RESUMO
In vivo 31P nuclear magnetic resonance (NMR) spectroscopy of the right ventricular (RV) free wall was employed to determine (a) whether phosphorus energy metabolites vary reciprocally with workload in the RV and (b) the mechanisms that limit RV contractile function in acute pressure overload. In 20 open-chest pigs, phosphocreatine (PCr)/ATP ratio (an index of energy metabolism inversely related to free ADP concentration), myocardial blood flow (microspheres), and segment shortening (sonomicrometry, n = 14) were measured at control (RV systolic pressure 31 +/- 1 mm Hg), and with pulmonary artery constriction to produce moderate pressure overload (RV systolic pressure 45 +/- 1 mm Hg), and maximal pressure overload before overt RV failure and systemic hypotension (RV systolic pressure 60 +/- 1 mm Hg). With moderate pressure overload, PCr/ATP declined to 89% of control (P = 0.01), while contractile function increased. Adenosine (n = 10, mean dose 0.16 mg/kg-min) increased RV blood flow by an additional 41% without increasing PCr/ATP, indicating that coronary reserve was not depleted and that the decrease in PCr/ATP from control was not due to ischemia. With maximal pressure overload and incipient RV failure, PCr/ATP fell further to 81% of control and RV blood flow did not increase further, even with adenosine. Thus: (a) The decline in PCr/ATP with moderate RV pressure overload, without evident ischemia or contractile dysfunction, supports the positive regulation of oxidative phosphorylation by ATP hydrolysis products. (b) Depletion of RV coronary flow reserve accompanies the onset of RV failure at maximal pressure overload.
Assuntos
Metabolismo Energético , Miocárdio/metabolismo , Trifosfato de Adenosina/análise , Animais , Baixo Débito Cardíaco/etiologia , Circulação Coronária , Feminino , Ventrículos do Coração , Hemodinâmica , Espectroscopia de Ressonância Magnética , Fosfocreatina/análise , SuínosRESUMO
OBJECTIVE: Inotropic agents are used clinically to improve ventricular function during ischaemia. The goal of this study was to determine whether inotropic stimulation during moderate left ventricular (LV) ischaemia exacerbated post-ischaemic LV dysfunction. METHODS: In 18 open-chest, anesthetized pigs, LV pressure versus subendocardial segment length loops were used to generate regional preload-recruitable stroke work (PRSW) and LV end-diastolic pressure (EDP) versus end-diastolic segment length (EDL) relations. Ischaemia was produced by constant, partial constriction of the mid anterior descending coronary artery for 90 min. Nine pigs received dobutamine (4 micrograms.kg-1.min-1, i.v.) during the final 60 min of ischaemia (Group 2), while 9 other pigs did not (Group 1). RESULTS: During unstimulated ischaemia, anterior subendocardial blood flow (Group 1, 0.27 +/- .05; Group 2, 0.30 +/- .07 ml.g-1.min.-1, mean +/- s.e.m.) and steady-state PRSW (Group 1, 30 +/- 4%; Group 2, 27 +/- 5% of baseline) were similar in both groups. Dobutamine stimulation during ischaemia increased heart rate, mean arterial pressure, subendocardial blood flow, oxygen consumption and steady-state PRSW of the ischaemia zone, but not lactate release. After 60 min reperfusion, steady-state ischaemic zone PRSW remained markedly and nearly equally reduced in both groups (Group 1, 28 +/- 4%; Group 2, 23 +/- 5% of baseline). Reduced PRSW after reperfusion was due primarily to persistent rightward shift of the PRSW intercept with only a modest contribution from reduced PRSW slope. CONCLUSIONS: Low-dose inotropic stimulation during moderate regional LV ischaemia increases aerobic, but not anaerobic energy metabolism, and does not worsen post-ischaemic dysfunction.
