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1.
Heart Rhythm ; 16(5): 765-772, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30414461

RESUMO

BACKGROUND: Type 2 diabetes (T2D) increases arrhythmia risk through incompletely elucidated mechanisms. Ventricular arrhythmias could be initiated by delayed afterdepolarizations (DADs) resulting from elevated spontaneous sarcoplasmic reticulum (SR) Ca2+ release (SR Ca2+ leak). OBJECTIVE: The purpose of this study was to test the role of DADs and SR Ca2+ leak in triggering arrhythmias in T2D hearts. METHODS: We compared rats with late-onset T2D that display pancreatic and cardiac phenotypes similar to those in humans with T2D (HIP rats) and their nondiabetic littermates (wild type [WT]). RESULTS: HIP rats showed higher propensity for premature ventricular complexes and ventricular tachyarrhythmias, whereas HIP myocytes displayed more frequent DADs and had lower SR Ca2+ content than WT. However, the threshold SR Ca2+ at which depolarizing transient inward currents (Itis) are generated was also significantly decreased in HIP myocytes and was below the actual SR Ca2+ load, which explains the increased DAD incidence despite reduced Ca2+ in SR. In agreement with these findings, Ca2+ spark frequency was augmented in myocytes from HIP vs WT rats, which suggests activation of ryanodine receptors (RyRs) in HIP hearts. Indeed, RyR phosphorylation (by CaMKII and protein kinase A) and oxidation are enhanced in HIP hearts, whereas there is no RyR O-GlcNAcylation in either HIP or control hearts. CaMKII inhibition dissipated the difference in Ca2+ spark frequency between HIP and WT myocytes. CONCLUSION: The threshold SR Ca2+ for generating depolarizing Itis is lower in T2D because of RyR activation after hyperphosphorylation and oxidation, which favors the occurrence of DADs despite low SR Ca2+ loads.

2.
Front Vet Sci ; 5: 149, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30023360

RESUMO

Kisspeptin is a neuropeptide that governs the reproductive axis upstream to GnRH. We wanted to study whether kisspeptin modulates plasma LH and FSH levels and ovarian follicular dynamics in buffaloes and whether kisspeptin can be used for fixed time artificial insemination (FTAI). We carried out these studies in comparison with buserelin, a potent GnRH agonist. Kisspeptin dose-dependently increased plasma LH levels. However, the kisspeptin-induced increase in LH was short-lived as the peak reached in 15-30 min returned to basal values by 1-2 h. The kisspeptin-induced increase in LH level was less compared to buserelin-induced increase in LH level which sustained over time. Kisspeptin did not enhance FSH release while buserelin resulted in a gradual increase over time. LH response to repeated injections of kisspeptin was greater than that induced by buserelin. While buserelin induced an increase in the number of follicles, kisspeptin induced an increase in the growth rate of the follicle. In adult cycling animals, while both the drugs increased plasma LH levels, the increase was greater in buserelin group compared to kisspeptin group. In contrast to the findings in pre-pubertal animals, kisspeptin induced an increase in both the number as well as the size of follicles compared to buserelin. Our studies on oestrus synchronization, using either kisspeptin-PGF2α-kisspeptin protocol or buserelin-PGF2α-buserelin Ovsynch protocol on day 0, 7, and 9, respectively, revealed that kisspeptin increased the number of follicles at wave emergence and the diameter of dominant follicle after 2nd dose of drug, the oestrus response rate and duration of oestrus, compared to buserelin. However, conception rate was not significantly different among the groups. From our studies, it appears that Kp and Buserelin differentially modulate follicular dynamics depending on the reproductive age of the animals.However, studies in a larger herd are required to confirm whether kisspeptin can be used for oestrous synchronization in buffaloes.

