RESUMEN
Diabetic patients often have impaired heart rate (HR) control. HR is regulated both intrinsically within the sinoatrial node (SAN) and via neuronal input. Previously, we found lower ex vivo HR in type 2 diabetic rat hearts, suggesting impaired HR generation within the SAN. The major driver of pacemaking within the SAN is the activity of hyperpolarisation-activated cyclic nucleotide-gated 4 (HCN(4)) channels. This study aimed to investigate whether the lower intrinsic HR in the type 2 diabetic heart is due to changes in HCN4 function, protein expression and/ or distribution. The intrinsic HR response to HCN4 blockade was determined in isolated Langendorff-perfused hearts of Zucker type 2 Diabetic Fatty (ZDF) rats (DM) and their non-diabetic ZDF littermates (nDM). HCN4 protein expression and membrane localisation were determined using western blot and immunofluorescence, respectively. We found that the intrinsic HR was lower in DM compared to nDM hearts. The change in intrinsic HR in response to HCN4 blockade with ivabradine was diminished in DM hearts, which normalised the intrinsic HR between the groups. HCN4 protein expression was decreased in the SAN of DM compared to nDM controls with no change in the fraction of HCN4 localised to the membrane of SAN cardiomyocytes. The lower intrinsic HR in DM is likely due to decreased HCN4 expression and depressed HCN4 function. Our study provides a novel understanding into the intrinsic mechanisms underlying altered HR control in type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2 , Nodo Sinoatrial , Ratas , Animales , Nodo Sinoatrial/metabolismo , Canales Regulados por Nucleótidos Cíclicos Activados por Hiperpolarización/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Ratas Zucker , Miocitos Cardíacos/metabolismo , Canales de Potasio/metabolismoRESUMEN
Nitric oxide (NO) is a key vasodilatory signalling molecule and NO releasing molecules (NO donors) are being examined as potential treatments for many pathologies. The photoresponsive NO donor tert-dodecane S-nitrosothiol (tDodSNO) has been designed to be highly resistant to metabolism; in principle photoactivation of tDodSNO should therefore enable the controlled release of NO in situ via light modulation. To investigate the therapeutic utility of tDodSNO, we tested drug efficacy in Sprague Dawley rats to assess systemic and localised hemodynamic responses under photoactivation, and to confirm drug safety. For comparison, drug action was evaluated alongside the existing NO donors sodium nitroprusside (SNP) and S-nitrosoglutathione (GSNO). Across a dosing range (0.1-3.0 mg/kg) tDodSNO exerted markedly reduced systemic hypotensive action compared to these standard NO donors, inducing a slight decrease in mean arterial pressure (maximum 14.2 ± 3.0%) without affecting heart rate. Target limb photoactivation of tDodSNO resulted in a substantial localized vasodilatory response, with increases to mean (26.0 ± 7.3%) and maximum (53.2 ± 10.4%) blood flow and decreases to vascular resistance (27.1 ± 3.9%) that were restricted to light exposed tissue. In comparison GSNO and SNP showed variable peripheral effects and were not responsive to photoactivation. tDodSNO did not induce met-Hb formation in blood, or display any signs of toxicity, and was rapidly cleared from the systemic circulation, with no hemodynamic effects detectable 5 min post administration. These data are the first demonstration that drugs based upon a metabolically stable S-nitrosothiol group can be photoactivated in vivo to release NO, and that such agents cause less systemic side effects than existing NO donors. Our data support the use of S-nitrosothiols to enable the spatiotemporal control of NO for therapeutic applications.
