Exercise preconditioning of myocardial infarct size in dogs is triggered by calcium.

We showed that exercise induces early and late myocardial preconditioning in dogs and that these effects are mediated through nicotinamide adenine dinucleotide phosphate reduced form (NADPH) oxidase activation. As the intracoronary administration of calcium induces preconditioning and exercise enhances the calcium inflow to the cell, we studied if this effect of exercise triggers exercise preconditioning independently of its hemodynamic effects. We analyzed in 81 dogs the effect of blocking sarcolemmal L-type Ca channels with a low dose of verapamil on early and late preconditioning by exercise, and in other 50 dogs, we studied the effect of verapamil on NADPH oxidase activation in early exercise preconditioning. Exercise reduced myocardial infarct size by 76% and 52% (early and late windows respectively; P < 0.001 both), and these effects were abolished by a single low dose of verapamil given before exercise. This dose of verapamil did not modify the effect of exercise on metabolic and hemodynamic parameters. In addition, verapamil blocked the activation of NADPH oxidase during early preconditioning. The protective effect of exercise preconditioning on myocardial infarct size is triggered, at least in part, by calcium inflow increase to the cell during exercise and, during the early window, is mediated by NADPH oxidase activation.

Late cardiac preconditioning by exercise in dogs is mediated by mitochondrial potassium channels.

We previously showed that exercise induces myocardial preconditioning in dogs and that early preconditioning is mediated through mitochondrial adenosine triphosphate-sensitive potassium channels. We decided to study if late preconditioning by exercise is also mediated through these channels. Forty-eight dogs, surgically instrumented and trained to run daily, were randomly assigned to 4 groups: (1) Nonpreconditioned dogs: under anesthesia, the coronary artery was occluded during 1 hour and then reperfused during 4.5 hours. (2) Late preconditioned dogs: similar to group 1, but the dogs run on the treadmill for 5 periods of 5 minutes each, 24 hours before the coronary occlusion. (3) Late preconditioned dogs plus 5-hydroxydecanoate (5HD): similar to group 2, but 5HD was administered before the coronary occlusion. (4) Nonpreconditioned dogs plus 5HD: similar to group 1, but 5HD was administered before the coronary occlusion. Infarct size (percent of the risk region) decreased by effect of exercise by 56% (P < 0.05), and this effect was abolished with 5HD. 5HD by itself did not modify infarct size. Exercise did not induce myocardial ischemia, and the hemodynamics during ischemia-reperfusion period did not differ among groups. These effects were independent of changes in collateral flow to the ischemic region. We concluded that late cardiac preconditioning by exercise is mediated through mitochondrial adenosine triphosphate-sensitive potassium channels.

Envejecimiento cardiovascular: [revisión] / Cardiovascular aging: [review]

Aging produces its own cardiovascular changes, mainly remodelling of arteries, heart and the microcirculation. These progressive changes, detected since adolescence, represent a major rísk factor for the development of cardiovascular diseases. Remodelling of arteries produces a thickening of the intima-media with fracture of elastic fibers and their replacement by collagen. These alterations induce an increase of the pulse wave and aortic impedance, with greater resistance to ventrícular ejection, that in turns induces the remodelling of the left ventricle. Ventricular remodelling leads to systolic, diastolic and chronotropic dysfunctions that explain the reduced capacity of old people to increase cardiac output during exercise. These alterations together with oxidative endothelial dysfunction and somatic mitochondrial mutations in the skeletal muscle decrease aerobic capacity, especially in adults aged >70 years. On the other hand, the transmission of an increased pulse wave to microvessels, mainly of the brain and kidneys, damage these organs. There is a search for candidate genes associated to this phenotype, especially those associated with arterial structure. Atpresent no specific treatment is available for cardiovascular aging. Exercise preserves a better aerobic capacity but does not prevent its decline with age. Vasodilator drugs may decrease aortic impedance and perhaps delay remodelling. However there is no clinical evidence available to recommend these drugs in young healthy people. Finally new drugs that modify aortic molecular structure are been investigated.

[Cardiovascular aging]. / Envejecimiento cardiovascular.

