American journal of physiology. Heart and circulatory physiology
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Am. J. Physiol. Heart Circ. Physiol. · May 2009
Contribution of nerve growth factor to augmented TRPV1 responses of muscle sensory neurons by femoral artery occlusion.
In rats, hindlimb muscle ischemia induced by femoral artery occlusion augments the sympathetic nervous response to stimulation of transient receptor potential vanilloid type 1 (TRPV1) by injection of capsaicin into the arterial blood supply of the hindlimb muscles. The enhanced sympathetic response is due to alterations in TRPV1 receptor expression and its responsiveness in sensory neurons. The underlying mechanism by which TRPV1 receptor responses are increased after muscle vascular insufficiency/ischemia is unclear. ⋯ With the addition of NGF in the culture dish containing the DRG neurons, the magnitude of the DRG neuron response to capsaicin was greater (6.4 +/- 0.27 nA; P < 0.05 vs. control) than that seen in control (2.9 +/- 0.16 nA). Note that this NGF effect was seen in isolectin B(4)-negative DRG neurons, a group of thin fiber nerves that contain neuropeptides and depend on NGF for survival. These data suggest that NGF affects a selective subpopulation of the afferent neurons in mediating augmented TRPV1 responses after femoral artery occlusion.
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Am. J. Physiol. Heart Circ. Physiol. · May 2009
ERK phosphorylation mediates sildenafil-induced myocardial protection against ischemia-reperfusion injury in mice.
Sildenafil, a selective inhibitor of phosphodiesterase type 5, induces powerful protection against myocardial ischemia-reperfusion injury through activation of cGMP-dependent protein kinase (PKG). We further hypothesized that PKG-dependent activation of survival kinase ERK may play a causative role in sildenafil-induced cardioprotection via induction of endothelial nitric oxide synthase (eNOS)/inducible nitric oxide synthase (iNOS) and Bcl-2. Our results show that acute intracoronary infusion of sildenafil in Langendorff isolated mouse hearts before global ischemia-reperfusion significantly reduced myocardial infarct size (from 29.4 +/- 2.4% to 15.9 +/- 3.0%; P < 0.05). ⋯ PD98059 inhibited the enhanced expression of iNOS, eNOS, and Bcl-2 and the phosphorylation of GSK-3beta. PD98059 had no effect on the sildenafil-induced activation of PKG. We conclude that these studies provide first direct evidence that PKG-dependent ERK phosphorylation is indispensable for the induction of eNOS/iNOS and Bcl-2 and the resulting cardioprotection by sildenafil.
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Am. J. Physiol. Heart Circ. Physiol. · May 2009
Activation of NF-kappaB is a critical element in the antiapoptotic effect of anesthetic preconditioning.
Anesthetic preconditioning (APC), defined as brief exposure to inhalational anesthetics before cardiac ischemia-reperfusion (I/R), limits injury in both animal models and in humans. APC can result in the production of reactive oxygen species (ROS), and prior work has shown that APC can modify activation of NF-kappaB during I/R, with consequent reduction in the expression of inflammatory mediators. However, the role of NF-kappaB activation before I/R is unknown. ⋯ ROS-dependent activation of NF-kappaB by APC before I/R is a critical element in the protective effect of APC. APC reduces apoptosis and functional impairment by increasing Bcl-2 expression before I/R. Interventions that increase NF-kappaB activation before I/R should protect hearts from I/R injury.
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Am. J. Physiol. Heart Circ. Physiol. · Apr 2009
Transient opening of mitochondrial permeability transition pore by reactive oxygen species protects myocardium from ischemia-reperfusion injury.
Reactive oxygen species (ROS) production during ischemia-reperfusion (I/R) is thought to be a critical factor for myocardial injury. However, a small amount of ROS during the ischemic preconditioning (IPC) may provide a signal for cardioprotection. We have previously reported that the repetitive pretreatment of a small amount of ROS [hydrogen peroxide (H(2)O(2)), 2 microM] mimicked the IPC-induced cardioprotection in the Langendorff-perfused rat hearts. ⋯ In isolated permeabilized myocytes, H(2)O(2) (1 microM) accelerated the calcein leakage from mitochondria in a CsA-sensitive manner, indicating the opening of mPTP by H(2)O(2). However, H(2)O(2) did not depolarize mitochondrial membrane potential (DeltaPsi(m)) even in the presence of oligomycin (F(1)/F(0) ATPase inhibitor; 1 microM) and decreased mitochondrial Ca(2+) concentration ([Ca(2+)](m)) by accelerating the mitochondrial Ca(2+) extrusion via an mPTP. We conclude that the transient mPTP opening could be involved in the H(2)O(2)-induced cardioprotection against reperfusion injury, and the reduction of [Ca(2+)](m) without the change in DeltaPsi(m) might be a possible mechanism for the protection.
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Am. J. Physiol. Heart Circ. Physiol. · Mar 2009
Phospholamban overexpression in rabbit ventricular myocytes does not alter sarcoplasmic reticulum Ca transport.
Phospholamban has been suggested to be a key regulator of cardiac sarcoplasmic reticulum (SR) Ca cycling and contractility and a potential therapeutic target in restoring the depressed Ca cycling in failing hearts. Our understanding of the function of phospholamban stems primarily from studies in genetically altered mouse models. To evaluate the significance of this protein in larger mammalian species, which exhibit Ca cycling properties similar to humans, we overexpressed phospholamban in adult rabbit cardiomyocytes. ⋯ These apparent differences between phospholamban overexpression in rabbit compared with previous findings in the mouse may be due to a significantly higher (1.5-fold) endogenous phospholamban-to-sarco(endo)plasmic reticulum Ca-ATPase (SERCA) 2a ratio and potential functional saturation of SERCA2a by phospholamban in rabbit cardiomyocytes. The findings suggest that important species-dependent differences in phospholamban regulation of SERCA2a occur. In larger mammals, a higher fraction of SERCA2a pumps are regulated by phospholamban, and this may influence therapeutic strategies to enhance cardiac contractility and functional cardiac reserve.