Asunto(s)
Donantes de Óxido Nítrico , S-Nitrosotioles , Animales , Ratas , Donantes de Óxido Nítrico/farmacología , Donantes de Óxido Nítrico/metabolismo , Vasodilatación , Ratas Sprague-Dawley , S-Nitrosotioles/farmacología , S-Nitrosotioles/metabolismo , Nitroprusiato/farmacología , Óxido Nítrico/metabolismoRESUMEN
NEW FINDINGS: What is the central question of this study? Are there specific contributions of ß1 - and ß2 -adrenoceptor subtypes to the impaired ß-adrenoceptor responsiveness of the type 2 diabetic heart? What is the main finding and its importance? In hearts isolated from the Zucker diabetic fatty rat model of type 2 diabetes, we showed that the ß1 -adrenoceptors are the main subtype to regulate heart rate, contraction and relaxation. Notably, the ß2 -adrenoceptor subtype actions seem to support function in the diabetic heart indirectly. ABSTRACT: Impaired ß-adrenoceptor (ß-AR) responsiveness causes cardiac vulnerability in patients with type 2 diabetes, but the independent contributions of ß1 - and ß2 -AR subtypes to ß-AR-associated cardiac dysfunction in diabetes are unknown. Our aim was to determine the specific ß1 - and ß2 -AR responsiveness of heart rate (HR), contraction and relaxation in the diabetic heart. Isolated Langendorff-perfused hearts of Zucker type 2 diabetic fatty (ZDF) rats were stimulated with the ß-AR agonist isoprenaline (1 × 10-11 to 3 × 10-8 mol l-1 ) with or without the selective ß1 -AR antagonist CGP20712A (3 × 10-8 mol l-1 ) or the ß2 -AR antagonist ICI-118,551 (5 × 10-8 mol l-1 ), and HR, contraction and relaxation were measured. Diabetic hearts showed lower basal HR (non-diabetic 216 ± 17 beats min-1 versus diabetic 151 ± 23 beats min-1 , P < 0.05). However, the ß-AR-induced increase in HR was similar and was completely blocked by the ß1 -AR antagonist, but not by the ß2 -AR antagonist. The ß-AR-induced increase in contraction and acceleration of relaxation was impaired in diabetic hearts, completely blocked by the ß1 -AR antagonist and partly impaired by the ß2 -AR antagonist. Western blots revealed 41% higher phosphorylation levels of AMP kinase (AMPK), a key regulator of cardiac energy metabolism, in diabetic hearts (non-diabetic 1.62 ± 0.19 a.u. versus diabetic 2.30 ± 0.25 a.u., P < 0.05). In conclusion, the ß1 -AR is the main subtype regulating chronotropic, inotropic and lusitropic ß-AR responses in the healthy heart and the type 2 diabetic heart. The ß2 -AR subtype indirectly supports the ß1 -AR functional response in the diabetic heart. This suggests that ß2 -ARs could be an indirect target to improve the function of the heart in type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/metabolismo , Corazón/efectos de los fármacos , Miocardio/metabolismo , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Agonistas Adrenérgicos beta/farmacología , Antagonistas Adrenérgicos beta/farmacología , Animales , Frecuencia Cardíaca/efectos de los fármacos , Imidazoles/farmacología , Preparación de Corazón Aislado , Isoproterenol/farmacología , Masculino , Ratas , Ratas Zucker , Transducción de Señal/efectos de los fármacosRESUMEN
NEW FINDINGS: What is the central question of the study? Is the reduced signalling of AMP-activated protein kinase (AMPK), a key regulator of energy homeostasis in the heart, responsible for the reduced ß-adrenergic responsiveness of the heart in obesity? What is the main finding and its importance? Inhibition of AMPK in isolated hearts prevented the reduced cardiac ß-adrenergic responsiveness of obese rats, which was accompanied by reduced phosphorylation of AMPK, a proxy of AMPK activity. This suggests a direct functional link between ß-adrenergic responsiveness and AMPK signalling in the heart, and it suggests that AMPK might be an important target to restore the ß-adrenergic responsiveness in the heart in obesity. ABSTRACT: The obesity epidemic impacts heavily on cardiovascular health, in part owing to changes in cardiac metabolism. AMP-activated protein kinase (AMPK) is a key regulator of energy homeostasis in the heart and is regulated by ß-adrenoceptors (ß-ARs) in normal conditions. In obesity, chronic sympathetic overactivation leads to impaired cardiac ß-AR responsiveness, although it is unclear whether AMPK signalling, downstream of