RESUMO
The adipokine adiponectin is decreased in severe obesity and is inversely associated with adipose mass. Adiponectin is associated with insulin sensitivity and cardioprotection. Obesity frequently results in the development of a "cardiometabolic syndrome" characterized by increased circulating insulin and leptin, and cardiac hypertrophy and dysfunction. This study examined if adiponectin-deficiency affects the development of metabolic and cardiac abnormalities in response to modest obesity. Mice were studied under normal conditions and with mild cardiac pressure-overload induced by abdominal aortic banding. After surgery, wild type and adiponectin-deficient mice were fed a high-fat diet for 8 weeks (45% energy from fat vs. 10%). In wild type mice the high-fat diet increased fat and whole body mass, which corresponded with elevated circulating insulin and leptin and a decrease the glucose/insulin ratio. On the other hand, in adiponectin-deficient mice the high-fat diet had less impact on body mass and no effect on fat mass, insulin, leptin, or glucose/insulin. There was modest cardiac hypertrophy with aortic banding, but no cardiac dysfunction or effects of adiponectin deficiency or diet. The results suggest that the increase in adipose mass, leptin and insulin induced by a high fat diet is dependent on adiponectin. The lack of accelerated cardiac hypertrophy and dysfunction in the adiponectin-deficient mice subjected to aortic banding and the high-fat diet suggest that adiponectin may not play a major role in protecting the heart during the early stages of diet-induced obesity.
Assuntos
Adiponectina/deficiência , Doenças Cardiovasculares/metabolismo , Gorduras na Dieta/efeitos adversos , Síndrome Metabólica/metabolismo , Obesidade/complicações , Tecido Adiposo/metabolismo , Animais , Pressão Sanguínea , Peso Corporal , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/fisiopatologia , Modelos Animais de Doenças , Feminino , Humanos , Insulina/metabolismo , Leptina/metabolismo , Masculino , Síndrome Metabólica/etiologia , Síndrome Metabólica/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Obesidade/metabolismo , Obesidade/fisiopatologiaRESUMO
This study tested the robustness of our computational model of myocardial metabolism by comparing responses to two different inputs with experimental data obtained in pigs under similar conditions. Accordingly, an abrupt and a gradual reduction in coronary flow of similar magnitude were implemented and used as model input. After flow reductions reached 60% from control values, ischemia was kept constant for 60 min in both groups. Our hypotheses were that: (1) these two flow-reduction profiles would result in different transients (concentrations and flux rates) while having similar steady-state values and (2) our model-simulated responses would predict the experimental results in an anesthetized swine model of myocardial ischemia. The two different ischemia-induction patterns resulted in the same decrease in steady-state MVO2 and in similar steady-state values for metabolite concentrations and flux rates at 60 min of ischemia. While both the simulated and experimental results showed decreased glycogen concentration, accumulation of lactate, and net lactate release with ischemia, the onset of glycogen depletion and the switch to lactate efflux were more rapid in the experiments than in the simulations. This study demonstrates the utility of computer models for predicting experimental outcomes in studies of metabolic regulation under physiological and pathological conditions.
Assuntos
Isquemia Miocárdica/metabolismo , Miocárdio/metabolismo , Animais , Simulação por Computador , Circulação Coronária , Modelos Animais de Doenças , Metabolismo Energético , Glicogênio/metabolismo , Ácido Láctico/metabolismo , Isquemia Miocárdica/etiologia , Miocárdio/patologia , Consumo de Oxigênio , Suínos , Fatores de TempoRESUMO
Evidence indicates that nitric oxide (NO) suppresses myocardial oxygen consumption (MVO(2)) and regulates myocardial substrate oxidation, however data from in vivo and isolated heart preparations are conflicting. In addition, cardiac endothelin (ET-1) release has been shown to increase with inhibition of NO synthase (NOS), however the effects of ET-1 on myocardial energetics is not clear. We employed the isolated rat heart model to assess the role of NO and ET-1 on myocardial function and metabolism. Oxidation of glucose and FFA was measured using [U-(14)C]glucose and [9,10-(3)H]palmitate. NOS inhibition with N(G)-methyl-L-arginine acetate salt (L-NMMA, 50 microM), resulted in an increase in MVO(2) at a given rate of myocardial external workload, and no change in myocardial glucose or FFA oxidation. ET-1 (25 pM), which caused coronary vasoconstriction similar to that produced by L-NMMA, also increased MVO(2) without an effect on cardiac workload, or substrate oxidation, suggesting a role for ET-I in the regulation of myocardial energetics. We assessed also the effect of ET(A)/ET(B) receptor blockade (tezosentan; 5 nM) on MVO(2) and glucose and FFA oxidation and observed no effect, suggesting that basal ET-1 production does not play a role in regulating MVO2 or substrate selection. In conclusion, inhibition of NOS or the addition of ET-1 resulted in an increase in MVO2, but did not affect glucose or FFA oxidation.
