Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 46
Filtrar
1.
J Pharmacol Exp Ther ; 379(2): 182-190, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34389654

RESUMEN

We previously demonstrated that the selective retinoic acid receptor (RAR) ß 2 agonist AC261066 reduces oxidative stress in an ex vivo murine model of ischemia/reperfusion. We hypothesized that by decreasing oxidative stress and consequent fibrogenesis, AC261066 could attenuate the development of contractile dysfunction in post-ischemic heart failure (HF). We tested this hypothesis in vivo using an established murine model of myocardial infarction (MI), obtained by permanent occlusion of the left anterior descending coronary artery. Treating mice with AC261066 in drinking water significantly attenuated the post-MI deterioration of echocardiographic indices of cardiac function, diminished remodeling, and reduced oxidative stress, as evidenced by a decrease in malondialdehyde level and p38 mitogen-activated protein kinase expression in cardiomyocytes. The effects of AC261066 were also associated with a decrease in interstitial fibrosis, as shown by a marked reduction in collagen deposition and α-smooth muscle actin expression. In cardiac murine fibroblasts subjected to hypoxia, AC261066 reversed hypoxia-induced decreases in superoxide dismutase 2 and angiopoietin-like 4 transcriptional levels as well as the increase in NADPH oxidase 2 mRNA, demonstrating that the post-MI cardioprotective effects of AC261066 are associated with an action at the fibroblast level. Thus, AC261066 alleviates post-MI cardiac dysfunction by modulating a set of genes involved in the oxidant/antioxidant balance. These AC261066 responsive genes diminish interstitial fibrogenesis and remodeling. Since MI is a recognized major cause of HF, our data identify RARß 2 as a potential pharmacological target in the treatment of HF. SIGNIFICANCE STATEMENT: A previous report showed that the selective retinoic acid receptor (RAR) ß 2 agonist AC261066 reduces oxidative stress in an ex vivo murine model of ischemia/reperfusion. This study shows that AC261066 attenuates the development of contractile dysfunction and maladaptive remodeling in post-ischemic heart failure (HF) by modulating a set of genes involved in oxidant/antioxidant balance. Since myocardial infarction is a recognized major cause of HF, these data identify RARß 2 as a potential pharmacological target in the treatment of HF.


Asunto(s)
Benzoatos/uso terapéutico , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/tratamiento farmacológico , Receptores de Ácido Retinoico/agonistas , Tiazoles/uso terapéutico , Animales , Benzoatos/farmacología , Insuficiencia Cardíaca/metabolismo , Insuficiencia Cardíaca/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Receptores de Ácido Retinoico/metabolismo , Tiazoles/farmacología
3.
J Pharmacol Exp Ther ; 366(2): 314-321, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29907698

RESUMEN

We previously discovered that oral treatment with AC261066, a synthetic selective agonist for the retinoic acid ß2-receptor, decreases oxidative stress in the liver, pancreas, and kidney of mice fed a high-fat diet (HFD). Since hyperlipidemic states are causally associated with myocardial ischemia and oxidative stress, we have now investigated the effects of AC261066 in an ex vivo ischemia/reperfusion (I/R) injury model in hearts of two prototypic dysmetabolic mice. We found that a 6-week oral treatment with AC261066 in both genetically hypercholesterolemic (ApoE-/-) and obese (HFD-fed) wild-type mice exerts protective effects when their hearts are subsequently subjected to I/R ex vivo in the absence of added drug. In ApoE-/- mice this cardioprotection ensued without hyperlipidemic changes. Cardioprotection consisted of attenuation of infarct size, diminution of norepinephrine (NE) spillover, and alleviation of reperfusion arrhythmias. This cardioprotection was associated with a reduction in oxidative stress and mast cell (MC) degranulation. We suggest that the reduction in myocardial injury and adrenergic activation, and the antiarrhythmic effects, result from decreased formation of oxygen radicals and toxic aldehydes known to elicit the release of MC-derived renin, promoting the activation of the local renin-angiotensin system leading to enhanced NE release and reperfusion arrhythmias. Because these beneficial effects of AC261066 occurred at the ex vivo level following oral drug treatment, our data suggest that AC261066 could be viewed as a therapeutic means to reduce I/R injury of the heart, and potentially also be considered in the treatment of other cardiovascular ailments such as chronic arrhythmias and cardiac failure.


Asunto(s)
Benzoatos/farmacología , Cardiotónicos/farmacología , Receptores de Ácido Retinoico/agonistas , Tiazoles/farmacología , Animales , Mastocitos/efectos de los fármacos , Mastocitos/inmunología , Ratones , Daño por Reperfusión Miocárdica/inmunología , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Estrés Oxidativo/efectos de los fármacos
4.
J Pharmacol Exp Ther ; 362(2): 230-242, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-28500264

RESUMEN

In the ischemic-reperfused (I/R) heart, renin-containing mast cells (MC) release enzymatically active renin, activating a local renin-angiotensin system (RAS), causing excessive norepinephrine release and arrhythmic dysfunction. Activation of Gi-receptors on MC and/or ischemic preconditioning (IPC) prevent renin release, thus providing anti-RAS cardioprotection. We questioned whether sphingosine-1-phosphate (S1P), a sphingolipid produced in the I/R heart, might afford anti-RAS cardioprotection by activating Gi-coupled S1P1 receptors (S1P1R) on MC. We report that activation of Gi-coupled S1P1R in cardiac MC confers IPC-like anti-RAS cardioprotection due to S1P1R-mediated inhibition of I/R-induced cardiac MC degranulation and renin release. This results from an initial translocation of protein kinase C subtype-ε and subsequent activation of aldehyde dehydrogenase type 2 (ALDH2), culminating in the elimination of the MC-degranulating effects of acetaldehyde and other toxic species produced during I/R. Inhibition of toxic aldehydes-induced MC-renin release prevents local RAS activation, reduces infarct size, and alleviates arrhythmias. Notably, these cardioprotective effects are lacking in hearts and MC from gene-targeted knock-in mice (ALDH2*2) in which ALDH2 enzymatic activity is maximally reduced. Thus, ALDH2 appears to play a pivotal role in this protective process. Our findings suggest that MC S1P1R may represent a new pharmacologic and therapeutic target for the direct alleviation of RAS-induced cardiac dysfunctions, including ischemic heart disease and congestive heart failure.