Assuntos
Cardiotônicos/uso terapêutico , Dobutamina/uso terapêutico , Isquemia Miocárdica/fisiopatologia , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Feminino , Frequência Cardíaca/efeitos dos fármacos , Ácido Láctico/metabolismo , Contração Miocárdica/efeitos dos fármacos , Isquemia Miocárdica/tratamento farmacológico , Isquemia Miocárdica/metabolismo , Miocárdio/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Fluxo Sanguíneo Regional/efeitos dos fármacos , SuínosRESUMO
OBJECTIVE: Acute pulmonary hypertension may cause right ventricular (RV) contractile failure. While it has been assumed that restoration of normal loading conditions after acute pulmonary hypertension is sufficient for complete recovery of RV function, this has not been rigorously examined. The purpose of this study was to test the hypothesis that acute RV pressure overload produces RV contractile dysfunction that persists following restoration of control loading conditions. METHODS: We subjected 18 autonomically-blocked, chloralose-anesthetized, open-chest pigs to 1 h of pulmonary artery constriction to increase RV systolic pressure from 35 +/- 1 to 55 +/- 1 mmHg, followed by 2 h of measurements after pulmonary artery constriction release. We determined regional RV free wall function from pressure-segment length loops and preload recruitable stroke work relations, and global RV function from stroke work vs. end-diastolic pressure relations. RESULTS: As expected, RV free wall systolic shortening diminished during pulmonary artery constriction, but the endo/epi blood flow ratio, lactate uptake, and coronary venous pH were not significantly changed. Following release of pulmonary artery constriction, RV systolic and diastolic pressure returned to control values. Nonetheless, contractile dysfunction persisted, with depressed RV free wall systolic shortening (70 +/- 22% of control), RV regional external work (59 +/- 11% of control at control end-diastolic length), and global RV stroke work (56 +/- 14% of control at control end-diastolic pressure). Depressed regional work was due to a parallel, rightward shift of the preload recruitable stroke work relation. Five pigs identically instrumented but not subjected to pulmonary artery constriction showed no significant over 3 h. CONCLUSIONS: Acute pulmonary hypertension causes RV contractile dysfunction that persists at least 2 h after restoration of control loading conditions. Contractile dysfunction is not attributable to RV ischemia during pressure overload.
Assuntos
Hipertensão Pulmonar/fisiopatologia , Disfunção Ventricular Direita/fisiopatologia , Doença Aguda , Animais , Circulação Coronária , Feminino , Coração/fisiopatologia , Hemodinâmica , Volume Sistólico , Suínos , Fatores de TempoRESUMO
AIMS/HYPOTHESIS: Opening of ATP-sensitive potassium (K(ATP)) channels during myocardial ischaemia shortens action potential duration and is believed to be an adaptive, energy-sparing response. Thiazolidinedione drugs block K(ATP) channels in non-cardiac cells in vitro. This study determined whether thiazolidinedione drugs block cardiac K(ATP) channels in vivo. METHODS: Experiments in 68 anaesthetised pigs determined: (1) effects of inert vehicle, troglitazone (10 mg/kg i.v.) or rosiglitazone (0.1 or 1.0 mg/kg i.v.) on epicardial monophasic action potential (MAP) during 90 min low-flow ischaemia; (2) effects of troglitazone, rosiglitazone or pioglitazone (1 mg/kg i.v.) on response of MAP to intracoronary infusion of a K(ATP) channel opener, levcromakalim; and (3) effects of inert vehicle, rosiglitazone (1 mg/kg i.v.) or the sarcolemmal K(ATP) blocker HMR-1098 on time to onset of ventricular fibrillation following complete coronary occlusion. RESULTS: With vehicle, epicardial MAP shortened by 44+/-9 ms during ischaemia. This effect was attenuated to 12+/-8 ms with troglitazone and 6+/-6 ms with rosiglitazone (p<0.01 for both vs vehicle), suggesting K(ATP) blockade. Intracoronary levcromakalim shortened MAP by 38+/-10 ms, an effect attenuated to 12+/-8, 13+/-4 and 9+/-5 ms during co-treatment with troglitazone, rosiglitazone or pioglitazone (p<0.05 for each), confirming K(ATP) blockade. During coronary occlusion, median time to ventricular fibrillation was 29 min in pigs treated with vehicle and 6 min in pigs treated with rosiglitazone or HMR-1098 (p<0.05 for both vs vehicle), indicating that K(ATP) blockade promotes ischaemic ventricular fibrillation in this model. CONCLUSIONS/INTERPRETATION: Thiazolidinedione drugs block cardiac K(ATP) channels at clinically relevant doses and promote onset of ventricular fibrillation during severe ischaemia.