Assuntos
Endotelina-1/metabolismo , Glucose/metabolismo , Miocárdio/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Consumo de Oxigênio/efeitos dos fármacos , Palmitatos/metabolismo , Animais , Circulação Coronária/efeitos dos fármacos , Diástole/efeitos dos fármacos , Diástole/fisiologia , Antagonistas do Receptor de Endotelina A , Antagonistas do Receptor de Endotelina B , Endotelina-1/farmacologia , Glucose/química , Frequência Cardíaca/efeitos dos fármacos , Frequência Cardíaca/fisiologia , Ventrículos do Coração/efeitos dos fármacos , Ácido Láctico/química , Ácido Láctico/metabolismo , Masculino , Miocárdio/química , Palmitatos/química , Piridinas/administração & dosagem , Piridinas/farmacocinética , Piridinas/farmacologia , Ratos , Receptor de Endotelina A/fisiologia , Receptor de Endotelina B/fisiologia , Tetrazóis/administração & dosagem , Tetrazóis/farmacocinética , Tetrazóis/farmacologia , Trítio , Função Ventricular , Água/metabolismo , ômega-N-Metilarginina/farmacologiaRESUMO
In the well-perfused heart, pyruvate carboxylation accounts for 3-6% of the citric acid cycle (CAC) flux, and CAC carbon is lost via citrate release. We investigated the effects of an acute reduction in coronary flow on these processes and on the tissue content of CAC intermediates. Measurements were made in an open-chest anesthetized swine model. Left anterior descending coronary artery blood flow was controlled by a extracorporeal perfusion circuit, and flow was decreased by 40% for 80 min to induce myocardial hibernation (n = 8). An intracoronary infusion of [U-(13)C(3)]lactate and [U-(13)C(3)]pyruvate was given to measure the entry of pyruvate into the CAC through pyruvate carboxylation from the (13)C-labeled isotopomers of CAC intermediates. Compared with normal coronary flow, myocardial hibernation resulted in parallel decreases of 65% and 79% in pyruvate carboxylation and net citrate release by the myocardium, respectively, and maintenance of the CAC intermediate content. Elevation of the arterial pyruvate concentration by 1 mM had no effect. Thus a 40% decrease in coronary blood flow resulted in a concomitant decrease in pyruvate carboxylation and citrate release as well as maintenance of the CAC intermediates.
Assuntos
Ácido Cítrico/metabolismo , Miocárdio Atordoado/metabolismo , Ácido Pirúvico/metabolismo , Doença Aguda , Animais , Descarboxilação , Malato Desidrogenase/metabolismo , Concentração Osmolar , Piruvato Carboxilase/metabolismo , SuínosRESUMO
This study assessed the effects of streptozotocin diabetes in swine on the heart rate response to beta-adrenergic stimulation the adenylyl cyclase signal transduction pathway. Diabetic animals (n = 9) were hyperglycemic compared to the control group (n = 10) (12.6 +/- 1.0 vs. 3.53 +/- 0.29 mM). There were no significant differences between the diabetic and nondiabetic groups in the heart rate response to isoproterenol, however, there was a significant reduction (14%) in beta-adrenergic receptor density in the right atrium in the diabetic (61 +/- 3 fmol/mg protein) versus the nondiabetic group (71 +/- 3) (P < 0.05). The content of guanosine triphosphate binding regulatory proteins (Gs and Gi) in the right atrium was not affected by diabetes, nor was adenylyl cyclase activity under unstimulated conditions or with receptor-dependent stimulation with isoproterenol. On the other hand, adenylyl cyclase activity was 34% lower when directly stimulated with forskolin, and it was reduced by 23% when stimulated through Gs with Gpp(NH)p. In conclusion, beta-adrenergic stimulation of heart rate with isoproteronol and the receptor-dependent signal transduction pathway remained intact in the right atrium of diabetic swine despite reduced beta-adrenergic receptor density, G-protein content, and direct stimulation of adenylyl cyclase activity.