ß-ARs, contributes to this dysfunction. Therefore, we aimed to determine whether reduced AMPK signalling is responsible for the reduced ß-AR responsiveness in obesity. In isolated hearts of lean and obese Zucker rats, we tested ß-AR responsiveness to the ß1 -AR agonist isoprenaline (ISO, 1 × 10-10 to 5 × 10-8 m) in the absence and presence of the AMPK inhibitor, compound C (CC, 10 µm). The ß1 -AR expression and AMPK phosphorylation were assessed by Western blot. ß-Adrenergic responsiveness was reduced in the hearts of obese rats (logEC50 of ISO-developed pressure dose-response curves: lean -8.53 ± 0.13 × 10x m versus obese -8.35 ± 0.10 × 10x m ; P < 0.05 lean versus obese, n = 6 per group). This difference was not apparent after AMPK inhibition (logEC50 of ISO-developed pressure curves: lean CC -8.19 ± 0.12 × 10x m versus obese CC 8.17 ± 0.13 × 10x m, P < 0.05, n = 6 per group). ß1 -Adrenergic receptor expression and AMPK phosphorylation were reduced in hearts of obese rats (AMPK at Thr172 : lean 1.73 ± 0.17 a.u. versus lean CC 0.81 ± 0.13 a.u., and obese 1.18 ± 0.09 a.u. versus obese CC 0.81 ± 0.16 a.u., P < 0.05, n = 6 per group). Thus, a direct functional link between ß-adrenergic responsiveness and AMPK signalling in the heart exists, and AMPK might be an important target to restore the reduced cardiac ß-adrenergic responsiveness in obesity.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Corazón/efectos de los fármacos , Obesidad/metabolismo , Agonistas Adrenérgicos beta/farmacología , Animales , Isoproterenol/farmacología , Masculino , Miocardio/metabolismo , Fosforilación/efectos de los fármacos , Ratas , Ratas Zucker , Transducción de Señal/efectos de los fármacosRESUMEN
NEW FINDINGS: What is the central question of the study? The sympathetic system regulates heart rate via ß-adrenoceptors; this is impaired during diabetes. However, the specific ß-adrenoceptor subtype contributions in heart rate regulation in diabetes in vivo are unknown. What is the main finding and its importance? Telemetric recordings in conscious non-diabetic and type 2 diabetic rats demonstrated that the ß1 -adrenoceptor subtype, and not the ß2 -adrenoceptor, regulated the lower resting heart rate and increased ß-adrenoceptor responsiveness in diabetes in vivo. This provides new physiological insight into the dysregulation of heart rate in type 2 diabetes, which is important for improving therapeutic strategies targeting the diabetic chronotropic incompetence. ß-Adrenoceptor blockers are widely used to reduce heart rate, the strongest predictor of mortality in cardiac patients, but are less effective in diabetic patients. This study aimed to determine the specific contributions of ß1 - and ß2 -adrenoceptor subtypes to chronotropic responses in type 2 diabetes in vivo, which are currently unknown. Type 2 diabetic and non-diabetic rats were implanted with radiotelemeters to measure arterial blood pressure and derive heart rate in conscious conditions. Vascular access ports were implanted to inject isoprenaline (ß1 - and ß2 -adrenoceptor agonist, 0.1-300 µg kg-1 ) in the presence of atenolol (ß1 -adrenoceptor antagonist, 2000 µg kg-1 ) or nadolol (ß1 - and ß2 -adrenoceptor agonist, 4000 µg kg-1 ) to determine the chronotropic contributions of the ß-adrenoceptor subtypes. Resting heart rate was reduced in diabetic rats (388 ± 62 versus 290 ± 37 beats min-1 non-diabetic versus diabetic, P < 0.05, mean ± SD), which remained after atenolol or nadolol administration. Overall ß-adrenoceptor chronotropic responsiveness was increased in diabetic rats (change in heart rate at highest dose of isoprenaline: 135 ± 66 versus 205 ± 28 beats min-1 , non-diabetic versus diabetic, P < 0.05), a difference that diminished after ß1 -adrenoceptor blockade with atenolol (change in heart rate at highest dose of isoprenaline: 205 ± 37 versus 195 ± 22 beats min-1 , non-diabetic versus diabetic, P < 0.05). In conclusion, the ß1 -adrenoceptor is the main subtype to modulate chronotropic ß-adrenoceptor responses in healthy and diabetic rats. This study provides new insights into the pathological basis of dysregulation of heart rate in type 2 diabetes, which could be important for improving the current therapeutic strategies targeting diabetic chronotropic incompetence.