3.
Am J Transl Res ; 7(3): 522-34, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26045892

RESUMO

Administration of 17ß-estradiol has been shown to exert myocardial protective effects in hemorrhagic shock. We hypothesized that similar protective effects could help improve resuscitation from cardiac arrest. Three series of 18, 40, and 12 rats each, underwent ventricular fibrillation for 8 minutes followed by 8 minutes of chest compression and delivery of electrical shocks. In series-1, rats were randomized 1:1 to receive a bolus dose of 17ß-estradiol (1 mg/kg) or 0.9% NaCl before chest compression; in series-2, rats were randomized 1:1:1:1 to receive a continuous infusion of 0.9% NaCl or a 17ß-estradiol solution designed to attain a plasma level of 10(0), 10(2), or 10(4) nM during chest compression; and in series-3, rats were randomized 1:1 to receive a continuous infusion of 17ß-estradiol to attain a plasma level of 10(2) nM or 0.9% NaCl during chest compression, providing inotropic support during the post-resuscitation interval using dobutamine infusion. 17ß-estradiol failed to facilitate resuscitation in each of the 3 series. In series-1 and series-2, resuscitability and short-term survival was reduced in 17ß-estradiol groups attaining statistical significance in series-2 when the three 17ß-estradiol groups were combined (p = 0.035). In series-3, all rats were resuscitated and survived for 180 minutes aided by dobutamine which partially reversed post-resuscitation myocardial dysfunction but without additional benefits on myocardial function in the 17ß-estradiol group. The present study failed to support a beneficial effect of 17ß-estradiol for resuscitation from cardiac arrest and raised the possibility of detrimental cardiac effects compromising initial resuscitability and subsequent survival in a male rat model of ventricular fibrillation and closed chest resuscitation.

4.
PLoS One ; 9(11): e110908, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25365317

RESUMO

OBJECTIVE: To determine whether erythropoietin given during hemorrhagic shock (HS) ameliorates organ injury while improving resuscitation and survival. METHODS: Three series of 24 pigs each were studied. In an initial series, 50% of the blood volume (BV) was removed in 30 minutes and normal saline (threefold the blood removed) started at minute 90 infusing each third in 30, 60, and 150 minutes with shed blood reinfused at minute 330 (HS-50BV). In a second series, the same HS-50BV protocol was used but removing an additional 15% of BV from minute 30 to 60 (HS-65BV). In a final series, blood was removed as in HS-65BV and intraosseous vasopressin given from minute 30 (0.04 U/kg min(-1)) until start of shed blood reinfusion at minute 150 (HS-65BV+VP). Normal saline was reduced to half the blood removed and given from minute 90 to 120 in half of the animals. In each series, animals were randomized 1:1 to receive erythropoietin (1,200 U/kg) or control solution intraosseously after removing 10% of the BV. RESULTS: In HS-50BV, O2 consumption remained near baseline yielding minimal lactate increases, 88% resuscitability, and 60% survival at 72 hours. In HS-65BV, O2 consumption was reduced and lactate increased yielding 25% resuscitability. In HS-65BV+VP, vasopressin promoted hemodynamic stability yielding 92% resuscitability and 83% survival at 72 hours. Erythropoietin did not affect resuscitability or subsequent survival in any of the series but increased interleukin-10, attenuated lactate increases, and ameliorated organ injury based on lesser troponin I, AST, and ALT increases and lesser neurological deficits in the HS-65BV+VP series. CONCLUSIONS: Erythropoietin given during HS in swine failed to alter resuscitability and 72 hour survival regardless of HS severity and concomitant treatment with fluids and vasopressin but attenuated acute organ injury. The studies also showed the efficacy of vasopressin and restrictive fluid resuscitation for hemodynamic stabilization and survival.


Assuntos
Eritropoetina/administração & dosagem , Choque Hemorrágico/terapia , Animais , Citocinas/sangue , Modelos Animais de Doenças , Eritropoetina/farmacocinética , Coração/fisiopatologia , Hemodinâmica , Infusões Intraósseas , Ácido Láctico/sangue , Masculino , Miocárdio/metabolismo , Consumo de Oxigênio , Ressuscitação , Choque Hemorrágico/metabolismo , Choque Hemorrágico/mortalidade , Choque Hemorrágico/fisiopatologia , Suínos
5.
PLoS One ; 9(2): e87495, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24498331