Assuntos
Adenilil Ciclases/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Diabetes Mellitus Experimental/metabolismo , Frequência Cardíaca/efeitos dos fármacos , Isoproterenol/farmacologia , Transdução de Sinais/fisiologia , Animais , Colforsina/farmacologia , Feminino , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Subunidades alfa Gs de Proteínas de Ligação ao GTP/metabolismo , Átrios do Coração/efeitos dos fármacos , Átrios do Coração/metabolismo , Frequência Cardíaca/fisiologia , Receptores Adrenérgicos beta/metabolismo , Transdução de Sinais/efeitos dos fármacos , Suínos , Porco MiniaturaRESUMO
Cardiac work is supported by high rates of combustion of carbon fuel and oxygen consumption. Fatty acids are the main fuel for the healthy heart, supplying approximately 60-80% of the energy. The balance of the energy comes from the oxidation of glucose and lactate. ATP is broken down to fuel contractile work. ATP is resynthesized in the mitochondria using energy from the oxidation of fatty acids, glucose, and lactate. Myocardial ischaemia dramatically alters fuel metabolism. Ischaemia occurs when the coronary blood flow is insufficient to supply enough oxygen to combust carbon fuels and resynthesize ATP at the normal rate. During partial reductions in coronary blood flow (30-60% of normal) there is a proportional decrease in the rates of oxygen consumption and production of ATP, and an increase in uptake of glucose by the heart. However, unlike under normal aerobic conditions, the glucose taken up by the ischaemic myocardium is not readily oxidized in the mitochondria, but rather is converted to lactate and there is a switch from uptake of lactate by the heart to lactate production. This causes a dramatic disruption in cell homeostasis: ATP content decreases; there is accumulation of lactate and H+, a fall in intracellular pH and a decrease in contractile work. Paradoxically, the ischaemic tissue continues to derive most of its energy (50-70%) from the oxidation of fatty acids despite there being a high rate of lactate production. This ischaemia-induced disruption of cardiac metabolism can be minimized by metabolic agents that decrease oxidation of fatty acids and increase the rates of combustion of glucose and lactate, resulting in clinical benefit to the ischaemic patient.
Assuntos
Metabolismo Energético , Isquemia Miocárdica/metabolismo , Miocárdio/metabolismo , Animais , Ácidos Graxos/metabolismo , Humanos , NAD/metabolismo , Oxirredução , Consumo de OxigênioRESUMO
The purpose of this study was to examine the effect of acute (24 h) and chronic (5 wk) hypobaric hypoxic exposure equivalent to a simulated altitude of 4,300 m (446 mmHg) on the enzymes of fat metabolism. Heart, liver, and skeletal muscle were taken from 32 male Sprague-Dawley rats. Altitude exposure did not affect the activity of citrate synthase in any of the tissues, suggesting that mitochondrial content was unchanged. Carnitine palmitoyltransferase-I (CPT-I) activity was significantly reduced in the heart by both acute and chronic high altitude exposure compared with controls. A similar reduction was found for CPT-I activity in extensor digitorum longus after acute and chronic exposure compared with control animals. CPT-I activity was not affected by altitude exposure in the soleus muscle or the liver. 3-Hydroxyacyl-CoA dehydrogenase (beta-HAD) activity was significantly depressed in the hearts of chronically exposed animals compared with controls. No difference between acute and control animals was found in the heart for beta-HAD activity. Liver beta-HAD activity was also significantly decreased in the acclimatized as well as in the acute animals compared with the control group. Quadriceps beta-HAD activity was reduced for the chronic animals only compared with controls. These data suggest that acclimatization to high altitude selectively decreases key enzymes in fat utilization and oxidation in the heart, liver, and select skeletal muscles.