Asunto(s)
Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Frecuencia Cardíaca/fisiología , Receptores Adrenérgicos beta 1/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Antagonistas Adrenérgicos beta/farmacología , Animales , Atenolol/farmacología , Presión Sanguínea/efectos de los fármacos , Modelos Animales de Enfermedad , Frecuencia Cardíaca/efectos de los fármacos , Isoproterenol/farmacología , Masculino , Contracción Miocárdica/efectos de los fármacos , Ratas , Ratas Zucker , Transducción de Señal/efectos de los fármacosRESUMEN
NEW FINDINGS: What is the central question of this study? Can bilateral renal denervation, an effective antihypertensive treatment in clinical and experimental studies, improve cardiac ß-adrenoceptor responsiveness in a diabetic model with underlying hypertension? What is the main finding and its importance? Bilateral renal denervation did not affect ß-adrenergic responsiveness in the diabetic hypertensive rat heart, but denervation reduced the hypertension-induced concentric hypertrophic remodelling. This suggests that the positive haemodynamic changes induced by renal denervation are most likely to reflect an attenuation of sympathetic effects on the systemic vasculature and/or the renal function rather than direct sympathetic modulation of the heart. Bilateral renal denervation (BRD) has been shown to normalise blood pressure in clinical and experimental studies of hypertension by reducing systemic sympathetic output. This study determined the effect of BRD on cardiac ß-adrenoceptor (AR) responsiveness in a diabetic model with underlying hypertension using the transgenic (mRen-2)27 rats. Bilateral renal denervation or sham surgeries were conducted repeatedly at 3, 6 and 9 weeks in Ren-2 rats with or without streptozotocin (STZ)-induced diabetes (4 × n = 7); Sprague-Dawley rats (n = 6) served as control animals. Cardiac function was determined in isolated hearts at 18 weeks of age. Normalised left ventricular developed pressure and relaxation was recorded in response to incremental concentrations of the ß-AR agonist isoprenaline (from 10-10 to 10-7 m) or the ß3 -AR agonist BRL37344 (from 10(-13) to 10(-6 ) m). Expression levels of ß1 -AR were determined by Western blot. Both inotropic and lusitropic ß-AR responsiveness was reduced in the hypertensive diabetic hearts, but these responses were unaltered after BRD. Expression levels of ß1 -AR were increased after BRD (Sham, 0.85 ± 0.11 versus 1.01 ± 0.05 a.u.; BRD, 1.45 ± 0.11 versus 1.46 ± 0.07 a.u.; Ren-2 versus Ren-2 STZ, P < 0.05 versus Sham). No effect of ß3 -AR agonist stimulation with BRL37344 was observed. Interestingly, BRD increased left ventricular diastolic volume in both the Ren-2 and the Ren-2 STZ groups. Bilateral renal denervation did not restore the attenuated cardiac ß-AR responsiveness in the diabetic hypertensive rats, but it reduced the extent of hypertension-induced concentric hypertrophic remodelling. Thus, the haemodynamic protection offered by renal denervation appears to reflect an attenuated sympathetic innervation of the systemic vasculature and/or kidney rather than a direct cardiac effect.
