Abstract-The transient receptor potential vanilloid (TRPV1) channels expressed in sensory afferent fibers innervating the heart may be activated by protons or endovanilloids released during myocardial ischemia (MI), leading to angina. Although our previous in vitro data indicate that TRPV1 activation may preserve cardiac function after ischemiareperfusion injury, the underlying mechanisms are largely unknown. To test the hypothesis that TRPV1 modulates inflammatory and early remodeling processes to prevent cardiac functional deterioration after myocardial infarction, TRPV1-null mutant (TRPV1) and wild-type (WT) mice were subjected to left anterior descending coronary ligation or sham operation. The infarct size was greater in TRPV1 Ϫ/Ϫ than in WT mice (PϽ0.001) 3 days after MI, and the mortality rate was higher in TRPV1 Ϫ/Ϫ than in WT mice (PϽ0.05) 7 days after MI. The levels of plasma cardiac troponin I; cytokines, including tumor necrosis factor-␣, interleukin-1, and interleukin-6; chemokines, including monocyte chemoattractant protein-1 and macrophage inflammatory protein-2; and infiltration of inflammatory cells, including neutrophils, macrophages, and myofibroblasts; as well as collagen contents, were greater in TRPV1Ϫ/Ϫ than in WT mice (PϽ0.05) in the infarct area on days 3 and 7 after MI. Changes in left ventricular geometry led to increased end-systolic and -diastolic diameters and reduced contractile function in TRPV1Ϫ/Ϫ compared with WT mice. These data show that TRPV1 gene deletion results in excessive inflammation, disproportional left ventricular remodeling, and deteriorated cardiac function after MI, indicating that TRPV1 may prevent infarct expansion and cardiac injury by inhibiting inflammation and abnormal tissue remodeling. tor is a ligand-gated nonselective cation channel, primarily expressed in sensory nerves innervating the heart and blood vessels. 1,2 TRPV1 may function as a molecular integrator of multiple chemical and physical stimuli, including protons, noxious heat, endovanilloids, and capsaicin. 3,4 Myocardial ischemia causes the release of protons and bradykinin, which may activate or sensitize TRPV1 expressed in cardiac sensory nerve terminals, including unmyelinated C-fibers and thinly myelinated A␦-fibers, to cause angina. 5,6 Indeed, ischemic stimulation of cardiac afferent nerves has been shown to be mediated by activation of TRPV1. 1 Using the isolated, perfused Langendorff heart preparation, we showed that TRPV1 protects the heart from postischemic reperfusion injury possibly via increasing substance P release from sensory nerve terminals. 7 Moreover, TRPV1 contributes to the beneficial effects of preconditioning of the heart against ischemia-reperfusion injury via triggering the release of substance P and/or calcitonin gene-related peptide. 8 It has been shown that patients with preinfarction angina have a better prognosis after acute infarction than those without, a phenomenon ascribed to ischemic preconditioning. 9 However, it is unknown whether TRPV1, a molecular transmitt...
Thang LV, Demel SL, Crawford R, Kaminski NE, Swain GM, Van Rooijen N, Galligan JJ. Macrophage depletion lowers blood pressure and restores sympathetic nerve ␣ 2-adrenergic receptor function in mesenteric arteries of DOCA-salt hypertensive rats. Am J Physiol Heart Circ Physiol 309: H1186 -H1197, 2015. First published August 28, 2015; doi:10.1152/ajpheart.00283.2015.-We tested the hypothesis that vascular macrophage infiltration and O 2 Ϫ release impairs sympathetic nerve ␣ 2-adrenergic autoreceptor (␣2AR) function in mesenteric arteries (MAs) of DOCA-salt hypertensive rats. Male rats were uninephrectomized or sham operated (sham). DOCA pellets were implanted subcutaneously in uninephrectomized rats who were provided high-salt drinking water or high-salt water with apocynin. Sham rats received tap water. Blood pressure was measured using radiotelemetry. Treatment of sham and DOCA-salt rats with liposome-encapsulated clodronate was used to deplete macrophages. After 3-5, 10 -13, and 18 -21 days of DOCA-salt treatment, MAs and peritoneal fluid were harvested from euthanized rats. Norepinephrine (NE) release from periarterial sympathetic nerves was measured in vitro using amperometry with microelectrodes. Macrophage infiltration into MAs as well as TNF-␣ and p22 phox were measured using immunohistochemistry. Peritoneal macrophage activation was measured by flow cytometry. O 2 Ϫ was measured using dihydroethidium staining. Hypertension developed over 28 days, and apocynin reduced blood pressure on days 18 -21. O 2 Ϫ and macrophage infiltration were greater in DOCA-salt MAs compared with sham MAs after day 10. Peritoneal macrophage activation occurred after day 10 in DOCA-salt rats. Macrophages expressing TNF-␣ and p22 phox were localized near sympathetic nerves. Impaired ␣2AR function and increased NE release from sympathetic nerves occurred in MAs from DOCA-salt rats after day 18. Macrophage depletion reduced blood pressure and vascular O 2 Ϫ while restoring ␣2AR function in DOCA-salt rats. Macrophage infiltration into the vascular adventitia contributes to increased blood pressure in DOCA-salt rats by releasing O 2 Ϫ , which disrupts ␣2AR function, causing enhanced NE release from sympathetic nerves.salt-sensitive hypertension; immune activation; sympathetic nervous system; ␣2-adrenergic autoreceptors; amperometry NEW & NOTEWORTHYWe have identified a novel mechanism by which salt-sensitive hypertension disrupts normal function of the sympathetic nervous system. Antioxidants may be helpful in treating some forms of hypertension.INCREASED SYMPATHETIC nerve activity contributes to high blood pressure in some animal models of hypertension, including the DOCA-salt model (10, 57). Hypertension in the DOCA-salt model is driven by reduced renal mass (removal of one kidney), high circulating mineralocorticoid levels, and high salt intake (57). Elevated salt increases central sympathetic drive to the cardiovascular system (17, 48), but there are also alterations in the local mechanisms that modulate sympathetic neurotransmiss...
Noxious cold sensation is commonly associated with peripheral neuropathies, however, there has been limited progress in understanding the mechanism of cold pain. Transient receptor potential (TRP) A1 channels facilitate the perception of noxious cold at the level of dorsal root ganglia (DRG), where kappa opioid receptors (KOR) are also expressed but have not previously been implicated in cold sensation. Here we identify a new role for KOR in enhancing cold hypersensitivity. First, we show that systemic KOR agonism (U50,488, KOR agonist), significantly potentiates the latency to jump and the number of jumps on the cold plate compared controls at 3°C. Importantly, NorBNI (KOR antagonist) attenuates U50,488-induced cold hypersensitivity. However, the central administration of NorBNI does not block U50,488-induced cold hypersensitivity suggesting that peripheral KOR likely modulate this effect. Furthermore, the peripherally-restricted KOR agonist, ff(nle)r-NH2 also induces cold hypersensitivity. Using fluorescent in situ hybridization, we show that KOR mRNA colocalizes with the transcripts for the cold-activated TRPA1 and TRPM8 channels in DRG. Finally, using calcium imaging in DRG, we show that intracellular calcium release is potentiated during the simultaneous application of a TRPA1 agonist, mustard oil (MO), and a KOR agonist (U50,488), when compared to MO alone. This potentiated calcium response is absent in TRPA1 KO mice. Together our data suggest that KOR-induces cold hypersensitivity through modulation of peripheral TRPA1 channels. These findings indicate that whether activation of peripheral KOR is protective or not may be dependent on the pain modality.
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