Aging produces its own cardiovascular changes, mainly remodelling of arteries, heart and the microcirculation. These progressive changes, detected since adolescence, represent a major risk factor for the development of cardiovascular diseases. Remodelling of arteries produces a thickening of the intima-media with fracture of elastic fibers and their replacement by collagen. These alterations induce an increase of the pulse wave and aortic impedance, with greater resistance to ventricular ejection, that in turns induces the remodelling of the left ventricle. Ventricular remodelling leads to systolic, diastolic and chronotropic dysfunctions that explain the reduced capacity of old people to increase cardiac output during exercise. These alterations together with oxidative endothelial dysfunction and somatic mitochondrial mutations in the skeletal muscle decrease aerobic capacity, especially in adults aged >70 years. On the other hand, the transmission of an increased pulse wave to microvessels, mainly of the brain and kidneys, damage these organs. There is a search for candidate genes associated to this phenotype, especially those associated with arterial structure. At present no specific treatment is available for cardiovascular aging. Exercise preserves a better aerobic capacity but does not prevent its decline with age. Vasodilator drugs may decrease aortic impedance and perhaps delay remodelling. However there is no clinical evidence available to recommend these drugs in young healthy people. Finally new drugs that modify aortic molecular structure are been investigated.

Exercise and tachycardia increase NADPH oxidase and ryanodine receptor-2 activity: possible role in cardioprotection.

AIM: Our objective was to investigate in cardiac muscle the contribution of NADPH oxidase to (a) ryanodine receptor-2 (RyR2) S-glutathionylation and (b) the preconditioning effects of exercise and tachycardia on infarct size following coronary artery occlusion. METHODS AND RESULTS: We measured NADPH oxidase activity, RyR2 S-glutathionylation, and calcium release kinetics in sarcoplasmic reticulum (SR) vesicles isolated from dog ventricular muscle after exercise and tachycardia, plus or minus prior administration of the NADPH oxidase inhibitor apocynin. In ventricular muscle sections, we studied the colocalization of NADPH oxidase and RyR2 by confocal microscopy using fluorescent antibodies. We determined the effect of apocynin on the infarct size produced by occlusion of the descendent anterior coronary artery in animals preconditioned by exercise or tachycardia. Exercise and tachycardia increased NADPH oxidase activity, RyR2 S-glutathionylation, and calcium release rates in isolated SR vesicles. Cardiac muscle sections displayed significant colocalization of NADPH oxidase and RyR2, suggesting direct and specific effects of reactive oxygen species (ROS) produced by NADPH oxidase on RyR2 activation. The NADPH oxidase inhibitor apocynin prevented the increase in RyR2 S-glutathionylation, reduced calcium release activity, and completely prevented the protective effects of exercise and tachycardia on infarct size. CONCLUSIONS: The loss of cardioprotection induced by the NADPH oxidase inhibitor suggests that ROS generated by this enzyme are important mediators of the preconditioning response, which presumably involves NADPH oxidase-induced RyR2 S-glutathionylation.

Participación de Ca2+ en el precondicionamiento del miocardio por ejercicio / Role of Ca2+ in exercise induced myocardial preconditioning

Antecedentes: Episodios breves de ejercicio previos a la oclusión prolongada de una arteria coronaria disminuyen el tamaño del infarto inducido por ésta. Objetivo: Dado que la administración intracoronaria de Ca2+ induce precondicionamiento, y el ejercicio probablemente aumenta el calcio citosólico, decidimos estudiar si el precondicionamiento por ejercicio está mediado por Ca2+. Material y método: Para ello analizamos el efecto del bloqueo de los canales de calcio del sarcolema, con verapamilo, sobre la acción precondicionante del ejercicio. Se midió tamaño del infarto en perros entrenados a correr en cinta sin finasignados aleatoriamente a los siguientes grupos. I: Isquemia inducida por oclusión coronaria durante 1 hora seguida de reperfusión por 4 hrs. E+I: Similar al grupo I, pero los perros hicieron ejercicio antes de inducir la isquemia. V+I: Similar al grupo I, pero se administró verapamilo antes de inducir la isquemia. V+E+I : Similar al grupo E+I, pero se administró verapamilo antes del ejercicio. Para estudiar el posible rol mediador del retículo sarcoplasmático (RS) en los efectos de la isquemia y de verapamilo, se midió la captación y la liberación de calcio en vesículas de RS de la pared del ventrículo izquierdo sometida a isquemia con o sin verapamilo en perros con y sin precondicionamiento con ejercicio. Los resultados, expresados como promedio +/- ES, se analizaron mediante ANOVA seguido del test de Holm para comparaciones múltiples. Resultados: Verapamilo revirtió el efecto protector del ejercicio sobre el tamaño del infarto (E+I: 6,0 +/- 9,4; N=12 vs V+E+I: 27,7+/-9,6; N=15; P<0.05), pero no modificó el efecto protector del ejercicio precondicionante sobre los trastornos de transporte de calcio en el RS inducidos por la isquemia. Conclusiones: Nuestros resultados sugieren que el precondicionamiento inducido por ejercicio está mediado por la entrada de calcio a la célula...