Asunto(s)
Aldehído Deshidrogenasa Mitocondrial/fisiología , Cardiotónicos/metabolismo , Mastocitos/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Receptores de Lisoesfingolípidos/metabolismo , Sistema Renina-Angiotensina/fisiología , Animales , Hipoxia de la Célula/fisiología , Línea Celular Tumoral , Técnicas de Sustitución del Gen/métodos , Cobayas , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Infarto del Miocardio/metabolismo , Infarto del Miocardio/prevención & control , Isquemia Miocárdica/metabolismo , Isquemia Miocárdica/prevención & control , Daño por Reperfusión Miocárdica/prevención & control , Técnicas de Cultivo de Órganos , Porcinos
5.
FASEB J ; 29(1): 61-9, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25318477

RESUMEN

Ischemia/reperfusion (I/R) elicits renin release from cardiac mast cells (MC), thus activating a local renin-angiotensin system (RAS), culminating in ventricular fibrillation. We hypothesized that in I/R, neurogenic ATP could degranulate juxtaposed MC and that ecto-nucleoside triphosphate diphosphohydrolase 1/CD39 (CD39) on MC membrane could modulate ATP-induced renin release. We report that pharmacological inhibition of CD39 in a cultured human mastocytoma cell line (HMC-1) and murine bone marrow-derived MC with ARL67156 (100 µM) increased ATP-induced renin release (≥2-fold), whereas purinergic P2X7 receptors (P2X7R) blockade with A740003 (3 µM) prevented it. Likewise, CD39 RNA silencing in HMC-1 increased ATP-induced renin release (≥2-fold), whereas CD39 overexpression prevented it. Acetaldehyde, an I/R product (300 µM), elicited an 80% increase in ATP release from HMC-1, in turn, causing an autocrine 20% increase in renin release. This effect was inhibited or potentiated when CD39 was overexpressed or silenced, respectively. Moreover, P2X7R silencing prevented ATP- and acetaldehyde-induced renin release. I/R-induced RAS activation in ex vivo murine hearts, characterized by renin and norepinephrine overflow and ventricular fibrillation, was potentiated (∼2-fold) by CD39 inhibition, an effect prevented by P2X7R blockade. Our data indicate that by regulating ATP availability at the MC surface, CD39 modulates local renin release and thus, RAS activation, ultimately exerting a cardioprotective effect.


Asunto(s)
Antígenos CD/metabolismo , Apirasa/metabolismo , Mastocitos/metabolismo , Reperfusión Miocárdica , Renina/metabolismo , Adenosina Trifosfato/análogos & derivados , Adenosina Trifosfato/metabolismo , Adenosina Trifosfato/farmacología , Animales , Antígenos CD/genética , Apirasa/antagonistas & inhibidores , Apirasa/genética , Cardiotónicos/metabolismo , Degranulación de la Célula , Línea Celular , Humanos , Masculino , Mastocitos/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Miocardio/citología , ARN Interferente Pequeño/genética , Receptores Purinérgicos P2X7/genética , Receptores Purinérgicos P2X7/metabolismo , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiología
6.
Pharmacol Res ; 113(Pt A): 290-299, 2016 11.
Artículo en Inglés | MEDLINE | ID: mdl-27616550

RESUMEN

The endogenous gasotransmitter hydrogen sulphide (H2S) is an important regulator of the cardiovascular system, particularly of myocardial function. Moreover, H2S exhibits cardioprotective activity against ischemia/reperfusion (I/R) or hypoxic injury, and is considered an important mediator of "ischemic preconditioning", through activation of mitochondrial potassium channels, reduction of oxidative stress, activation of the endogenous "anti-oxidant machinery" and limitation of inflammatory responses. Accordingly, H2S-donors, i.e. pro-drugs able to generate exogenous H2S, are viewed as promising therapeutic agents for a number of cardiovascular diseases. The novel H2S-donor 4-carboxy phenyl-isothiocyanate (4CPI), whose vasorelaxing effects were recently reported, was tested here in different experimental models of myocardial I/R. In Langendorff-perfused rat hearts subjected to I/R, 4CPI significantly improved the post-ischemic recovery of myocardial functional parameters and limited tissue injury. These effects were antagonized by 5-hydroxydecanoic acid (a blocker of mitoKATP channels). Moreover, 4CPI inhibited the formation of reactive oxygen species. We found the whole battery of H2S-producing enzymes to be present in myocardial tissue: cystathionine γ-lyase (CSE), cystathionine ß-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (MPST). Notably, 4CPI down-regulated the post-ischemic expression of CSE. In Langendorff-perfused mouse hearts, 4CPI reduced the post-ischemic release of norepinephrine and the incidence of ventricular arrhythmias. In both rat and mouse hearts, 4CPI did not affect the degranulation of resident mast cells. In isolated rat cardiac mitochondria, 4CPI partially depolarized the mitochondrial membrane potential; this effect was antagonized by ATP (i.e., the physiological inhibitor of KATP channels). Moreover, 4CPI abrogated calcium uptake in the mitochondrial matrix. Finally, in an in vivo model of acute myocardial infarction in rats, 4CPI significantly decreased I/R-induced tissue injury. In conclusion, H2S-donors, and in particular isothiocyanate-based H2S-releasing drugs like 4CPI, can actually be considered a suitable pharmacological option in anti-ischemic therapy.