Assuntos
3-Hidroxiacil-CoA Desidrogenases/metabolismo , Altitude , Carnitina O-Palmitoiltransferase/metabolismo , Metabolismo dos Lipídeos , Animais , Citrato (si)-Sintase/metabolismo , Fígado/metabolismo , Masculino , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , Ratos , Ratos Sprague-Dawley , Fatores de TempoRESUMO
The goal of this study was to measure flux through pyruvate carboxylation and decarboxylation in the heart in vivo. These rates were measured in the anterior wall of normal anesthetized swine hearts by infusing [U-(13)C(3)]lactate and/or [U-(13)C(3)] pyruvate into the left anterior descending (LAD) coronary artery. After 1 h, the tissue was freeze-clamped and analyzed by gas chromatography-mass spectrometry for the mass isotopomer distribution of citrate and its oxaloacetate moiety. LAD blood pyruvate and lactate enrichments and concentrations were constant after 15 min of infusion. Under near-normal physiological concentrations of lactate and pyruvate, pyruvate carboxylation and decarboxylation accounted for 4.7 +/- 0.3 and 41.5 +/- 2.0% of citrate formation, respectively. Similar relative fluxes were found when arterial pyruvate was raised from 0.2 to 1.1 mM. Addition of 1 mM octanoate to 1 mM pyruvate inhibited pyruvate decarboxylation by 93% without affecting carboxylation. The absence of M1 and M2 pyruvate demonstrated net irreversible pyruvate carboxylation. Under our experimental conditions we found that pyruvate carboxylation in the in vivo heart accounts for at least 3-6% of the citric acid cycle flux despite considerable variation in the flux through pyruvate decarboxylation.
Assuntos
Ciclo do Ácido Cítrico/fisiologia , Ácido Láctico/metabolismo , Miocárdio/metabolismo , Ácido Pirúvico/metabolismo , Ácido 3-Hidroxibutírico/metabolismo , Animais , Caprilatos/farmacologia , Isótopos de Carbono , Ácido Cítrico/metabolismo , Ciclo do Ácido Cítrico/efeitos dos fármacos , Vasos Coronários/fisiologia , Ácidos Graxos não Esterificados/farmacocinética , Feminino , Glucose/farmacocinética , Infusões Intra-Arteriais , Ácido Láctico/administração & dosagem , Masculino , Oxirredução/efeitos dos fármacos , Complexo Piruvato Desidrogenase/antagonistas & inibidores , Ácido Pirúvico/administração & dosagem , Suínos , Distribuição Tecidual/efeitos dos fármacosRESUMO
BACKGROUND: Inhibition of dopamine beta-hydroxylase (DBH) results in a decrease in norepinephrine synthesis. The present study was a randomized, blinded, placebo-controlled investigation of the long-term effects of therapy with the DBH inhibitor nepicastat (NCT) on the progression of left ventricular (LV) dysfunction and remodeling in dogs with chronic heart failure (HF). METHODS AND RESULTS: Moderate HF (LV ejection fraction [LVEF] 30% to 40%) was produced in 30 dogs by intracoronary microembolization. Dogs were randomized to low-dose NCT (0.5 mg/kg twice daily, n=7) (L-NCT), high-dose NCT (2 mg/kg twice daily, n=7) (H-NCT), L-NCT plus enalapril (10 mg twice daily, n=8) (L-NCT+ENA), or placebo (PL, n=8). Transmyocardial (coronary sinus-arterial) plasma norepinephrine (tNEPI), LVEF, end-systolic volume, and end-diastolic volume were measured before and 3 months after initiating therapy. tNEPI levels were higher in PL compared with NL (86+/-20 versus 13+/-14 pg/mL, P:<0.01). L-NCT alone and L-NCT+ENA reduced tNEPI toward normal (28+/-4 and 39+/-17 pg/mL respectively), whereas HD-NCT reduced tNEPI to below normal levels (3+/-10 pg/mL). In PL dogs, LVEF decreased but was unchanged with L-NCT and increased with L-NCT+ENA. L-NCT and L-NCT+ENA prevented progressive LV remodeling, as evidenced by lack of ongoing increase in end-diastolic volume and end-systolic volume, whereas H-NCT did not CONCLUSIONS: In dogs with HF, therapy with L-NCT prevented progressive LV dysfunction and remodeling. The addition of ENA to L-NCT afforded a greater increase in LV systolic function. NCT at doses that normalize tNEPI may be useful in the treatment of chronic HF.