Assuntos
Coração/fisiologia , Canais KATP/antagonistas & inibidores , Tiazolidinedionas/uso terapêutico , Fibrilação Ventricular/induzido quimicamente , Animais , Pressão Sanguínea/efeitos dos fármacos , Modelos Animais de Doenças , Coração/efeitos dos fármacos , Coração/fisiopatologia , Pioglitazona , Rosiglitazona , Suínos , Tiazolidinedionas/farmacologia , Tiazolidinedionas/toxicidadeRESUMO
Magnetic resonance spectroscopy provides information about metabolic processes in living tissues. The resulting information may be more sensitive and specific than that obtained using techniques that rely on functional or structural measurements. Although the preponderance of applications to date have been in physiologic investigations in animals, clinical applications are emerging. Reports in the past two years have appeared evaluating the clinical use of phosphorus spectroscopy to detect ischemic heart disease, cardiomyopathy, and cardiac transplant rejection. Active research using nuclei other than phosphorus for spectroscopy will expand the potential clinical applications. Technical developments, including improved surface coil design, wider use of high-field magnets and new pulse sequences, will allow improved sensitivity and spatial localization in the future.
Assuntos
Cardiopatias/diagnóstico , Espectroscopia de Ressonância Magnética , Animais , Rejeição de Enxerto , Cardiopatias/metabolismo , Transplante de Coração , Humanos , Miocárdio/metabolismoRESUMO
This study determined whether dobutamine enhances regional systolic function in the ischemic right ventricle (RV) at the cost of adverse effects on regional energy metabolism. Seventeen alpha-chloralose-anesthetized, open-chest pigs were studied under four conditions: 1) control; 2) dobutamine infusion (mean dose 9 micrograms.kg-1.min-1); 3) RV ischemia (45 +/- 5% reduction in RV free wall blood flow for 100 min); and 4) continued ischemia with dobutamine. Regional RV free wall high-energy phosphate metabolites were measured by 31P nuclear magnetic resonance (NMR) spectroscopy or by high-speed drill biopsies of the RV free wall. Regional RV free wall substrate and O2 consumption were measured using coronary venous blood sampling. Global RV systolic function was assessed by the maximal first derivative of RV pressure (dP/dtmax), and regional RV free wall systolic function was assessed by systolic segment shortening in the ischemic zone. Right coronary artery constriction caused markedly depressed regional RV systolic function, net lactate production, and coronary venous acidosis. Surprisingly, high-energy phosphates were unchanged compared with control. Addition of dobutamine caused a further decline in coronary venous pH and continued lactate production but did not reduce high-energy phosphates. While dobutamine markedly enhanced global RV systolic function (RV dP/dtmax 201 +/- 19% of control), systolic shortening in the ischemic RV free wall remained severely depressed (47 +/- 18% of control) despite dobutamine. The mechanism of high-energy phosphate preservation is likely due to diminished consumption of ATP in the hypocontractile ischemic region.
Assuntos
Metabolismo Energético , Contração Miocárdica , Isquemia Miocárdica/fisiopatologia , Função Ventricular Direita , Animais , Biópsia , Circulação Coronária , Dobutamina/farmacologia , Estimulação Elétrica , Feminino , Espectroscopia de Ressonância Magnética , Miocárdio/metabolismo , Miocárdio/patologia , Consumo de Oxigênio , Fósforo , Suínos , Sístole , Função Ventricular Direita/efeitos dos fármacosRESUMO
Volume expansion and inotropic stimulation are used clinically to augment cardiac output during acute right ventricular (RV) pressure overload. We previously showed that a brief period of RV pressure overload causes RV free wall dysfunction that persists after normal loading conditions have been restored. However, the impact of volume expansion and inotropic stimulation on the severity of RV dysfunction after acute pressure overload is unknown. We hypothesized that the severity of RV dysfunction after RV pressure overload would be related to the level of RV free wall systolic stress during RV pressure overload, rather than to the specific interventions used to augment RV function. Chloralose-anesthetized, open-chest pigs were subjected to 1 h of RV pressure overload caused by pulmonary artery constriction, followed by 1 h of recovery after release of pulmonary artery constriction. A wide range of RV free wall systolic stress during RV pressure overload was achieved by either closing or opening the pericardium (to simulate volume expansion) and by administering or not administering dobutamine. The severity of RV free wall dysfunction 1 h after RV pressure overload was strongly and directly correlated with the values of two hemodynamic variables during RV pressure overload: RV free wall area at peak RV systolic pressure (determined by sonomicrometry) and peak RV systolic pressure, two of the major determinants of peak RV free wall systolic stress. Opening or closing the pericardium, and using or not using dobutamine during RV pressure overload, had no independent effects on the severity of RV dysfunction. The findings suggest that the goal of therapeutic intervention during RV pressure overload should be to achieve the required augmentation of cardiac output with the smallest possible increase in RV free wall systolic stress.