Asunto(s)
Cardiotónicos/farmacología , Sulfuro de Hidrógeno/metabolismo , Isotiocianatos/farmacología , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Estrés Oxidativo/efectos de los fármacos , Canales de Potasio/metabolismo , Animales , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/metabolismo , Cistationina betasintasa/metabolismo , Cistationina betasintasa/farmacología , Cistationina gamma-Liasa/metabolismo , Cisteína/análogos & derivados , Cisteína/farmacología , Ácidos Decanoicos/farmacología , Corazón/efectos de los fármacos , Hidroxiácidos/farmacología , Masculino , Mastocitos/efectos de los fármacos , Mastocitos/metabolismo , Ratones , Ratones Endogámicos C57BL , Mitocondrias Cardíacas/efectos de los fármacos , Mitocondrias Cardíacas/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/metabolismo , Isquemia Miocárdica/tratamiento farmacológico , Isquemia Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Ratas , Ratas Wistar , Especies Reactivas de Oxígeno/metabolismo
7.
Am J Pathol ; 184(2): 376-81, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24262755

RESUMEN

Renin is a newly discovered constituent of mast cells. Given that mast cells play a major role in IgE-mediated allergic hypersensitivity, we investigated whether activation of the high-affinity IgE receptor FcεRI elicits release of mast-cell renin. Cross-linking of FcεRI on the surface of mature bone marrow-derived mast cells elicited release of enzymatically active renin protein. The angiotensin I-forming activity of the renin protein was completely blocked by the selective renin inhibitor BILA 2157, which excludes formation of angiotensin I by proteases other than renin. FcεRI-mediated mast-cell renin release was inhibited by dexamethasone and potentiated by the proinflammatory mediator PGE2. Furthermore, cross-linking of mast-cell FcεRI in ex vivo murine hearts passively sensitized with monoclonal anti-DNP IgE also resulted in mast-cell degranulation and overflow of renin. Our findings indicate that IgE-mediated allergic hypersensitivity provokes release of renin from both cultured and resident cardiac mast cells, a process likely to be exacerbated in a chronic inflammatory background. Given the widespread distribution of mast cells, and the presence of angiotensinogen and angiotensin-converting enzyme in many tissues, renin release in immediate hypersensitivity reactions could result in local angiotensin II generation and multiorgan dysfunctions.


Asunto(s)
Mastocitos/enzimología , Mastocitos/metabolismo , Receptores de IgE/metabolismo , Renina/metabolismo , Animales , Degranulación de la Célula/efectos de los fármacos , Reactivos de Enlaces Cruzados/farmacología , Dexametasona/farmacología , Dinoprostona/farmacología , Histamina/metabolismo , Técnicas In Vitro , Masculino , Mastocitos/efectos de los fármacos , Mastocitos/fisiología , Ratones , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas c-kit/metabolismo
8.
FASEB J ; 28(2): 935-45, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24225147

RESUMEN

Mutations in the human KCNE3 potassium channel ancillary subunit gene are associated with life-threatening ventricular arrhythmias. Most genes underlying inherited cardiac arrhythmias, including KCNE3, are not exclusively expressed in the heart, suggesting potentially complex disease etiologies. Here we investigated mechanisms of KCNE3-linked arrhythmogenesis in Kcne3(-/-) mice using real-time qPCR, echo- and electrocardiography, ventricular myocyte patch-clamp, coronary artery ligation/reperfusion, blood analysis, cardiac synaptosome exocytosis, microarray and pathway analysis, and multitissue histology. Kcne3 transcript was undetectable in adult mouse atria, ventricles, and adrenal glands, but Kcne3(-/-) mice exhibited 2.3-fold elevated serum aldosterone (P=0.003) and differentially expressed gene networks consistent with an adrenal-targeted autoimmune response. Furthermore, 8/8 Kcne3(-/-) mice vs. 0/8 Kcne3(+/+) mice exhibited an activated-lymphocyte adrenal infiltration (P=0.0002). Kcne3 deletion also caused aldosterone-dependent ventricular repolarization delay (19.6% mean QTc prolongation in females; P<0.05) and aldosterone-dependent predisposition to postischemia arrhythmogenesis. Thus, 5/11 Kcne3(-/-) mice vs. 0/10 Kcne3(+/+) mice exhibited sustained ventricular tachycardia during reperfusion (P<0.05). Kcne3 deletion is therefore arrhythmogenic by a novel mechanism in which secondary hyperaldosteronism, associated with an adrenal-specific lymphocyte infiltration, impairs ventricular repolarization. The findings highlight the importance of considering extracardiac pathogenesis when investigating arrhythmogenic mechanisms, even in inherited, monogenic channelopathies.


Asunto(s)
Arritmias Cardíacas/metabolismo , Canales de Potasio con Entrada de Voltaje/deficiencia , Aldosterona/sangre , Animales , Arritmias Cardíacas/sangre , Arritmias Cardíacas/genética , Electrocardiografía , Femenino , Masculino , Ratones , Ratones Mutantes , Canales de Potasio/metabolismo , Canales de Potasio con Entrada de Voltaje/genética , Reacción en Cadena en Tiempo Real de la Polimerasa
9.
J Pharmacol Exp Ther ; 349(3): 508-17, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24696042

RESUMEN

Renin released by ischemia/reperfusion (I/R) from cardiac mast cells (MCs) activates a local renin-angiotensin system (RAS) causing arrhythmic dysfunction. Ischemic preconditioning (IPC) inhibits MC renin release and consequent activation of this local RAS. We postulated that MC histamine H4-receptors (H4Rs), being Gαi/o-coupled, might activate a protein kinase C isotype-ε (PKCε)-aldehyde dehydrogenase type-2 (ALDH2) cascade, ultimately eliminating MC-degranulating and renin-releasing effects of aldehydes formed in I/R and associated arrhythmias. We tested this hypothesis in ex vivo hearts, human mastocytoma cells, and bone marrow-derived MCs from wild-type and H4R knockout mice. We found that activation of MC H4Rs mimics the cardioprotective anti-RAS effects of IPC and that protection depends on the sequential activation of PKCε and ALDH2 in MCs, reducing aldehyde-induced MC degranulation and renin release and alleviating reperfusion arrhythmias. These cardioprotective effects are mimicked by selective H4R agonists and disappear when H4Rs are pharmacologically blocked or genetically deleted. Our results uncover a novel cardioprotective pathway in I/R, whereby activation of H4Rs on the MC membrane, possibly by MC-derived histamine, leads sequentially to PKCε and ALDH2 activation, reduction of toxic aldehyde-induced MC renin release, prevention of RAS activation, reduction of norepinephrine release, and ultimately to alleviation of reperfusion arrhythmias. This newly discovered protective pathway suggests that MC H4Rs may represent a new pharmacologic and therapeutic target for the direct alleviation of RAS-induced cardiac dysfunctions, including ischemic heart disease and congestive heart failure.