Assuntos
Dopamina beta-Hidroxilase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Imidazóis/farmacologia , Tionas/farmacologia , Disfunção Ventricular Esquerda/tratamento farmacológico , Animais , Doença Crônica , Modelos Animais de Doenças , Progressão da Doença , Cães , Relação Dose-Resposta a Droga , Enalapril/administração & dosagem , Enalapril/farmacologia , Inibidores Enzimáticos/administração & dosagem , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/enzimologia , Imidazóis/administração & dosagem , Norepinefrina/sangue , Volume Sistólico/efeitos dos fármacos , Tionas/administração & dosagem , Disfunção Ventricular Esquerda/sangue , Disfunção Ventricular Esquerda/complicações , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
We determined the effect of insulin on the fate of glucose and contractile function in isolated working hypertrophied hearts from rats with an aortic constriction (n = 27) and control hearts from sham-operated rats (n = 27). Insulin increased glycolysis and glycogen in control and hypertrophied hearts. The change in glycogen was brought about by increased glycogen synthesis and decreased glycogenolysis in both groups. However, the magnitude of change in glycolysis, glycogen synthesis, and glycogenolysis caused by insulin was lower in hypertrophied hearts than in control hearts. Insulin also increased glucose oxidation and contractile function in control hearts but not in hypertrophied hearts. Protein content of glucose transporters, protein kinase B, and phosphatidylinositol 3-kinase was not different between the two groups. Thus hypertrophied hearts are less responsive to the metabolic and functional effects of insulin. The reduced responsiveness involves multiple aspects of glucose metabolism, including glycolysis, glucose oxidation, and glycogen metabolism. The absence of changes in content of key regulatory molecules indicates that other sites, pathways, or factors regulating glucose utilization are responsible for these findings.
Assuntos
Cardiomegalia/fisiopatologia , Insulina/fisiologia , Proteínas Serina-Treonina Quinases , Animais , Cardiomegalia/metabolismo , Glucose/metabolismo , Glicogênio/metabolismo , Glicólise/efeitos dos fármacos , Glicólise/fisiologia , Hemodinâmica/efeitos dos fármacos , Hemodinâmica/fisiologia , Immunoblotting , Técnicas In Vitro , Insulina/farmacologia , Masculino , Proteínas de Transporte de Monossacarídeos/metabolismo , Tamanho do Órgão , Oxirredução , Perfusão , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt , Ratos , Ratos Sprague-DawleyAssuntos
Metabolismo Energético , Insuficiência Cardíaca/metabolismo , Mitocôndrias Cardíacas/metabolismo , Trifosfato de Adenosina/biossíntese , Antagonistas Adrenérgicos beta/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Metoprolol/uso terapêutico , Mitocôndrias Cardíacas/efeitos dos fármacos , Miopatias Mitocondriais/tratamento farmacológico , Miopatias Mitocondriais/metabolismo , Piruvatos/metabolismoRESUMO
This review examines the in vivo techniques that are available for evaluation of the metabolic effects and efficacy of agents intended for the treatment of myocardial ischemia. Energy substrate metabolism is complex, and requires simultaneous measurement of a variety of processes in order to obtain a thorough understanding of the biochemical mechanisms underlying any functional response. Small animals (from the mouse to the rabbit) are generally not very useful in the study of cardiac metabolism in vivo because it is not possible to sample the coronary venous drainage and measure the rate of substrate uptake or metabolite efflux. Anesthetized open-chest swine or dog models allows simultaneous serial measurement of myocardial substrate use, and repeated tissue sampling for the activities and contents of key enzymes and metabolites. The swine model is particularly good because pigs, like humans, lack innate collateral vessels, thus one can induce regional myocardial ischemia in the left anterior descending coronary artery and sample the venous effluent from the anterior interventricular vein. In this review the biochemical and physiological methods that can be used in conjunction with this preparation are described.
Assuntos
Isquemia Miocárdica/metabolismo , Miocárdio/metabolismo , Animais , Doença das Coronárias/tratamento farmacológico , Doença das Coronárias/metabolismo , Cães , Humanos , Camundongos , Microdiálise , Isquemia Miocárdica/tratamento farmacológico , Perfusão , Coelhos , SuínosRESUMO
BACKGROUND: Pharmacological inhibition of carnitine palmitoyl transferase I (CPT-I), the enzyme controlling the rate of fatty acid transport into the mitochondria, prevents the contractile dysfunction, myosin isozyme shift and deterioration in sarcoplasmic reticulum Ca2+ handling that occurs in rat models of left ventricular hypertrophy. In this study we examine whether the improved cardiac function with beta blockade therapy in heart failure is associated with an alteration in CPT-I activity. METHODS AND RESULTS: We examined dogs with coronary microembolism-induced heart failure treated for 12 weeks with metoprolol (25 mg twice daily). Myocardial activities of CPT-I, medium-chain acyl co-enzyme A dehydrogenase (MCAD, a beta-oxidation enzyme), citrate synthase, and triglyceride content were measured. The progressive decrease in cardiac function was prevented by treatment with metoprolol, as reflected by an improved ejection fraction over 12 weeks in the metoprolol group (from 35% to 40%) compared to the untreated heart failure dogs (decrease from 36% to 26%). Dogs treated with metoprolol had a marked decrease in CPT-I activity (0.46 +/- 0.03 vs. 0.64 +/- 0.02 micromol min(-1) g(-1) wet weight; P < .02) along with an increase in triglyceride concentration compared to untreated heart failure dogs (3.9 +/- 0.3 v 4.9 +/- 0.2 micromol/g wet weight, respectively; P < .003). By contrast, MCAD and citrate synthase activities did not change. CONCLUSION: Metoprolol induced a decrease in CPT-I activity and an increase in triglyceride content. These results suggest that the improved function observed with beta blockers in heart failure could be due, in part, to a decrease in CPT-I activity and less fatty acid oxidation by the heart.
Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Carnitina O-Palmitoiltransferase/sangue , Insuficiência Cardíaca/enzimologia , Metoprolol/uso terapêutico , Animais , Modelos Animais de Doenças , Cães , Ácidos Graxos/metabolismo , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica/efeitos dos fármacos , Ratos , Volume Sistólico/efeitos dos fármacos , Triglicerídeos/análiseRESUMO
Nepicastat (RS-25560-197) is a novel, selective, and potent inhibitor of dopamine beta-hydroxylase, which modulates catecholamine levels (reduces norepinephrine and elevates dopamine) in cardiovascular tissues. This study was designed to evaluate the cardiovascular effects of nepicastat. Acute oral administration of nepicastat (0.3, 1, 3, 10, and 30 mg/kg) produced attenuation of the pressor and positive chronotropic responses to preganglionic sympathetic nerve stimulation (about twofold to sixfold shift in the frequency-response curve) in pithed spontaneously hypertensive rats (SHRs). In inactin-anesthetized SHRs, the antihypertensive effects of nepicastat (3 mg/kg, i.v.) were accompanied by a significant decrease in renal vascular resistance (38%), a tendency toward an increase in renal blood flow (22%), and no adverse effects on urine output and Na/K excretion. In conscious, unrestrained, telemetry-implanted SHRs, nepicastat (30 and 100 mg/kg/day for 30 days) produced dose-dependent decreases in mean arterial blood pressure (peak decrease of 20 and 42 mm Hg, respectively) without evoking reflex tachycardia. Long-term, concurrent administration of nepicastat (30 mg/kg/day, p.o.) and a subthreshold dose of enalapril (1 mg/kg/day, p.o.) produced greater antihypertensive effects than those produced by nepicastat alone. In normal dogs, nepicastat (5.0 mg/kg, p.o., b.i.d., for 4.5 days) blunted the positive chronotropic and pressor response to tyramine. These findings suggest that nepicastat functionally modulates sympathetic drive to cardiovascular tissues and may be of value in the treatment of cardiovascular disorders associated with overactivation of the sympathetic nervous system such as hypertension and congestive heart failure.
Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Dopamina beta-Hidroxilase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Tionas/farmacologia , Animais , Cães , Estimulação Elétrica , Enalapril/farmacologia , Hemodinâmica/efeitos dos fármacos , Rim/irrigação sanguínea , Rim/efeitos dos fármacos , Masculino , Ratos , Ratos Endogâmicos SHR , Tiramina/farmacologiaRESUMO
1. Ranolazine shifts ATP production away from fatty acid oxidation toward glucose oxidation. 2. Because more oxygen is required to phosphorylate a given amount of ATP during fatty acid oxidation than during carbohydrate oxidation, the ranolazine-induced shift in substrate selection reduces the cell's demand for oxygen without decreasing its ability to do work. The shift also maintains coupling of glycolysis to glucose oxidation during ischemia, thus reducing tissue acidosis. 3. This unique, non-hemodynamic mechanism offers the potential to treat angina without reducing blood pressure, heart rate or myocardial contractility. 4. At least three double-blind, randomized, placebo-controlled clinical trials have yielded data consistent with this hypothesis.