Background: Brief episodes of exercise prior to a prolonged occlusion of a coronary artery substantially reduce infarct size. Aim: Since the intracoronary administration of Ca2+ induces preconditioning and exercise most likely increases cytosolic calcium we put forward the hypothesis that preconditioning by exercise is mediated by calcium. Methods: For this purpose we analyzed the effect of verapamil, a sarcolemmal calcium channel blocker, on preconditioning by exercise. We measured infarct size in dogs randomly assigned to one of the following groups. I: Ischemia induced by coronary occlusion during 1 hour followed by reperfusion during 4 hours. E+I: Similar to group I, but the dogs run on a treadmill prior to ischemia. V+I: Similar to group I but verapamil was administered before the coronary occlusion. V+E+I: Similar to group E+I but verapamil was administered before exercise. SR vesicles from ventricular tissue were isolated from dogs subjected to the same experimental protocols and calcium release and active calcium uptake were measured. Results were expressed as Mean +/- SE and analyzed by ANOVA followed by Holm test for multiple comparisons. Results: Verapamil reverted the protective effect of exercise on infarct size (E+I: 6,0 +/- 9,4; N=12 vs V+E+I: 27,7 +/- 9,6;N=15; P<0.05) however it did not modify the protective effect of exercise on the alterations produced by ischemia on calcium transport in the RS. Conclusions: These results suggest that the preconditioning effect of exercise is mediated by calcium entering the cell through the sarcolemma but not by exercise effects on SR calcium transport.

Effect of tachycardia on myocardial sarcoplasmic reticulum and Ca2+ dynamics: a mechanism for preconditioning?

We have previously demonstrated that brief episodes of tachycardia prior to a prolonged occlusion of a coronary artery, followed by reperfusion, substantially reduce the infarct size. Adenosine receptors and mitochondrial ATP-dependent K(+) channels mediate this effect. Since preconditioning can be induced or reverted by maneuvers that increase or decrease [Ca(2+)](i), respectively, and tachycardia increases [Ca(2+)](i), we studied the participation of sarcoplasmic reticulum and Ca(2+) in the preconditioning effect of tachycardia. We measured the effect of ischemia and tachycardia on Ca(2+) uptake and release by sarcoplasmic reticulum vesicles isolated from left ventricular canine myocardium. Myocardial ischemia increased Ca(2+)-release rate constants and decreased both the initial rates of Ca(2+) uptake and [(3)H]-ryanodine binding by sarcoplasmic reticulum. In addition, ischemia induced a decrease in the pentameric form of phospholamban and in the content of ryanodine-receptor Ca(2+)-release channel protein. All these effects were reverted in hearts preconditioned with tachycardia. Furthermore, tachycardia by itself increased [(3)H]-ryanodine binding, Ca(2+)-release rate constants and the protein levels of ryanodine-receptor Ca(2+)-release channels and the ATP-dependent Ca(2+) pump. These results suggest that tachycardia preserves the integrity of the sarcoplasmic reticulum preventing the excess of release and the decrease of uptake of Ca(2+) produced by ischemia, thereby avoiding cytosolic Ca(2+) overload. This sarcoplasmic reticulum protection could partly explain the preconditioning effect of tachycardia.

Exercise induces early and late myocardial preconditioning in dogs.