Asunto(s)
Aldehído Deshidrogenasa/metabolismo , Precondicionamiento Isquémico , Mastocitos/metabolismo , Daño por Reperfusión Miocárdica/metabolismo , Proteína Quinasa C-epsilon/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Histamínicos/metabolismo , Renina/metabolismo , Aldehído Deshidrogenasa Mitocondrial , Animales , Diferenciación Celular , Línea Celular , Activación Enzimática , Cobayas , Humanos , Técnicas In Vitro , Mastocitos/enzimología , Ratones , Ratones Noqueados , Daño por Reperfusión Miocárdica/enzimología , Daño por Reperfusión Miocárdica/fisiopatología , Daño por Reperfusión Miocárdica/prevención & control , Receptores Acoplados a Proteínas G/genética , Receptores Histamínicos/genética , Receptores Histamínicos H4 , Sistema Renina-Angiotensina/fisiología
10.
Circulation ; 125(2): 298-307, 2012 Jan 17.
Artículo en Inglés | MEDLINE | ID: mdl-22158783

RESUMEN

BACKGROUND: Although natriuretic peptides are considered cardioprotective, clinical heart failure trials with recombinant brain natriuretic peptide (nesiritide) failed to prove it. Unsuspected proadrenergic effects might oppose the anticipated benefits of natriuretic peptides. METHODS AND RESULTS: We investigated whether natriuretic peptides induce catecholamine release in isolated hearts, sympathetic nerve endings (cardiac synaptosomes), and PC12 cells bearing a sympathetic neuron phenotype. Perfusion of isolated guinea pig hearts with brain natriuretic peptide elicited a 3-fold increase in norepinephrine release, which doubled in ischemia/reperfusion conditions. Brain natriuretic peptide and atrial natriuretic peptide also released norepinephrine from cardiac synaptosomes and dopamine from nerve growth factor-differentiated PC12 cells in a concentration-dependent manner. These catecholamine-releasing effects were associated with an increase in intracellular calcium and abolished by blockade of calcium channels and calcium transients, demonstrating a calcium-dependent exocytotic process. Activation of the guanylyl cyclase-cyclic GMP-protein-kinase-G system with nitroprusside or membrane-permeant cyclic GMP analogs mimicked the proexocytotic effect of natriuretic peptides, an action associated with an increase in intracellular cyclic AMP (cAMP) and protein-kinase-A activity. Cyclic AMP enhancement resulted from an inhibition of phosphodiesterase type 3-induced cAMP hydrolysis. Collectively, these findings indicate that, by inhibiting phosphodiesterase type 3, natriuretic peptides sequentially enhance intracellular cAMP levels, protein kinase A activity, intracellular calcium, and catecholamine exocytosis. CONCLUSIONS: Our results show that natriuretic peptides, at concentrations likely to be reached at cardiac sympathetic nerve endings in advanced congestive heart failure, promote norepinephrine release via a protein kinase G-induced inhibition of phosphodiesterase type 3-mediated cAMP hydrolysis. We propose that this proadrenergic action may counteract the beneficial cardiac and hemodynamic effects of natriuretic peptides and thus explain the ineffectiveness of nesiritide as a cardiac failure medication.


Asunto(s)
Catecolaminas/metabolismo , Proteínas Quinasas Dependientes de GMP Cíclico/metabolismo , Péptido Natriurético Encefálico/farmacología , Péptidos Natriuréticos/fisiología , Inhibidores de Fosfodiesterasa 3/farmacología , Animales , Calcio , AMP Cíclico/metabolismo , Corazón , Insuficiencia Cardíaca , Natriuréticos , Células PC12 , Ratas , Sistema Nervioso Simpático
11.
J Exp Med ; 203(9): 2191-200, 2006 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-16940168

RESUMEN

Sympathetic neurons synthesize and release tissue plasminogen activator (t-PA). We investigated whether t-PA modulates sympathetic activity. t-PA inhibition markedly reduced contraction of the guinea pig vas deferens to electrical field stimulation (EFS) and norepinephrine (NE) exocytosis from cardiac synaptosomes. Recombinant t-PA (rt-PA) induced exocytotic and carrier-mediated NE release from cardiac synaptosomes and cultured neuroblastoma cells; this was a plasmin-independent effect but was potentiated by a fibrinogen cleavage product. Notably, hearts from t-PA-null mice released much less NE upon EFS than their wild-type (WT) controls (i.e., a 76.5% decrease; P<0.01), whereas hearts from plasminogen activator inhibitor-1 (PAI-1)-null mice released much more NE (i.e., a 275% increase; P<0.05). Furthermore, vasa deferentia from t-PA-null mice were hyporesponsive to EFS (P<0.0001) but were normalized by the addition of rt-PA. In contrast, vasa from PAI-1-null mice were much more responsive (P<0.05). Coronary NE overflow from hearts subjected to ischemia/reperfusion was much smaller in t-PA-null than in WT control mice (P<0.01). Furthermore, reperfusion arrhythmias were significantly reduced (P<0.05) in t-PA-null hearts. Thus, t-PA enhances NE release from sympathetic nerves and contributes to cardiac arrhythmias in ischemia/reperfusion. Because the risk of arrhythmias and sudden cardiac death is increased in hyperadrenergic conditions, targeting the NE-releasing effect of t-PA may have valuable therapeutic potential.