Assuntos
Angina Pectoris/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Piperazinas/uso terapêutico , Acetanilidas , Trifosfato de Adenosina/biossíntese , Angina Pectoris/metabolismo , Ensaios Clínicos como Assunto , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Ácidos Graxos/metabolismo , Glucose/metabolismo , Hemodinâmica/efeitos dos fármacos , Humanos , Estudos Multicêntricos como Assunto , Oxirredução , Piperazinas/química , Piperazinas/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , RanolazinaRESUMO
1. Inhibitory modulation of sympathetic nerve function may have a favourable impact on the progression of congestive heart failure. Nepicastat is a novel inhibitor of dopamine-beta-hydroxylase, the enzyme which catalyses the conversion of dopamine to noradrenaline in sympathetic nerves. The in vitro pharmacology and in vivo catecholamine modulatory effects of nepicastat were investigated in the present study. 2. Nepicastat produced concentration-dependent inhibition of bovine (IC50 = 8.5 +/- 0.8 nM) and human (IC50 = 9.0 +/- 0.8 nM) dopamine-beta-hydroxylase. The corresponding R-enantiomer (RS-25560-198) was approximately 2-3 fold less potent than nepicastat. Nepicastat had negligible affinity (> 10 microM) for twelve other enzymes and thirteen neurotransmitter receptors. 3. Administration of nepicastat to spontaneously hypertensive rats (SHRs) (three consecutive doses of either 3, 10, 30 or 100 mg kg-1, p.o.; 12 h apart) or beagle dogs (0.05, 0.5, 1.5 or 5 mg kg-1, p.o.; b.i.d., for 5 days) produced dose-dependent decreases in noradrenaline content, increases in dopamine content and increases in dopamine/noradrenaline ratio in the artery (mesenteric or renal), left ventricle and cerebral cortex. At the highest dose studied, the decreases in tissue noadrenaline were 47%, 35% and 42% (in SHRs) and 88%, 91% and 96% (in dogs) in the artery, left ventricle and cerebral cortex, respectively. When tested at 30 mg kg-1, p.o., in SHRs, nepicastat produced significantly greater changes in noradrenaline and dopamine content, as compared to the R-enantiomer (RS-25560-198), in the mesenteric artery and left ventricle. 4. Administration of nepicastat (2 mg kg-1, b.i.d, p.o.) to beagle dogs for 15 days produced significant decreases in plasma concentrations of noradrenaline and increases in plasma concentrations of dopamine and dopamine/noradrenaline ratio. The peak reduction (52%) in plasma concentration of noradrenaline and the peak increase (646%) in plasma concentration of dopamine were observed on day-6 and day-7 of dosing, respectively. 5. The findings of this study suggest that nepicastat is a potent, selective and orally active inhibitor of dopamine-beta-hydroxylase which produces gradual modulation of the sympathetic nervous system by inhibiting the biosynthesis of noradrenaline. This drug may, therefore, be of value in the treatment of cardiovascular disorders associated with over-activation of the sympathetic nervous system, such as congestive heart failure.
Assuntos
Catecolaminas/metabolismo , Dopamina beta-Hidroxilase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Imidazóis/farmacologia , Tionas/farmacologia , Animais , Bovinos , Cães , Relação Dose-Resposta a Droga , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Masculino , Ratos , Ratos Endogâmicos SHRRESUMO
The individual enantiomers 8 and 12 of the potent and highly selective racemic A1-adenosine antagonist 1,3-dipropyl-8-[2-(5,6-epoxynorbornyl)]xanthine (ENX, 4) were synthesized utilizing asymmetric Diels-Alder cycloadditions for the construction of the norbornane moieties. The absolute configuration of 12 was determined by X-ray crystallography of the 4-bromobenzoate 14, which was derived from the bridged secondary alcohol 13. The latter was obtained from 12 by an acid-catalyzed intramolecular rearrangement. The binding affinities of the enantiomers 8 and 12 and the racemate 4 at guinea pig, rat, and cloned human A1- and A2a-adenosine receptor subtypes were determined. The S-enantiomer 12 (CVT-124) appears to be one of the more potent and clearly the most A1-selective antagonist reported to date, with K1 values of 0.67 and 0.45 nM, respectively, at the rat and cloned human A1-receptors and with 1800-fold (rat) and 2400-fold (human) subtype selectivity. Both enantiomers, administered intravenously to saline-loaded rats, induced diuresis via antagonism of renal A1-adenosine receptors.
