pressure perturbation (AIC(start), start of the Arterially detected Isovolumic Contraction), and proposed the retrograde coronary blood volume flow in combination with a backwards traveling pressure wave as its most likely origin. In this study, we tested this hypothesis by means of a coronary artery occlusion protocol. In six Yorkshire × Landrace swine, we simultaneously occluded the left anterior descending (LAD) and left circumflex (LCx) artery for 5 s followed by a 20-s reperfusion period and repeated this sequence at least two more times. A similar procedure was used to occlude only the right coronary artery (RCA) and finally all three main coronary arteries simultaneously. None of the occlusion protocols caused a decrease in the arterial pressure perturbation in the aorta during occlusion (P > 0.20) nor an increase during reactive hyperemia (P > 0.22), despite a higher deceleration of coronary blood volume flow (P = 0.03) or increased coronary conductance (P = 0.04) during hyperemia. These results show that the pre-systolic aortic pressure perturbation does not originate from the coronary arteries.


Asunto(s)
Aorta/fisiopatología , Estenosis Coronaria/fisiopatología , Vasos Coronarios/fisiopatología , Contracción Miocárdica/fisiología , Animales , Electrocardiografía , Femenino , Hemodinámica/fisiología , Hiperemia/fisiopatología , Sus scrofa
17.
Exp Biol Med (Maywood) ; 236(7): 874-82, 2011 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-21680754

RESUMEN

Different preconditioning stimuli can activate divergent signaling pathways. In rats, adenosine-independent pathways (triple 3-min coronary artery occlusion [3CAO3]) and adenosine-dependent pathways (one 15-min coronary artery occlusion [ICAO15]) exist, both ultimately converging at the level of the mitochondrial respiratory chain. Furthermore, while 3CAO3, 1CAO15 and exogenous adenosine (ADO) are equally cardioprotective, only 1CAO15 increases interstitial myocardial adenosine levels. Reperfusion Injury Salvage Kinase (RISK) pathway kinases have been implicated in ischemic preconditioning, but not all preconditioning stimuli activate this pathway. Consequently, we evaluated in anesthetized rats the effects of three distinctly different preconditioning stimuli (3CAO3, 1CAO15 or ADO) on infarct size (IS), signaling pathways with a special emphasis on kinases belonging to the RISK pathway (phosphatidylinositol 3-kinase-Akt-nitric oxide synthase and extracellular signal-related kinase [ERK]) and mitochondrial respiration. All three stimuli increased state-2 respiration (using succinate as complex-II substrate), thereby decreasing the respiratory control index, which was accompanied by a limitation of IS produced by a 60-min coronary artery occlusion (CAO). Nitric oxide synthase inhibition abolished the mitochondrial effects and the cardioprotection by 3CAO3, 1CAO15 or ADO. In contrast, the PI3 kinase inhibitor, wortmannin, blocked protection by 1CAO15, but did not affect protection by 3CAO3 or ADO. Western blotting confirmed that phosphorylation of Akt and ERK were increased by 1CAO15 (which was inhibited by wortmannin), but not by 3CAO3 or ADO. In conclusion, while the three cardioprotective stimuli 3CAO3, 1CAO15 and ADO afford cardioprotection via nitric oxide-mediated modulation of mitochondrial respiration, only the 1CAO15 exerts its protection via activation of kinases belonging to the RISK pathway.


Asunto(s)
Precondicionamiento Isquémico Miocárdico , Daño por Reperfusión Miocárdica/prevención & control , Fosfotransferasas/metabolismo , Transducción de Señal , Adenosina/metabolismo , Animales , Respiración de la Célula , Mitocondrias/metabolismo , Óxido Nítrico/metabolismo , Ratas
18.
Am J Physiol Heart Circ Physiol ; 292(3): H1551-60, 2007 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-17122197