OBJECTIVE: We tested the hypothesis that exercise induces myocardial preconditioning in dogs. METHODS: We instrumented dogs with a snare on the anterior descending coronary artery and catheters in the root of the aorta, left ventricular cavity and coronary sinus. After recovering from surgery the dogs were trained to stay in the laboratory and run on a treadmill. Subsequently, they were randomly allocated to five groups: (1) non-preconditioned dogs: under anesthesia, the anterior descending coronary artery was occluded during 1 h and then reperfused during 4.5 h. (2) Early preconditioned dogs: procedure similar to group 1 but the dogs performed exercise on a treadmill for five periods of 5 min each before the coronary occlusion. (3) Late preconditioned dogs: procedure similar to group 2 but 24 h were allowed to elapse between the preconditioning exercise and the coronary occlusion. (4) Early preconditioned dogs plus 5-hydroxydecanoate: procedure similar to group 2 but 5-hydroxydecanoate was administered prior to exercise. (5) Non-preconditioned dogs with 5-hydroxydecanoate: procedure similar to group 1 but 5-hydroxydecanoate was administered at a time equivalent to that in group 4. RESULTS: Exercise did not induce myocardial ischemia and the hemodynamics during the experiments did not differ between groups. Exercise immediately before the coronary occlusion decreased the infarct size (percent of the risk region) by 78% (P<0.05), an effect that was abolished with 5-hydroxydecanoate. Exercise 24 h prior to coronary occlusion decreased infarct size by 46% (P<0.05 vs. non-preconditioned dogs, P<0.05 vs. early preconditioned dogs). 5-Hydroxydecanoate by itself did not modify infarct size. These effects could not be explained by changes in collateral flow to the ischemic region. CONCLUSIONS: Exercise prior to a coronary occlusion induces early and late preconditioning of the infarct size. The early effect is mediated through mitochondrial ATP-sensitive potassium channels.

Effects of alpha-1 adrenergic blockade on regional flow in the ischemic heart

Aunque la isquemia induce una poderosa vasodilatación coronaria, persiste un tono vasoconstrictor alfa en el miocardio isquémico. Con el fin de determinar si este tono vasoconstrictor es mediado por receptores alfa, nosotros medimos el flujo coronario con microesferas radiactivas en el ventrículo izquierdo normal e isquémico del perro, antes y durante el bloqueo alfa-1 adrenérgico con trimazosin. La isquemia se produjo disminuyendo la presión de perfusión coronaria a 22 ñ 1.4 mmHg. La frecuencia cardíaca y la presión arterial se mantuvieron constantes en cada experimento. Trimazosin aumentó el flujo significativamente en la pared ventricular normal, en mayor proporción en el subepicardio que en el subendocardio produciendo una disminución del cociente del flujo subendocárdico/subepicárdico de 1.38 ñ 0.12 a 1.20 ñ 0.11 (p < 0.05). En la región isquémica Trimazosin no modificó el flujo transmural, pero disminuyó el flujo en el subendocardio y lo aumentó en el subepicardio con la consiguiente disminución del cociente de flujo subendocárdico/subepicárdico de 0.63 ñ 0.09 a 0.38 ñ 0.06 (p < 0.01). Estos resultados muestran que en el miocardio isquémico persiste un tono vasoconstrictor mediado por receptores alfa-1 adrenérgicos, y el bloqueo de éstos deteriora la perfusión del subendocardio

Effects of alpha-1 adrenergic blockade on regional flow in the ischemic heart

Aunque la isquemia induce una poderosa vasodilatación coronaria, persiste un tono vasoconstrictor alfa en el miocardio isquémico. Con el fin de determinar si este tono vasoconstrictor es mediado por receptores alfa, nosotros medimos el flujo coronario con microesferas radiactivas en el ventrículo izquierdo normal e isquémico del perro, antes y durante el bloqueo alfa-1 adrenérgico con trimazosin. La isquemia se produjo disminuyendo la presión de perfusión coronaria a 22 ñ 1.4 mmHg. La frecuencia cardíaca y la presión arterial se mantuvieron constantes en cada experimento. Trimazosin aumentó el flujo significativamente en la pared ventricular normal, en mayor proporción en el subepicardio que en el subendocardio produciendo una disminución del cociente del flujo subendocárdico/subepicárdico de 1.38 ñ 0.12 a 1.20 ñ 0.11 (p < 0.05). En la región isquémica Trimazosin no modificó el flujo transmural, pero disminuyó el flujo en el subendocardio y lo aumentó en el subepicardio con la consiguiente disminución del cociente de flujo subendocárdico/subepicárdico de 0.63 ñ 0.09 a 0.38 ñ 0.06 (p < 0.01). Estos resultados muestran que en el miocardio isquémico persiste un tono vasoconstrictor mediado por receptores alfa-1 adrenérgicos, y el bloqueo de éstos deteriora la perfusión del subendocardio (AU)