Asunto(s)
Fibras Adrenérgicas/fisiología , Contracción Muscular/fisiología , Unión Neuromuscular/fisiología , Activador de Tejido Plasminógeno/metabolismo , Fibras Adrenérgicas/efectos de los fármacos , Animales , Estimulación Eléctrica , Exocitosis/fisiología , Eliminación de Gen , Cobayas , Técnicas In Vitro , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Contracción Muscular/efectos de los fármacos , Miocardio/citología , Miocardio/metabolismo , Neuroblastoma , Norepinefrina/metabolismo , Inhibidor 1 de Activador Plasminogénico/genética , Inhibidor 1 de Activador Plasminogénico/metabolismo , Daño por Reperfusión , Simpatomiméticos/metabolismo , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Activador de Tejido Plasminógeno/genética , Activador de Tejido Plasminógeno/farmacología , Células Tumorales Cultivadas , Conducto Deferente/anatomía & histología , Conducto Deferente/efectos de los fármacos , Conducto Deferente/metabolismo
12.
J Pharmacol Exp Ther ; 340(1): 185-91, 2012 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22011436

RESUMEN

In severe myocardial ischemia, histamine 3 (H3) receptor activation affords cardioprotection by preventing excessive norepinephrine release and arrhythmias; pivotal to this action is the inhibition of neuronal Na⁺/H⁺ exchanger (NHE). Conversely, angiotensin II, formed locally by mast cell-derived renin, stimulates NHE via angiotensin II type 1 (AT1) receptors, facilitating norepinephrine release and arrhythmias. Thus, ischemic dysfunction may depend on a balance between the NHE-modulating effects of H3 receptors and AT1 receptors. The purpose of this investigation was therefore to elucidate the H3/AT1 receptor interaction in myocardial ischemia/reperfusion. We found that H3 receptor blockade with clobenpropit increased norepinephrine overflow and arrhythmias in Langendorff-perfused guinea pig hearts subjected to ischemia/reperfusion. This coincided with increased neuronal AT1 receptor expression. NHE inhibition with cariporide prevented both increases in norepinephrine release and AT1 receptor expression. Moreover, norepinephrine release and AT1 receptor expression were increased by the nitric oxide (NO) synthase inhibitor N(G)-methyl-L-arginine and the protein kinase C activator phorbol myristate acetate. H3 receptor activation in differentiated sympathetic neuron-like PC12 cells permanently transfected with H3 receptor cDNA caused a decrease in protein kinase C activity and AT1 receptor protein abundance. Collectively, our findings suggest that neuronal H3 receptor activation inhibits NHE by diminishing protein kinase C activity. Reduced NHE activity sequentially causes intracellular acidification, increased NO synthesis, and diminished AT1 receptor expression. Thus, H3 receptor-mediated NHE inhibition in ischemia/reperfusion not only opposes the angiotensin II-induced stimulation of NHE in cardiac sympathetic neurons, but also down-regulates AT1 receptor expression. Cardioprotection ultimately results from the combined attenuation of angiotensin II and norepinephrine effects and alleviation of arrhythmias.


Asunto(s)
Corazón/efectos de los fármacos , Agonistas de los Receptores Histamínicos/farmacología , Miocardio/metabolismo , Neuronas/metabolismo , Receptor de Angiotensina Tipo 1/biosíntesis , Receptores Histamínicos H3/fisiología , Angiotensina II/metabolismo , Animales , Cobayas , Corazón/inervación , Masculino , Isquemia Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/patología , Terminaciones Nerviosas/metabolismo , Óxido Nítrico/farmacología , Células PC12 , Proteína Quinasa C/metabolismo , Ratas , Receptores Histamínicos H3/efectos de los fármacos , Intercambiadores de Sodio-Hidrógeno/metabolismo , Sistema Nervioso Simpático/citología , Sistema Nervioso Simpático/efectos de los fármacos , Sistema Nervioso Simpático/metabolismo , Sinaptosomas/metabolismo , Acetato de Tetradecanoilforbol/farmacología
13.
J Pharmacol Exp Ther ; 343(3): 568-77, 2012 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-22923736

RESUMEN

We reported previously that natriuretic peptides, including brain natriuretic peptide (BNP), promote norepinephrine release from cardiac sympathetic nerves and dopamine release from differentiated pheochromocytoma PC12 cells. These proexocytotic effects are mediated by an increase in intracellular calcium secondary to cAMP/protein kinase A (PKA) activation caused by a protein kinase G (PKG)-mediated inhibition of phosphodiesterase type 3 (PDE3). The purpose of the present study was to search for novel means to prevent the proadrenergic effects of natriuretic peptides. For this, we focused our attention on neuronal inhibitory Gα(i/o)-coupled histamine H(3) and H(4) receptors. Our findings show that activation of neuronal H(3) and H(4) receptors inhibits the release of catecholamines elicited by BNP in cardiac synaptosomes and differentiated PC12 cells. This effect results from a decrease in intracellular Ca(2+) due to reduced intracellular cAMP/PKA activity, caused by H(3) and H(4) receptor-mediated PKG inhibition and consequent PDE3-induced increase in cAMP metabolism. Indeed, selective H(3) and H(4) receptor agonists each synergized with a PKG inhibitor and a PDE3 activator in attenuating BNP-induced norepinephrine release from cardiac sympathetic nerve endings. This indicates that PKG inhibition and PDE3 stimulation are pivotal for the H(3) and H(4) receptor-mediated attenuation of BNP-induced catecholamine release. Cardiac sympathetic overstimulation is characteristic of advanced heart failure, which was recently found not to be improved by the administration of recombinant BNP (nesiritide), despite the predicated beneficial effects of natriuretic peptides. Because excessive catecholamine release is likely to offset the desirable effects of natriuretic peptides, our findings suggest novel means to alleviate their adverse effects and improve their therapeutic potential.