Assuntos
Antagonistas de Receptores Purinérgicos P1 , Xantinas/síntese química , Animais , Diurese/efeitos dos fármacos , Cobaias , Humanos , Modelos Moleculares , Estrutura Molecular , Ratos , Receptores Purinérgicos P1/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade , Xantinas/química , Xantinas/metabolismo , Xantinas/farmacologiaRESUMO
The effects of diabetes on myocardial metabolism are complex in that they are tied to the systemic metabolic abnormalities of the disease (hyperglycemia and elevated levels of free fatty acid and ketone bodies), and changes in cardiomyocyte phenotype (e.g., down-regulation of glucose transporters and PDH activity). The cardiac adaptations appear to be driven by the severity of the systemic abnormalities of the disease. The diabetes-induced changes in the plasma milieu and cardiac phenotype both cause impaired glycolysis, pyruvate oxidation, and lactate uptake, and a greater dependency on fatty acids as a source of acetyl CoA. Studies in isolated hearts suggest that therapies aimed at decreasing fatty acid oxidation, or directly stimulating pyruvate oxidation would be of benefit to the diabetic heart during and following myocardial ischemia.
Assuntos
Cardiomiopatias/metabolismo , Diabetes Mellitus/metabolismo , Metabolismo Energético/fisiologia , Miocárdio/metabolismo , Animais , Cardiomiopatias/complicações , Complicações do Diabetes , Ácidos Graxos/metabolismo , Glucose/metabolismo , Glicólise , Humanos , Insulina/metabolismo , Mitocôndrias Cardíacas/metabolismo , RatosRESUMO
The purpose of the study was to assess myocardial glucose uptake in nondiabetic (n = 5) and streptozotocin-diabetic (n = 6) Yucatan miniature swine under matched hyperglycemic and hypoinsulinemic conditions. Fasting conscious diabetic swine had significantly higher plasma glucose levels (20.9 +/- 2.6 v 5.2 +/- 0.3 mmol/L) and lower insulin levels (6 +/- 1 v 14 +/- 4 microU/mL) than nondiabetic animals. Myocardial glucose uptake was measured in open-chest anesthetized animals under aerobic and ischemic conditions 12 weeks after streptozotocin treatment. Coronary blood flow was controlled by an extracorporeal perfusion circuit. Ischemia was induced by reducing left anterior descending (LAD) coronary artery blood flow by 60% for 40 minutes. Animals were treated with somatostatin to suppress insulin secretion, and nondiabetic swine received intravenous (IV) glucose to match the hyperglycemia in the diabetic animals. The rate of glucose uptake by the myocardium was not statistically different under aerobic conditions, but was significantly lower in diabetic swine during ischemia (0.20 +/- 0.08 v 0.63 +/- 0.14 micromol x g(-1) x min(-1), P < .01). Myocardial glucose transporter (GLUT4) protein concentration was decreased by 31% in diabetic swine. In conclusion, 12 weeks of streptozotocin diabetes in swine caused a significant decrease in myocardial GLUT4 protein and a decrease in myocardial glucose uptake during ischemia.
Assuntos
Diabetes Mellitus Experimental/metabolismo , Glucose/metabolismo , Proteínas Musculares , Isquemia Miocárdica/metabolismo , Miocárdio/metabolismo , Animais , Glicemia/análise , Circulação Coronária , Jejum/metabolismo , Ácidos Graxos não Esterificados/sangue , Transportador de Glucose Tipo 4 , Insulina/análise , Ácido Láctico/sangue , Masculino , Proteínas de Transporte de Monossacarídeos/metabolismo , Suínos , Porco Miniatura , Função Ventricular/fisiologiaRESUMO
It is now clear that the availability of different metabolic substrates can have a profound influence on the extent of damage incurred during episodes of cardiac ischaemia, and on cardiac functional recovery on reperfusion following ischaemia. In particular, increases in fatty acid availability and oxidation, compared to glucose oxidation, under such conditions leads to a worsening of outcome. Therefore metabolic interventions aimed at enhancing glucose utilisation and pyruvate oxidation at the expense of fatty acid oxidation is a valid therapeutic approach to the treatment of myocardial ischaemia. In particular, the development of agents which will promote full glucose oxidation as opposed to glycolysis alone, offer clear advantages. This can be accomplished by different means, including direct or indirect inhibition of CPT-I or inhibition of fatty acid beta-oxidation, or by direct or indirect activation of PDH. It is not yet clear which of these approaches offers the best treatment of cardiac ischaemia. To date, trimetazidine and carnitine have received limited approval in Europe for the treatment of angina; large scale clinical trials with the other agents mentioned above have not been completed. The increasing availability of agents affecting these specific sites, and the increasingly sophisticated techniques for assessing myocardial metabolism, should allow elucidation of the optimum metabolic targets and development of novel pharmacological agents for the treatment of ischaemic heart disease.