RESUMEN

Postconditioning (POC) is known as the phenomenon whereby brief intermittent ischemia applied at the onset of reperfusion following index ischemia limits myocardial infarct size. Whereas there is evidence that the algorithm of the POC stimulus is an important determinant of the protective efficacy, the importance of the duration of index ischemia on the outcome of the effects of POC has received little attention. Pentobarbital sodium-anesthetized Wistar rats were therefore subjected to index ischemia produced by coronary artery occlusions (CAO) of varying duration (15-120 min) followed by reperfusion, without or with postconditioning produced by three cycles of 30-s reperfusion and reocclusion (3POC30). 3POC30 limited infarct size produced by 45-min CAO (CAO45) from 45 +/- 3% to 31 +/- 5%, and CAO60 from 60 +/- 3% to 47 +/- 6% (both P < or = 0.05). In contrast, 3POC30 increased infarct size produced by CAO15 from 3 +/- 1% to 19 +/- 6% and CAO30 from 36 +/- 6 to 48 +/- 4% (both P < or = 0.05). This deleterious effect of 3POC30 was not stimulus sensitive because postconditioning with 3POC5 and 3POC15 after CAO30 also increased infarct size. The cardioprotection by 3POC30 after CAO60 was accompanied by an increased stimulation of Akt phosphorylation at 7 min of reperfusion and a 36% lower superoxide production, measured by dihydroethidium fluorescence, after 2 h of reperfusion. Consistent with these results, cardioprotection by 3POC30 was abolished by phosphatidylinositol-3-OH-kinase inhibition, as well as nitric oxide (NO) synthase inhibition. The deleterious effect of 3POC30 after CAO15 was accompanied by an increased superoxide production with no change in Akt phosphorylation and was not affected by NO synthase inhibition. In conclusion, the effect of cardiac POC depends critically on the duration of the index ischemia and can be either beneficial or detrimental. These paradoxical effects of POC may be related to the divergent effects on Akt phosphorylation and superoxide production.


Asunto(s)
Isquemia Miocárdica/fisiopatología , Isquemia Miocárdica/terapia , Reperfusión Miocárdica , Animales , Fibrilación Atrial/fisiopatología , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas Wistar , Factores de Tiempo , Fibrilación Ventricular/fisiopatología
19.
Am J Physiol Heart Circ Physiol ; 288(3): H1165-72, 2005 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-15486028

RESUMEN

Clinical studies on cardioprotection by preinfarct angina are ambiguous, which may involve development of tolerance to repeated episodes of ischemia. Not all preconditioning stimuli use identical signaling pathways, and because patients likely experience varying numbers of episodes of preinfarct angina of different degrees and durations, it is important to know whether myocardium tolerant to a particular preconditioning stimulus can still be protected by stimuli employing alternative signaling pathways. We tested the hypothesis that development of tolerance to a particular stimulus does not affect cardioprotection by stimuli that employ different signaling pathways. Anesthetized rats underwent classical, remote or pharmacological preconditioning. Infarct size (IS), produced by a 60-min coronary artery occlusion (CAO), was determined after 120 min of reperfusion. Preconditioning by two 15-min periods of CAO (2CAO15, an adenosine-dependent stimulus) limited IS from 69 +/- 2% to 37 +/- 6%, but when 2CAO15 was preceded by 4CAO15, protection by 2CAO15 was absent (IS = 68 +/- 1%). This development of tolerance coincided with a loss of cardiac interstitial adenosine release, whereas two 15-min infusions of adenosine (200 microg/min i.v.) still elicited cardioprotection (IS = 40 +/- 4%). Furthermore, cardioprotection was produced when 4CAO15 was followed by the adenosine-independent stimulus 3CAO3 (IS = 50 +/- 8%) or the remote preconditioning stimulus of two 15-min periods of mesenteric artery occlusion (IS = 49 +/- 6%). In conclusion, development of tolerance to cardioprotection by an adenosine-dependent preconditioning stimulus still allows protection by pharmacological or ischemic stimuli intervention employing different signaling pathways.


Asunto(s)
Adenosina/farmacología , Precondicionamiento Isquémico Miocárdico/métodos , Infarto del Miocardio/fisiopatología , Miocardio/metabolismo , Transducción de Señal/fisiología , Vasodilatadores/farmacología , Adaptación Fisiológica/efectos de los fármacos , Adaptación Fisiológica/fisiología , Animales , Presión Sanguínea , Modelos Animales de Enfermedad , Frecuencia Cardíaca , Masculino , Infarto del Miocardio/metabolismo , Infarto del Miocardio/mortalidad , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos
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