RESUMO

Spontaneous calcium waves in cardiac myocytes are caused by diastolic sarcoplasmic reticulum release (SR Ca(2+) leak) through ryanodine receptors. Beta-adrenergic (ß-AR) tone is known to increase this leak through the activation of Ca-calmodulin-dependent protein kinase (CaMKII) and the subsequent phosphorylation of the ryanodine receptor. When ß-AR drive is chronic, as observed in heart failure, this CaMKII-dependent effect is exaggerated and becomes potentially arrhythmogenic. Recent evidence has indicated that CaMKII activation can be regulated by cellular oxidizing agents, such as reactive oxygen species. Here, we investigate how the cellular second messenger, nitric oxide, mediates CaMKII activity downstream of the adrenergic signaling cascade and promotes the generation of arrhythmogenic spontaneous Ca(2+) waves in intact cardiomyocytes. Both SCaWs and SR Ca(2+) leak were measured in intact rabbit and mouse ventricular myocytes loaded with the Ca-dependent fluorescent dye, fluo-4. CaMKII activity in vitro and immunoblotting for phosphorylated residues on CaMKII, nitric oxide synthase, and Akt were measured to confirm activity of these enzymes as part of the adrenergic cascade. We demonstrate that stimulation of the ß-AR pathway by isoproterenol increased the CaMKII-dependent SR Ca(2+) leak. This increased leak was prevented by inhibition of nitric oxide synthase 1 but not nitric oxide synthase 3. In ventricular myocytes isolated from wild-type mice, isoproterenol stimulation also increased the CaMKII-dependent leak. Critically, in myocytes isolated from nitric oxide synthase 1 knock-out mice this effect is ablated. We show that isoproterenol stimulation leads to an increase in nitric oxide production, and nitric oxide alone is sufficient to activate CaMKII and increase SR Ca(2+) leak. Mechanistically, our data links Akt to nitric oxide synthase 1 activation downstream of ß-AR stimulation. Collectively, this evidence supports the hypothesis that CaMKII is regulated by nitric oxide as part of the adrenergic cascade leading to arrhythmogenesis.


Assuntos
Adrenérgicos/farmacologia , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cálcio/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Óxido Nítrico/metabolismo , Retículo Sarcoplasmático/metabolismo , Animais , Western Blotting , Células Cultivadas , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Isoproterenol/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Óxido Nítrico Sintase Tipo I/deficiência , Óxido Nítrico Sintase Tipo I/genética , Fosforilação/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/metabolismo , Coelhos , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo
6.
Endocrinology ; 151(6): 2681-8, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20332196

RESUMO

Secretin is a 27-amino acid brain-gut peptide from duodenal S-cells. We tested the effects of systemic administration of secretin to simulate its postprandial release on neuroendocrine neurons of the supraoptic nucleus (SON) in urethane-anesthetized female rats. Secretin dose-dependently increased the firing rate of oxytocin neurons, more potently than cholecystokinin, and dose-dependently increased plasma oxytocin concentration. The effect of secretin on SON vasopressin neurons was also predominantly excitatory, in contrast to the inhibitory actions of cholecystokinin. To explore the involvement of noradrenergic inputs in secretin-induced excitation, benoxathian, an alpha1-adrenoceptor antagonist, was infused intracerebroventricularly. Benoxathian intracerebroventricular infusion blocked the excitation by secretin of both oxytocin and vasopressin neurons. To test the role of local noradrenaline release in the SON, benoxathian was microdialyzed onto the SON. The basal firing rate of oxytocin neurons was slightly reduced and the secretin-induced excitation was attenuated during benoxathian microdialysis. Hence, noradrenergic pathways mediate the excitation by systemic secretin of oxytocin neurons via alpha1-adrenoceptors in the SON. As both systemic secretin and oxytocin are involved in regulating gastrointestinal functions and natriuresis, systemically released secretin might act partly through oxytocin.


Assuntos
Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Ocitocina/metabolismo , Secretina/farmacologia , Núcleo Supraóptico/citologia , Vasopressinas/metabolismo , Animais , Colecistocinina/farmacologia , Eletrofisiologia , Feminino , Microdiálise , Ocitocina/sangue , Radioimunoensaio , Ratos , Ratos Sprague-Dawley , Secretina/administração & dosagem , Vasopressinas/sangue
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