Asunto(s)
Cardiomegalia/cirugía , Diabetes Mellitus Tipo 1/cirugía , Hipertensión/cirugía , Riñón/inervación , Miocardio/metabolismo , Receptores Adrenérgicos beta 1/metabolismo , Simpatectomía , Sistema Nervioso Simpático/cirugía , Remodelación Ventricular , Agonistas de Receptores Adrenérgicos beta 1/farmacología , Animales , Presión Sanguínea , Cardiomegalia/metabolismo , Cardiomegalia/fisiopatología , Cardiotónicos/farmacología , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus Tipo 1/fisiopatología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Femenino , Hipertensión/metabolismo , Hipertensión/fisiopatología , Preparación de Corazón Aislado , Contracción Miocárdica , Ratas Sprague-Dawley , Ratas Transgénicas , Receptores Adrenérgicos beta 1/efectos de los fármacos , Transducción de Señal , Sistema Nervioso Simpático/metabolismo , Sistema Nervioso Simpático/fisiopatología , Factores de Tiempo , Función Ventricular Izquierda , Presión Ventricular , Remodelación Ventricular/efectos de los fármacosRESUMEN
BACKGROUND: Increasing numbers of type 2 diabetic and obese patients with enhanced rates of cardiovascular complications require surgical interventions, however they have a higher incidence of perioperative haemodynamic complications, which has been linked to adrenergic dysfunction. Therefore, we aimed to determine how α- and ß-adrenoceptor (AR)-mediated haemodynamic responses are affected by isoflurane anaesthesia in experimental type 2 diabetes and obesity in vivo. METHODS: Sixteen-week old male Zucker type 2 Diabetic Fatty (ZDF) rats, Zucker Obese rats and their lean counterparts (n = 7-9 per group) were instrumented with radio telemeters to record blood pressure and heart rate and with vascular access ports for non-invasive intravenous drug delivery in vivo. Haemodynamic effects of α-AR (phenylephrine; 1-100 µg x kg(-1)) or ß-AR (dobutamine; 2-120 µg x kg(-1)) stimulation were assessed under conscious and anaesthetised (isoflurane; 2%) conditions. RESULTS: Vascular α-AR sensitivity was increased in both diabetic (non-diabetic 80 ± 3 vs. diabetic 95 ± 4 ΔmmHg at 100 µg x kg(-1); p < 0.05) and obese (lean 65 ± 6 vs. obese 84 ± 6 ΔmmHg at 20 µg x kg(-1); p < 0.05) conscious rats. Interestingly, anaesthesia exacerbated and prolonged the increased α-AR function in both diabetic and obese animals (non-diabetic 51 ± 1 vs. diabetic 68 ± 4 ΔmmHg, lean 61 ± 5 vs. obese 84 ± 2 ΔmmHg at 20 µg x kg(-1); p < 0.05). Meanwhile, ß-AR chronotropic sensitivity was reduced in conscious diabetic and obese rats (non-diabetic 58 ± 7 vs. diabetic 27 ± 8 Δbpm, lean 103 ± 12 vs. obese 61 ± 9 Δbpm at 15 µg x kg(-1); p < 0.05). Anaesthesia normalised chronotropic ß-AR responses, via either a limited reduction in obese (lean 51 ± 3 vs. obese 66 ± 5 Δbpm; NS at 15 µg x kg(-1)) or increased responses in diabetic animals (non-diabetic 49 ± 8 vs. diabetic 63 ± 8 Δbpm, at 15 µg x kg(-1); NS at 15 µg x kg(-1)). CONCLUSIONS: Long term metabolic stress, such as during type 2 diabetes and obesity, alters α- and ß-AR function, its dynamics and the interaction with isoflurane anaesthesia. During anaesthesia, enhanced α-AR sensitivity and normalised ß-AR function may impair cardiovascular function in experimental type 2 diabetes and obesity.
Asunto(s)
Anestésicos por Inhalación/farmacología , Glucemia/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Diabetes Mellitus Tipo 2/metabolismo , Hemodinámica/efectos de los fármacos , Isoflurano/farmacología , Obesidad/fisiopatología , Animales , Diabetes Mellitus Experimental/sangre , Masculino , Ratas , Ratas ZuckerRESUMEN
Recent studies have shown that adiponectin is able to increase nitric oxide (NO) production by the endothelium and relax preconstricted isolated aortic rings, suggesting that adiponectin may act as a vasodilator. Endothelin-1 (ET-1) is a potent vasoconstrictor, elevated levels of which are associated with obesity, type 2 diabetes, hypertension, and cardiovascular disease. We hypothesized that adiponectin has NO-dependent vascular actions opposing the vasoconstrictor actions of ET-1. We studied the vascular and metabolic effects of a physiological concentration of adiponectin (6.5 µg/ml) on hooded Wistar rats in the constant-flow pump-perfused rat hindlimb. Adiponectin alone had no observable vascular activity; however, adiponectin pretreatment and coinfusion inhibited the increase in perfusion pressure and associated metabolic stimulation caused by low-dose (1 nM) ET-1. Adiponectin was not able to oppose vasoconstriction when infusion was commenced after ET-1. This is in contrast to the NO donor sodium nitroprusside, which significantly reduced the pressure due to established ET-1 vasoconstriction, suggesting dissociation of the actions of adiponectin and NO. In addition, adiponectin had no effect on vasoconstriction caused by either high-dose (20 nM) ET-1 or low-dose (50 nM) norepinephrine. Our findings suggest that adiponectin has specific, apparently NO-independent, vascular activity to oppose the vasoconstrictor effects of ET-1. The hemodynamic actions of adiponectin may be an important aspect of its insulin-sensitizing ability by regulating access of insulin and glucose to myocytes. Imbalance in the relationship between adiponectin and ET-1 in obesity may contribute to the development of insulin resistance and cardiovascular disease.