Asunto(s)
Corazón/inervación , Péptido Natriurético Encefálico/farmacología , Neuronas/efectos de los fármacos , Norepinefrina/antagonistas & inhibidores , Receptores Acoplados a Proteínas G/metabolismo , Receptores Histamínicos H3/metabolismo , Receptores Histamínicos/metabolismo , Sistema Nervioso Simpático/efectos de los fármacos , Animales , Calcio/metabolismo , AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Proteínas Quinasas Dependientes de GMP Cíclico/antagonistas & inhibidores , Fosfodiesterasas de Nucleótidos Cíclicos Tipo 3/metabolismo , Cobayas , Agonistas de los Receptores Histamínicos/farmacología , Antagonistas de los Receptores Histamínicos/farmacología , Humanos , Neuronas/metabolismo , Norepinefrina/metabolismo , Células PC12 , Inhibidores de Proteínas Quinasas/farmacología , Ratas , Receptores Histamínicos H3/genética , Receptores Histamínicos H4 , Sistema Nervioso Simpático/metabolismo , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo , Transfección
14.
J Pharmacol Exp Ther ; 343(1): 97-105, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22761303

RESUMEN

During myocardial ischemia/reperfusion, lipid peroxidation leads to the formation of toxic aldehydes that contribute to ischemic dysfunction. Mitochondrial aldehyde dehydrogenase type 2 (ALDH2) alleviates ischemic heart damage and reperfusion arrhythmias via aldehyde detoxification. Because excessive norepinephrine release in the heart is a pivotal arrhythmogenic mechanism, we hypothesized that neuronal ALDH2 activation might diminish ischemic norepinephrine release. Incubation of cardiac sympathetic nerve endings with acetaldehyde, at concentrations achieved in myocardial ischemia, caused a concentration-dependent increase in norepinephrine release. A major increase in norepinephrine release also occurred when sympathetic nerve endings were incubated in hypoxic conditions. ALDH2 activation substantially reduced acetaldehyde- and hypoxia-induced norepinephrine release, an action prevented by inhibition of ALDH2 or protein kinase Cε (PKCε). Selective activation of G(i/o)-coupled adenosine A(1), A(3), or histamine H(3) receptors markedly inhibited both acetaldehyde- and hypoxia-induced norepinephrine release. These effects were also abolished by PKCε and/or ALDH2 inhibition. Moreover, A(1)-, A(3)-, or H(3)-receptor activation increased ALDH2 activity in a sympathetic neuron model (differentiated PC12 cells stably transfected with H(3) receptors). This action was prevented by the inhibition of PKCε and ALDH2. Our findings suggest the existence in sympathetic neurons of a protective pathway initiated by A(1)-, A(3)-, and H(3)-receptor activation by adenosine and histamine released in close proximity of these terminals. This pathway comprises the sequential activation of PKCε and ALDH2, culminating in aldehyde detoxification and inhibition of hypoxic norepinephrine release. Thus, pharmacological activation of PKCε and ALDH2 in cardiac sympathetic nerves may have significant protective effects by alleviating norepinephrine-induced life-threatening arrhythmias that characterize myocardial ischemia/reperfusion.


Asunto(s)
Aldehído Deshidrogenasa/metabolismo , Proteínas Mitocondriales/metabolismo , Isquemia Miocárdica/metabolismo , Norepinefrina/metabolismo , Proteína Quinasa C-epsilon/fisiología , Receptores Histamínicos/metabolismo , Receptores Purinérgicos P1/metabolismo , Aldehído Deshidrogenasa Mitocondrial , Animales , Activación Enzimática/efectos de los fármacos , Activación Enzimática/fisiología , Cobayas , Hipoxia/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Norepinefrina/antagonistas & inhibidores , Células PC12 , Ratas , Fibras Simpáticas Posganglionares/efectos de los fármacos , Fibras Simpáticas Posganglionares/metabolismo , Sinaptosomas/efectos de los fármacos , Sinaptosomas/metabolismo
15.
Adv Pharmacol ; 94: 365-409, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35659376

RESUMEN

Cancer patients are at an increased risk of cardiovascular events. Both old-generation cytostatics/cytotoxics and new-generation "targeted" drugs can in fact damage cardiomyocytes, endothelial cells of veins and arteries, specialized cells of the conduction system, pericardium, and valves. A new discipline, cardio-oncology, has therefore developed with the aim of protecting cancer patients from cardiovascular events, while also providing them with the best possible oncologic treatment. Anthracyclines have long been known to elicit cardiotoxicity that, depending on treatment- or patient-related factors, may progress with a variable velocity toward cardiomyopathy and systolic heart failure. However, early compromise of diastolic function may precede systolic dysfunction, and a progression of early diastolic dysfunction to diastolic rather than systolic heart failure has been documented in long-term cancer survivors. This chapter first describes general notions about hypertension in the cancer patient and then moves on reviewing the pathophysiology and clinical trajectories of diastolic dysfunction, and the molecular mechanisms of anthracycline-induced diastolic dysfunction. Diastolic dysfunction can in fact be caused and/or aggravated by hypertension. Pharmacologic foundations and therapeutic opportunities to prevent or treat diastolic dysfunction before it progresses toward heart failure are also reviewed, with a special emphasis on the mechanisms of action of drugs that raised hopes to treat diastolic dysfunction in the general population (sacubitril/valsartan, guanylyl cyclase activators, phosphodiesterase inhibitors, ranolazine, inhibitors of type-2 sodium-glucose-inked transporter). Cardio-oncologists will be confronted with the risk:benefit ratio of using these drugs in the cancer patient.


Asunto(s)
Antineoplásicos , Cardiomiopatías , Insuficiencia Cardíaca Sistólica , Hipertensión , Neoplasias , Aminobutiratos , Antraciclinas/efectos adversos , Antineoplásicos/farmacología , Compuestos de Bifenilo , Cardiomiopatías/inducido químicamente , Cardiomiopatías/tratamiento farmacológico , Células Endoteliales , Insuficiencia Cardíaca Sistólica/inducido químicamente , Insuficiencia Cardíaca Sistólica/tratamiento farmacológico , Humanos , Hipertensión/inducido químicamente , Hipertensión/tratamiento farmacológico , Neoplasias/tratamiento farmacológico
16.
Circulation ; 122(8): 771-81, 2010 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-20697027