Assuntos
Hipertensão/fisiopatologia , Disfunção Ventricular Direita/fisiopatologia , Animais , Atropina/farmacologia , Cateterismo Cardíaco/instrumentação , Cardiotônicos/farmacologia , Fármacos Cardiovasculares/farmacologia , Diástole/efeitos dos fármacos , Dilatação Patológica/fisiopatologia , Modelos Animais de Doenças , Dobutamina/farmacologia , Feminino , Coração/efeitos dos fármacos , Coração/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Hexametônio/farmacologia , Hipertensão/tratamento farmacológico , Modelos Lineares , Pericárdio/cirurgia , Artéria Pulmonar/fisiopatologia , Artéria Pulmonar/cirurgia , Suínos , Sístole/efeitos dos fármacos , Disfunção Ventricular Direita/tratamento farmacológicoRESUMO
This study tested the hypothesis that regional low-flow ischemia and reperfusion alter myocardial material properties by causing non-elastic deformation. Twenty-two anesthetized, open-chest pigs were studied. Pigs underwent 90 min of regional low-flow ischemia (anterior LV subendocardial blood flow 29+/-7% of baseline) followed by 90 min reperfusion. LV pressure and regional subendocardial segment length were recorded to derive end-diastolic pressure vs segment length (EDP vs EDL) and preload-recruitable stroke work (PRSW) relations. In vivo, non-elastic myocardial deformation was inferred from increases in minimally loaded myocardial dimensions: the EDL at zero EDP (L0) and the EDL at which no regional external work was performed (Lw, the PRSW intercept). In 15 pigs, ultrastructural confirmation of non-elastic deformation was obtained from sarcomere dimensions measured by transmission electron microscopy after in situ perfusion fixation under non-ischemic conditions, after 90 min ischemia, or after 90 min ischemia plus 90 min reperfusion. Ischemia increased L0 and Lw to 1.17+/-0.05 and 1. 13+/-0.04 times baseline, respectively. After reperfusion, L0 and Lw remained increased to 1.09+/-0.03 and 1.15+/-0.02 times baseline (all P<0.05). After reperfusion, PRSW slope was not different from baseline, but regional external work remained depressed (0.38+/-0.03 times baseline) due to the persistent increase in Lw. Neither L0 nor Lw changed in the posterior (non-ischemic) region. In hearts fixed after ischemia or after ischemia plus reperfusion, sarcomere length was significantly greater and transverse distance between thick myofilaments was significantly smaller in the anterior (ischemic) subendocardium than in the posterior (non-ischemic) subendocardium (P<0.01). We conclude that regional low-flow ischemia and reperfusion cause non-elastic deformation of myocardium, manifest in vivo by increased minimally loaded myocardial dimensions (L0 and Lw) and ultrastructurally by increased sarcomere length and decreased transverse interfilament distance. Non-elastic deformation of myocardium may contribute to contractile dysfunction in low-flow ischemia and reperfusion.
Assuntos
Circulação Coronária/fisiologia , Traumatismo por Reperfusão Miocárdica/patologia , Animais , Velocidade do Fluxo Sanguíneo , Elasticidade , Hemodinâmica/fisiologia , Microscopia Eletrônica , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Suínos , Função Ventricular/fisiologiaRESUMO
Changes in phosphate metabolites may play a role in the regulation of myocardial oxidative phosphorylation in vivo. We tested the hypothesis that changes in phosphate metabolites with increased myocardial oxygen consumption (MVO2) depend on the mechanism by which MVO2 is increased. In 17 open-chest pigs, regional MVO2 of the right ventricular (RV) free wall was increased from control by isoproterenol infusion (Iso) and by pulmonary artery constriction (PAC). The phosphocreatine-to-ATP ratio (PCr/ATP), which is inversely related to free ADP concentration ([ADP]), was determined by 31P-nuclear magnetic resonance (NMR) spectroscopy. Regional MVO2 and lactate, glucose, and free fatty acid (FFA) uptake were determined in the myocardium directly beneath the NMR coil. Iso and PAC increased MVO2 nearly equally, to approximately twice control, but produced directionally opposite changes in PCr/ATP: a significant decrease with PAC (control 1.52 +/- 0.06, PAC 1.35 +/- 0.06, means +/- SE) but a significant increase with Iso (to 1.72 +/- 0.07). Thus increased [ADP] may have stimulated oxidative phosphorylation during PAC but could not have done so during Iso. With Iso, uptake of FFA was more than three times that with PAC, and the sum of the oxygen extraction ratios for lactate, glucose, and FFA was more than double that with PAC. Enhanced substrate uptake during Iso may have increased mitochondrial NADH, which in turn may have provided an alternative stimulus to the rate of oxidative phosphorylation. These results support multifactorial control of RV oxidative phosphorylation in vivo.
Assuntos
Trifosfato de Adenosina/metabolismo , Metabolismo Energético , Miocárdio/metabolismo , Consumo de Oxigênio , Fosfocreatina/metabolismo , Difosfato de Adenosina/metabolismo , Animais , Metabolismo Energético/efeitos dos fármacos , Ácidos Graxos não Esterificados/metabolismo , Feminino , Glucose/metabolismo , Ventrículos do Coração , Isoproterenol/farmacologia , Lactatos/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Mitocôndrias Cardíacas/metabolismo , NAD/metabolismo , Fosforilação Oxidativa , Consumo de Oxigênio/efeitos dos fármacos , SuínosRESUMO
We previously observed that isoproterenol (ISO) stimulation of the in situ porcine right ventricle (RV) increases the ratio of phosphocreatine (PCr) to ATP, accompanied by marked augmentation of myocardial free fatty acid (FFA) uptake. We hypothesized that increased FFA uptake and utilization cause the increase in PCr/ATP and that inhibition of FFA metabolism during ISO would prevent such an increase. In open-chest pigs, myocardial oxygen consumption (MVO2) of the RV free wall was increased with ISO (0.15 microgram.kg-1.min-1 iv) in the absence (n = 6) and presence (n = 6) of oxfenicine (65 mg/kg iv), an inhibitor of carnitine palmitoyltransferase I. ISO caused twofold increases in MVO2 and arterial FFA concentration. In the absence of oxfenicine, ISO increased RV FFA uptake from a control of 0.01 +/- 0.01 to 0.11 +/- 0.02 (SE) mumol.g-1.min-1. The PCr/ATP, measured by 31P-nuclear magnetic resonance spectroscopy, rose from 1.75 +/- 0.05 to 2.22 +/- 0.10 (P < 0.05). In the presence of oxfenicine, FFA uptake did not increase with ISO, despite elevated arterial FFA concentration. PCr/ATP fell from 1.65 +/- 0.05 to 1.53 +/- 0.07 (P < 0.01 vs. response without oxfenicine). In four additional pigs, arterial FFA concentration was increased in the absence of ISO by infusion of Intralipid and heparin sodium. PCr/ATP increased in each pig. When oxfenicine was administered with Intralipid, PCr/ATP decreased in each pig. We conclude that increased utilization of FFA raises the RV PCr/ATP ratio in vivo. Inhibition of FFA metabolism prevents the rise in PCr/ATP otherwise observed with ISO or with high arterial FFA.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Trifosfato de Adenosina/metabolismo , Metabolismo Energético , Ácidos Graxos não Esterificados/antagonistas & inibidores , Miocárdio/metabolismo , Fosfocreatina/metabolismo , Animais , Emulsões Gordurosas Intravenosas/farmacologia , Ácidos Graxos não Esterificados/sangue , Feminino , Glicina/análogos & derivados , Glicina/farmacologia , Ventrículos do Coração , Hemodinâmica/efeitos dos fármacos , Heparina/farmacologia , Isoproterenol/farmacologia , Concentração Osmolar , Consumo de Oxigênio/efeitos dos fármacos , SuínosRESUMO