Asunto(s)
Adiponectina/farmacología , Endotelina-1/antagonistas & inhibidores , Miembro Posterior/irrigación sanguínea , Vasoconstricción/efectos de los fármacos , Angiotensina II/farmacología , Animales , ADN Complementario/biosíntesis , ADN Complementario/genética , Relación Dosis-Respuesta a Droga , Endotelina-1/farmacología , Glucosa/metabolismo , Hipoglucemiantes/farmacología , Insulina/farmacología , Masculino , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/efectos de los fármacos , Óxido Nítrico/fisiología , Donantes de Óxido Nítrico/farmacología , Norepinefrina/farmacología , Consumo de Oxígeno/efectos de los fármacos , Perfusión , Ratas , Ratas Wistar , Flujo Sanguíneo Regional/efectos de los fármacos , Vasoconstrictores/farmacologíaRESUMEN
Increased cardiac sympathetic nerve activity in type 2 diabetes mellitus (DM) suggests impaired autonomic control of the heart. However, the central regions that contribute to the autonomic cardiac pathologies in type 2 DM are unknown. Therefore, we tested the hypothesis that neuronal activation would be increased in central sympathoregulatory areas in a pre-clinical type 2 DM animal model. Immunohistochemistry in 20-week-old male Zucker diabetic fatty (ZDF) rats revealed an increased number of neurones expressing ΔFosB (a marker of chronic neuronal activation) in the intermediolateral column (IML) of the spinal cord in DM compared to non-diabetic (non-DM) rats (P < 0.05). Rostral ventrolateral medulla (RVLM) neurones activate IML neurones and receive inputs from the hypothalamic paraventricular nucleus (PVN), as well as the nucleus tractus solitarius (NTS) and area postrema (AP), in the brainstem. We observed more ΔFosB-positive noradrenergic RVLM neurones (P < 0.001) and corticotrophin-releasing hormone PVN neurones (P < 0.05) in DM compared to non-DM rats. More ΔFosB-positive neurones were also observed in the NTS (P < 0.05) and AP (P < 0.01) of DM rats compared to non-DM rats. Finally, because DM ZDF rats are obese, we also expected increased activation of pro-opiomelanocortin (POMC) arcuate nucleus (ARC) neurones in DM rats; however, fewer ΔFosB-positive POMC ARC neurones were observed in DM compared to non-DM rats (P < 0.01). In conclusion, increased neuronal activation in the IML of type 2 DM ZDF rats might be driven by RVLM neurones that are possibly activated by PVN, NTS and AP inputs. Elucidating the contribution of central sympathoexcitatory drive in type 2 DM might improve the effectiveness of pharmacotherapies for diabetic heart disease.
RESUMEN
Diabetes is associated with cardiac metabolic disturbances and increased heart failure risk. Plasma fructose levels are elevated in diabetic patients. A direct role for fructose involvement in diabetic heart pathology has not been investigated. The goals of this study were to clinically evaluate links between myocardial fructose and sorbitol (a polyol pathway fructose precursor) levels with evidence of cardiac dysfunction, and to experimentally assess the cardiomyocyte mechanisms involved in mediating the metabolic effects of elevated fructose. Fructose and sorbitol levels were increased in right atrial appendage tissues of type 2 diabetic patients (2.8- and 1.5-fold increase respectively). Elevated cardiac fructose levels were confirmed in type 2 diabetic rats. Diastolic dysfunction (increased E/e', echocardiography) was significantly correlated with cardiac sorbitol levels. Elevated myocardial mRNA expression of the fructose-specific transporter, Glut5 (43% increase), and the key fructose-metabolizing enzyme, Fructokinase-A (50% increase) was observed in type 2 diabetic rats (Zucker diabetic fatty rat). In neonatal rat ventricular myocytes, fructose increased glycolytic capacity and cytosolic lipid inclusions (28% increase in lipid droplets/cell). This study provides the first evidence that elevated myocardial fructose and sorbitol are associated with diastolic dysfunction in diabetic patients. Experimental evidence suggests that fructose promotes the formation of cardiomyocyte cytosolic lipid inclusions, and may contribute to lipotoxicity in the diabetic heart.
Asunto(s)
Diabetes Mellitus Tipo 2/patología , Fructosa/análisis , Metabolismo de los Lípidos , Miocardio/metabolismo , Miocitos Cardíacos/metabolismo , Sorbitol/análisis , Animales , Glucemia/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/metabolismo , Fructoquinasas , Fructosa/metabolismo , Glucosa/metabolismo , Humanos , Gotas Lipídicas/metabolismo , Masculino , Miocardio/química , Ratas , Ratas Zucker , Sorbitol/metabolismo , Disfunción Ventricular Izquierda/patologíaRESUMEN
The funny current, If, was first recorded in the heart 40 or more years ago by Dario DiFrancesco and others. Since then, we have learnt that If plays an important role in pacemaking in the sinus node, the innate pacemaker of the heart, and more recently evidence has accumulated to show that If may play an important role in action potential conduction through the atrioventricular (AV) node. Evidence has also accumulated to show that regulation of the transcription and translation of the underlying Hcn genes plays an important role in the regulation of sinus node pacemaking and AV node conduction under normal physiological conditions - in athletes, during the circadian rhythm, in pregnancy, and during postnatal development - as well as pathological states - ageing, heart failure, pulmonary hypertension, diabetes and atrial fibrillation. There may be yet more pathological conditions involving changes in the expression of the Hcn genes. Here, we review the role of If and the underlying HCN channels in physiological and pathological changes of the sinus and AV nodes and we begin to explore the signalling pathways (microRNAs, transcription factors, GIRK4, the autonomic nervous system and inflammation) involved in this regulation. This review is dedicated to Dario DiFrancesco on his retirement.
Asunto(s)
Fibrilación Atrial , Nodo Atrioventricular , Potenciales de Acción , Frecuencia Cardíaca , Humanos , Nodo SinoatrialRESUMEN
PURPOSE: Increasing cohorts of patients present with diabetic cardiomyopathy, and with no targeted options, treatment often rely on generic pharmaceuticals such as ß-blockers. ß-blocker efficacy is heterogenous, with second generation ß-blocker metoprolol selectively inhibiting ß1 -AR, while third generation ß-blocker carvedilol has α1 -AR inhibition, antioxidant, and anti-apoptotic actions alongside nonselective ß-AR inhibition. These additional properties have led to the hypothesis that carvedilol may improve cardiac contractility in the diabetic heart to a greater extent than metoprolol. The present study aimed to compare the efficacy of metoprolol and carvedilol on myocardial function in animal models and cardiac tissue from patients with type 2 diabetes and preserved ejection fraction. METHODS: Echocardiographic examination of cardiac function and assessment of myocardial function in isolated trabeculae was carried out in patients with and without diabetes undergoing coronary artery bypass grafting (CABG) who were prescribed metoprolol or carvedilol. Equivalent measures were undertaken in Zucker Diabetic Fatty (ZDF) rats following 4 weeks treatment with metoprolol or carvedilol. RESULTS: Patients receiving carvedilol compared to metoprolol had no difference in cardiac function, and no difference was apparent in myocardial function between ß-blockers. Both ß-blockers similarly improved myocardial function in diabetic ZDF rats treated for 4 weeks, without significantly affecting in vivo cardiac function. CONCLUSIONS: Metoprolol and carvedilol were found to have no effect on cardiac function in type 2 diabetes with preserved ejection fraction, and were similarly effective in preventing myocardial dysfunction in ZDF rats.
Asunto(s)
Antagonistas de Receptores Adrenérgicos beta 1/uso terapéutico , Carvedilol/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Corazón/efectos de los fármacos , Metoprolol/uso terapéutico , Anciano , Animales , Carvedilol/administración & dosificación , Puente de Arteria Coronaria/métodos , Diabetes Mellitus Tipo 2/fisiopatología , Modelos Animales de Enfermedad , Femenino , Corazón/fisiopatología , Humanos , Masculino , Metoprolol/administración & dosificación , Persona de Mediana Edad , Ratas Zucker , Resultado del TratamientoRESUMEN
Diabetic patients have increased cardiac complications during surgery, possibly due to impaired autonomic regulation. Anesthesia lowers blood pressure and heart rate (HR), whereas surgical intervention has opposing effects. The interaction of anesthesia and surgical intervention on hemodynamics in diabetes is unknown, despite being a potential perioperative risk factor. We aimed to determine the effect of diabetes on the integrative interaction between hemodynamics, anesthesia, and surgical incision. Zucker type 2 diabetic rats (DM) and their nondiabetic littermates (ND) were implanted with an intravenous port for drug delivery, and a radiotelemeter to measure mean arterial blood pressure (MAP) and derive HR (total n = 50). Hemodynamic pharmacological responses were assessed under conscious, isoflurane anesthesia (~2-2.5%), and anesthesia-surgical conditions; the latter performed as a laparotomy. MAP was not different between groups under conscious conditions (ND 120 ± 6 vs. DM 131 ± 4 mmHg, P > 0.05). Anesthesia reduced MAP, but not differently in DM (ND -30 ± 6 vs. DM -38 ± 4 ΔmmHg, P > 0.05). Despite adequate anesthesia, surgical incision increased MAP, which tended to be less in DM (ND +21 ± 4 vs. DM +13 ± 2 ΔmmHg, P = 0.052). Anesthesia disrupted central baroreflex HR responses to sympathetic activation (sodium nitroprusside 10 µg·kg-1, ND conscious 83 ± 13 vs. anesthetized 16 ± 5 Δbpm; P < 0.05) or to sympathetic withdrawal (phenylephrine 10 µg·kg-1, ND conscious -168 ± 37 vs. anesthetized -20 ± 6 Δbpm; P < 0.05) with no additional changes observed after surgical incision or during diabetes. During perioperative conditions, type 2 diabetes did not impact on short-term hemodynamic regulation. Anesthesia had the largest hemodynamic impact, whereas surgical effects were limited to modulation of baseline blood pressure.
Asunto(s)
Anestésicos por Inhalación/efectos adversos , Presión Sanguínea , Diabetes Mellitus Tipo 2/fisiopatología , Frecuencia Cardíaca , Isoflurano/efectos adversos , Procedimientos Quirúrgicos Vasculares/efectos adversos , Anestésicos por Inhalación/administración & dosificación , Animales , Isoflurano/administración & dosificación , Masculino , Complicaciones Posoperatorias/etiología , Ratas , Ratas ZuckerRESUMEN
Elevated sympathetic nerve activity (SNA) coupled with dysregulated ß-adrenoceptor (ß-AR) signaling is postulated as a major driving force for cardiac dysfunction in patients with type 2 diabetes; however, cardiac SNA has never been assessed directly in diabetes. Our aim was to measure the sympathetic input to and the ß-AR responsiveness of the heart in the type 2 diabetic heart. In vivo recording of SNA of the left efferent cardiac sympathetic branch of the stellate ganglion in Zucker diabetic fatty rats revealed an elevated resting cardiac SNA and doubled firing rate compared with nondiabetic rats. Ex vivo, in isolated denervated hearts, the intrinsic heart rate was markedly reduced. Contractile and relaxation responses to ß-AR stimulation with dobutamine were compromised in externally paced diabetic hearts, but not in diabetic hearts allowed to regulate their own heart rate. Protein levels of left ventricular ß1-AR and Gs (guanine nucleotide binding protein stimulatory) were reduced, whereas left ventricular and right atrial ß2-AR and Gi (guanine nucleotide binding protein inhibitory regulatory) levels were increased. The elevated resting cardiac SNA in type 2 diabetes, combined with the reduced cardiac ß-AR responsiveness, suggests that the maintenance of normal cardiovascular function requires elevated cardiac sympathetic input to compensate for changes in the intrinsic properties of the diabetic heart.