RESUMEN

BACKGROUND: Renin released by ischemia/reperfusion from cardiac mast cells activates a local renin-angiotensin system (RAS). This exacerbates norepinephrine release and reperfusion arrhythmias (ventricular tachycardia and fibrillation), making RAS a new therapeutic target in myocardial ischemia. METHODS AND RESULTS: We investigated whether ischemic preconditioning (IPC) prevents cardiac RAS activation in guinea pig hearts ex vivo. When ischemia/reperfusion (20 minutes of ischemia/30 minutes of reperfusion) was preceded by IPC (two 5-minute ischemia/reperfusion cycles), renin and norepinephrine release and ventricular tachycardia and fibrillation duration were markedly decreased, a cardioprotective anti-RAS effect. Activation and blockade of adenosine A(2b)/A(3) receptors and activation and inhibition of protein kinase Cepsilon (PKCepsilon) mimicked and prevented, respectively, the anti-RAS effects of IPC. Moreover, activation of A(2b)/A(3) receptors or activation of PKCepsilon prevented degranulation and renin release elicited by peroxide in cultured mast cells (HMC-1). Activation and inhibition of mitochondrial aldehyde dehydrogenase type-2 (ALDH2) also mimicked and prevented, respectively, the cardioprotective anti-RAS effects of IPC. Furthermore, ALDH2 activation inhibited degranulation and renin release by reactive aldehydes in HMC-1. Notably, PKCepsilon and ALDH2 were both activated by A(2b)/A(3) receptor stimulation in HMC-1, and PKCepsilon inhibition prevented ALDH2 activation. CONCLUSIONS: The results uncover a signaling cascade initiated by A(2b)/A(3) receptors, which triggers PKCepsilon-mediated ALDH2 activation in cardiac mast cells, contributing to IPC-induced cardioprotection by preventing mast cell renin release and the dysfunctional consequences of local RAS activation. Thus, unlike classic IPC in which cardiac myocytes are the main target, cardiac mast cells are the critical site at which the cardioprotective anti-RAS effects of IPC develop.


Asunto(s)
Aldehído Deshidrogenasa/fisiología , Arritmias Cardíacas/prevención & control , Mastocitos/fisiología , Daño por Reperfusión Miocárdica/prevención & control , Miocitos Cardíacos/metabolismo , Renina/antagonistas & inhibidores , Animales , Degranulación de la Célula , Línea Celular Tumoral , Activación Enzimática , Cobayas , Humanos , Precondicionamiento Isquémico Miocárdico , Masculino , Proteína Quinasa C-epsilon/fisiología , Receptor de Adenosina A2B/fisiología , Receptor de Adenosina A3/fisiología , Renina/metabolismo , Sistema Renina-Angiotensina/fisiología
17.
J Pharmacol Exp Ther ; 337(2): 524-32, 2011 May.
Artículo en Inglés | MEDLINE | ID: mdl-21325440

RESUMEN

Once released, norepinephrine is removed from cardiac synapses via reuptake into sympathetic nerves, whereas transmitter ATP is catabolized by ecto-NTP diphosphohydrolase 1 (E-NTPDase1)/CD39, an ecto-ATPase. Because ATP is known to modulate neurotransmitter release at prejunctional sites, we questioned whether this action may be ultimately controlled by the expression of E-NTPDase1/CD39 at sympathetic nerve terminals. Accordingly, we silenced E-NTPDase1/CD39 expression in nerve growth factor-differentiated PC12 cells, a cellular model of sympathetic neuron, in which dopamine is the predominant catecholamine. We report that E-NTPDase1/CD39 deletion markedly increases depolarization-induced exocytosis of ATP and dopamine and increases ATP-induced dopamine release. Moreover, overexpression of E-NTPDase1/CD39 resulted in enhanced removal of exogenous ATP, a marked decrease in exocytosis of ATP and dopamine, and a large decrease in ATP-induced dopamine release. Administration of a recombinant form of E-NTPDase1/CD39 reproduced the effects of E-NTPDase1/CD39 overexpression. Exposure of PC12 cells to simulated ischemia elicited a release of ATP and dopamine that was markedly increased in E-NTPDase1/CD39-silenced cells and decreased in E-NTPDase1/CD39-overexpressing cells. Therefore, transmitter ATP acts in an autocrine manner to promote its own release and that of dopamine, an action that is controlled by the level of E-NTPDase1/CD39 expression. Because ATP availability greatly increases in myocardial ischemia, recombinant E-NTPDase1/CD39 therapeutically used may offer a novel approach to reduce cardiac dysfunctions caused by excessive catecholamine release.


Asunto(s)
Antígenos CD/biosíntesis , Apirasa/biosíntesis , Exocitosis/fisiología , Neuronas/metabolismo , Neurotransmisores/metabolismo , Sistema Nervioso Simpático/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Antígenos CD/genética , Apirasa/genética , Western Blotting , Cartilla de ADN , Dopamina/metabolismo , Exocitosis/genética , Regulación Enzimológica de la Expresión Génica/fisiología , Silenciador del Gen , Isquemia/metabolismo , Factores de Crecimiento Nervioso/farmacología , Norepinefrina/metabolismo , Células PC12 , Potasio/farmacología , ARN Interferente Pequeño/metabolismo , Ratas , Receptores Purinérgicos P2X/efectos de los fármacos , Receptores Purinérgicos P2X/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Sistema Nervioso Simpático/citología
18.
Proc Natl Acad Sci U S A ; 105(4): 1315-20, 2008 Jan 29.
Artículo en Inglés | MEDLINE | ID: mdl-18202178

RESUMEN

We previously reported that mast cells express renin, the rate-limiting enzyme in the renin-angiotensin cascade. We have now assessed whether mast cell renin release triggers angiotensin formation in the airway. In isolated rat bronchial rings, mast cell degranulation released enzyme with angiotensin I-forming activity blocked by the selective renin inhibitor BILA2157. Local generation of angiotensin (ANG II) from mast cell renin elicited bronchial smooth muscle contraction mediated by ANG II type 1 receptors (AT(1)R). In a guinea pig model of immediate type hypersensitivity, anaphylactic mast cell degranulation in bronchial rings resulted in ANG II-mediated constriction. As in rat bronchial rings, bronchoconstriction (BC) was inhibited by a renin inhibitor, an AT(1)R blocker, and a mast cell stabilizer. Anaphylactic release of renin, histamine, and beta-hexosaminidase from mast cells was confirmed in the effluent from isolated, perfused guinea pig lung. To relate the significance of this finding to humans, mast cells were isolated from macroscopically normal human lung waste tissue specimens. Sequence analysis of human lung mast cell RNA showed 100% homology between human lung mast cell renin and kidney renin between exons 1 and 10. Furthermore, the renin protein expressed in lung mast cells was enzymatically active. Our results demonstrate the existence of an airway renin-angiotensin system triggered by release of mast-cell renin. The data show that locally produced ANG II is a critical factor governing BC, opening the possibility for novel therapeutic targets in the management of airway disease.