Mechanical properties of the myocardium at end diastole have been thought to be dominated by passive material properties rather than by active sarcomere cross-bridge interactions. This study tested the hypothesis that residual cross-bridges significantly contribute to end-diastolic mechanics in vivo and that changes in end-diastolic cross-bridge interaction parallel concurrent changes in systolic cross-bridge interaction. Open-chest anesthetized pigs were treated with intracoronary verapamil (n = 7) or 2,3-butanedione monoxime (BDM; n = 8). Regional left ventricular external work and end-diastolic pressure (EDP) versus end-diastolic segment length (EDL) relations were determined in the treated and untreated regions of each heart. Both agents reduced external work of treated regions to 31-38% of baseline and concurrently shifted EDP versus EDL relations to the right (i.e., greater EDL at a given EDP) by an average of 5% (P < 0.05). During washout of the drugs, EDP versus EDL returned to baseline in parallel with recovery of external work. Sarcomere length, measured by transmission electron microscopy in BDM-treated and untreated regions of the same hearts after diastolic arrest and perfusion fixation, was 8% greater in BDM-treated regions (P < 0.01). We concluded that residual diastolic cross-bridges significantly and reversibly influence end-diastolic mechanics in vivo. Alterations of end-diastolic and systolic cross-bridge interactions occur in parallel.
Assuntos
Diacetil/análogos & derivados , Diástole/fisiologia , Coração/fisiologia , Hemodinâmica/fisiologia , Contração Miocárdica/fisiologia , Sístole/fisiologia , Animais , Circulação Coronária/fisiologia , Diacetil/farmacologia , Diástole/efeitos dos fármacos , Coração/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Ventrículos do Coração , Hemodinâmica/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Miocárdio/ultraestrutura , Soluções para Preservação de Órgãos/farmacologia , Suínos , Sístole/efeitos dos fármacos , Função Ventricular Esquerda/fisiologia , Verapamil/farmacologiaRESUMO
Clinical and experimental studies have suggested benefit of treatment with intravenous glucose-insulin-potassium (GIK) in acute myocardial infarction. However, patients hospitalized with acute coronary syndromes often experience recurrent myocardial ischemia without infarction that may cause progressive left ventricular (LV) dysfunction. This study tested the hypothesis that anticipatory treatment with GIK attenuates both systolic and diastolic LV dysfunction resulting from ischemia and reperfusion without infarction in vivo. Open-chest, anesthetized pigs underwent 90 min of moderate regional ischemia (mean subendocardial blood flow 0.3 ml x g(-1) x min(-1)) and 90 min reperfusion. Eight pigs were treated with GIK (300 g/l glucose, 50 U/l insulin, and 80 meq/l KCl; infused at 2 ml x kg(-1) x h(-1)) beginning 30 min before ischemia and continuing through reperfusion. Eight untreated pigs comprised the control group. Regional LV wall area was measured with orthogonal pairs of sonomicrometry crystals. GIK significantly increased myocardial glucose uptake and lactate release during ischemia. After reperfusion, indexes of regional systolic function (external work and fractional systolic wall area reduction), regional diastolic function (maximum rate of diastolic wall area expansion), and global LV function (LV positive and negative maximum rate of change in pressure with respect to time) recovered to a significantly greater extent in GIK-treated pigs than in control pigs (all P < 0.05). The findings suggest that the clinical utility of GIK may extend beyond treatment of acute myocardial infarction to anticipatory metabolic protection of myocardium in patients at risk for recurrent episodes of ischemia.