Asunto(s)
Bronquios/enzimología , Broncoconstricción/fisiología , Mastocitos/enzimología , Sistema Renina-Angiotensina/fisiología , Renina/metabolismo , Angiotensina II/biosíntesis , Angiotensina II/fisiología , Animales , Bronquios/metabolismo , Bronquios/fisiología , Degranulación de la Célula/fisiología , Cobayas , Humanos , Pulmón/enzimología , Pulmón/metabolismo , Pulmón/fisiología , Masculino , Mastocitos/metabolismo , Mastocitos/fisiología , Contracción Muscular/fisiología , Músculo Liso/citología , Músculo Liso/metabolismo , Músculo Liso/fisiología , Ratas , Ratas Sprague-Dawley , Receptor de Angiotensina Tipo 1/metabolismo , Renina/química , Renina/genética , Renina/fisiología
19.
J Pharmacol Exp Ther ; 335(1): 76-84, 2010 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-20668055

RESUMEN

Renin, the rate-limiting enzyme in the activation of the renin-angiotensin system (RAS), is synthesized and stored in cardiac mast cells. In ischemia/reperfusion, cardiac sensory nerves release neuropeptides such as substance P that, by degranulating mast cells, might promote renin release, thus activating a local RAS and ultimately inducing cardiac dysfunction. We tested this hypothesis in whole hearts ex vivo, in cardiac nerve terminals in vitro, and in cultured mast cells. We found that substance P-containing nerves are juxtaposed to renin-containing cardiac mast cells. Chemical stimulation of these nerves elicited substance P release that was accompanied by renin release, with the latter being preventable by mast cell stabilization or blockade of substance P receptors. Substance P caused degranulation of mast cells in culture and elicited renin release, and both of these were prevented by substance P receptor blockade. Ischemia/reperfusion in ex vivo hearts caused the release of substance P, which was associated with an increase in renin and norepinephrine overflow and with sustained reperfusion arrhythmias; substance P receptor blockade prevented these changes. Substance P, norepinephrine, and renin were also released by acetaldehyde, a known product of ischemia/reperfusion, from cardiac synaptosomes and cultured mast cells, respectively. Collectively, our findings indicate that an important link exists in the heart between sensory nerves and renin-containing mast cells; substance P released from sensory nerves plays a significant role in the release of mast cell renin in ischemia/reperfusion and in the activation of a local cardiac RAS. This culminates in angiotensin production, norepinephrine release, and arrhythmic cardiac dysfunction.


Asunto(s)
Arritmias Cardíacas/patología , Mastocitos/patología , Daño por Reperfusión Miocárdica/patología , Miocardio/patología , Fibras Nerviosas Amielínicas/patología , Sistema Renina-Angiotensina/fisiología , Células Receptoras Sensoriales/patología , Aldehídos/metabolismo , Animales , Péptido Relacionado con Gen de Calcitonina/metabolismo , Degranulación de la Célula/efectos de los fármacos , Células Cultivadas , Técnica del Anticuerpo Fluorescente , Cobayas , Técnicas In Vitro , Masculino , Terminaciones Nerviosas/patología , Terminaciones Nerviosas/fisiología , Norepinefrina/metabolismo , Renina/metabolismo , Sustancia P/metabolismo , Sinaptosomas/metabolismo , Sinaptosomas/patología , beta-N-Acetilhexosaminidasas/metabolismo
20.
J Clin Invest ; 116(4): 1063-70, 2006 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-16585966

RESUMEN

Having identified renin in cardiac mast cells, we assessed whether its release leads to cardiac dysfunction. In Langendorff-perfused guinea pig hearts, mast cell degranulation with compound 48/80 released Ang I-forming activity. This activity was blocked by the selective renin inhibitor BILA2157, indicating that renin was responsible for Ang I formation. Local generation of cardiac Ang II from mast cell-derived renin also elicited norepinephrine release from isolated sympathetic nerve terminals. This action was mediated by Ang II-type 1 (AT1) receptors. In 2 models of ischemia/reperfusion using Langendorff-perfused guinea pig and mouse hearts, a significant coronary spillover of renin and norepinephrine was observed. In both models, this was accompanied by ventricular fibrillation. Mast cell stabilization with cromolyn or lodoxamide markedly reduced active renin overflow and attenuated both norepinephrine release and arrhythmias. Similar cardioprotection was observed in guinea pig hearts treated with BILA2157 or the AT1 receptor antagonist EXP3174. Renin overflow and arrhythmias in ischemia/reperfusion were much less prominent in hearts of mast cell-deficient mice than in control hearts. Thus, mast cell-derived renin is pivotal for activating a cardiac renin-angiotensin system leading to excessive norepinephrine release in ischemia/reperfusion. Mast cell-derived renin may be a useful therapeutic target for hyperadrenergic dysfunctions, such as arrhythmias, sudden cardiac death, myocardial ischemia, and congestive heart failure.


Asunto(s)
Angiotensinas/metabolismo , Arritmias Cardíacas/metabolismo , Mastocitos/metabolismo , Isquemia Miocárdica/metabolismo , Norepinefrina/metabolismo , Renina/metabolismo , Animales , Cobayas , Masculino , Ratones , Ratones Transgénicos , Modelos Biológicos , Reperfusión Miocárdica , Sistema Renina-Angiotensina/fisiología , Sistema Nervioso Simpático/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA