Effects of Beta; 1-adrenoceptors in the Basolateral Amygdala on Spatial Memory, Passive Avoidance, Long-term Potentiation and Neuronal Arborization in the Hippocampal CA1 Region in Response to Unavoidable Stress

Abstract Norepinephrine in the basolateral amygdala (BLA) plays a pivotal role in mediating the effects of stress on memory functions in the hippocampus, however, the functional contribution of β1-adrenergic receptors on the BLA inputs to the CA1 region of hippocampus and memory function are not well understood. In the present study the role of β1-adrenoreceptor in the BLA on memory, neuronal arborization and long-term potentiation (LTP) in the CA1 region of hippocampus was examined by infusion the β1-adrenoreceptor agonist (Dobutamine; 0.5µl/side) or antagonist (Atenolol; 0.25µL/side) bilaterally into the BLA before foot-shock stress. Passive avoidance test results showed that Step-through latency time was significantly decreased in the stress group rats one, four and seven days after the stress, which intra-BLA injection of Atenolol or Dobutamine before stress couldn't attenuate this reduction. Barnes-maze results revealed that infusion of Dobutamine and Atenolol significantly reduced spatial memory indicators such as increased latency time, the number of errors and the distance traveling to achieve the target hole in the stress group. These learning impairments in stress rats correlated with a reduction of LTP in hippocampal CA1 synapses in-vivo, which infusion of Dobutamine and Atenolol couldn't attenuate the population spike amplitude and mean-field excitatory postsynaptic potentials (fEPSP) slope reduction induced by stress. Also, the Golgi-Cox staining demonstrated that infusion of Atenolol attenuated stress decreased CA1 region dendritic and axonal arborization. These results suggest that β1-adrenergic receptors activation or block seem to exacerbate stress-induced hippocampal memory deficits and this effect is independent of CA1 LTP modulation.

An Alternative Method to Calculate Simplified Projected Aortic Valve Area at Normal Flow Rate / Um Método Alternativo para o Cálculo da Área Valvular Aórtica Projetada Simplificada em Uma Taxa de Fluxo Normal

Abstract Background: Simplified projected aortic valve area (EOAproj) is a valuable echocardiographic parameter in the evaluation of low flow low gradient aortic stenosis (LFLG AS). Its widespread use in clinical practice is hampered by the laborious process of flow rate (Q) calculation. Objetive: This study proposes a less burdensome, alternative method of Q calculation to be incorporated in the original formula of EOAproj and measures the agreement between the new proposed method of EOAproj calculation and the original one. Methods: Retrospective observational single-institution study that included all consecutive patients with classic LFLG AS that showed a Q variation with dobutamine infusion ≥ -15-% by both calculation methods. Results: Twenty-two consecutive patients with classical LFLG AS who underwent dobutamine stress echocardiography were included. Nine patients showed a Q variation with dobutamine infusion calculated by both classical and alternative methods ≥ -15-% and were selected for further statistical analysis. Using the Bland-Altman method to assess agreement we found a systematic bias of 0,037 cm2 (95% CI 0,004 - 0,066), meaning that on average the new method overestimates the EOAproj in 0,037 cm2 compared to the original method. The 95% limits of agreement are narrow (from -0,04 cm2 to 0,12 cm2), meaning that for 95% of individuals, EOAproj calculated by the new method would be between 0,04 cm2 less to 0,12 cm2 more than the EOAproj calculated by the original equation. Conclusion: The bias and 95% limits of agreement of the new method are narrow and not clinically relevant, supporting the potential interchangeability of the two methods of EOAproj calculation. As the new method requires less additional measurements, it would be easier to implement in clinical practice, promoting an increase in the use of EOAproj.

Resumo Fundamento: A área valvular aórtica projetada simplificada (AEOproj) é um parâmetro ecocardiográfico valioso na avaliação da estenose aórtica de baixo fluxo e baixo gradiente (EA BFBG). Sua utilização na prática clínica é limitada pelo trabalhoso processo de cálculo da taxa de fluxo (Q). Objetivos: Este estudo propõe um método alternativo, menos complexo, para o cálculo da Q para ser incorporado na fórmula original da AEOproj, e mede a concordância entre o novo método proposto para o cálculo da AEOproj em comparação ao método original. Métodos: Estudo retrospectivo, observacional, unicêntrico que incluiu todos os pacientes com AE BFBG clássica com variação da Q com infusão de dobutamina ≥ -15-% por ambos os métodos. Resultados: Foram incluídos 22 pacientes consecutivos com AE BFBG clássico, que se submeteram à ecocardiografia sob estresse com dobutamina. Nove pacientes apresentaram uma variação da Q com infusão de dobutamina calculada tanto pelo método clássico como pelo método alternativo ≥ -15-%, e foram selecionados para análise estatística. Utilizando método Bland-Altman para avaliar a concordância, encontramos um viés sistemático de 0,037 cm2 (IC 95% 0,004 - 0,066), o que significa que, em média, o novo método superestima a AEOproj em 0m037 cm2 em comparação ao método original. Os limites de concordância de 95% são estreitos (de -0,04 cm2 a 0,12 cm2), o que significa que para 95% dos indivídios, a AEOproj calculada pelo novo método estaria entre 0,04 cm2 menos a 0,12 cm2 mais que a AEOproj calculada pela equação original. Conclusão: O viés e os limites de 95% de concordância do novo método são estreitos e não são clinicamente relevantes, o que corrobora a intercambialidade dos dois métodos de cálculo da AEOproj. Uma vez que o novo método requer menos medidas, seria mais fácil de ser implementado na prática clínica, promovendo um aumento na utilização da AEOproj.

Effect of Nebivolol on MIBG Parameters and Exercise in Heart Failure with Normal Ejection Fraction / Efeito do Nebivolol sobre Parâmetros do MIBG e Exercício na Insuficiência Cardíaca com Fração de Ejeção Normal

Abstract Background: More than 50% of the patients with heart failure have normal ejection fraction (HFNEF). Iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy and cardiopulmonary exercise test (CPET) are prognostic markers in HFNEF. Nebivolol is a beta-blocker with vasodilating properties. Objectives: To evaluate the impact of nebivolol therapy on CPET and123I-MIBG scintigraphic parameters in patients with HFNEF. Methods: Twenty-five patients underwent 123I-MIBG scintigraphy to determine the washout rate and early and late heart-to-mediastinum ratios. During the CPET, we analyzed the systolic blood pressure (SBP) response, heart rate (HR) during effort and recovery (HRR), and oxygen uptake (VO2). After the initial evaluation, we divided our cohort into control and intervention groups. We then started nebivolol and repeated the tests after 3 months. Results: After treatment, the intervention group showed improvement in rest SBP (149 mmHg [143.5-171 mmHg] versus 135 mmHg [125-151 mmHg, p = 0.016]), rest HR (78 bpm [65.5-84 bpm] versus 64.5 bpm [57.5-75.5 bpm, p = 0.028]), peak SBP (235 mmHg [216.5-249 mmHg] versus 198 mmHg [191-220.5 mmHg], p = 0.001), peak HR (124.5 bpm [115-142 bpm] versus 115 bpm [103.7-124 bpm], p= 0.043), HRR on the 1st minute (6.5 bpm [4.75-12.75 bpm] versus 14.5 bpm [6.7-22 bpm], p = 0.025) and HRR on the 2nd minute (15.5 bpm [13-21.75 bpm] versus 23.5 bpm [16-31.7 bpm], p = 0.005), but no change in peak VO2 and 123I-MIBG scintigraphic parameters. Conclusion: Despite a better control in SBP, HR during rest and exercise, and improvement in HRR, nebivolol failed to show a positive effect on peak VO2 and 123I-MIBG scintigraphic parameters. The lack of effect on adrenergic activity may be the cause of the lack of effect on functional capacity.

Resumo Fundamento: Mais de 50% dos pacientes com insuficiência cardíaca têm fração de ejeção preservada (ICFEN). A cintilografia marcada com iodo 123 com metaiodobenzilguanidina (123I-MIBG) e o teste cardiopulmonar do exercício (TCPE) são marcadores de prognóstico da ICFEN. O nebivolol é um betabloqueador com propriedade vasodilatadora. Objetivos: Avaliar o impacto da terapia com nebivolol sobre as variáveis da cintilografia com 123I-MIBG e do TCPE em pacientes com ICFEN. Métodos: Vinte e cinco pacientes realizaram cintilografia com 123I-MIBG para avaliar a taxa de washout e a relação coração/mediastino precoce e tardia. Durante o TCPE, foi analisado o comportamento da pressão arterial sistólica (PAS), frequência cardíaca (FC) durante o esforço e a recuperação (FCR) e o consumo de oxigênio (VO2). Após avaliação inicial, separamos nossa amostra em grupos controle versus intervenção, iniciamos o nebivolol e repetimos os exames após 3 meses. Resultados: Após o tratamento, o grupo intervenção apresentou melhora na PAS (149 mmHg [143,5-171 mmHg] versus 135 mmHg [125-151 mmHg, p = 0,016]), FC em repouso (78 bpm [65,5-84 bpm] versus 64,5 bpm [57,5-75,5 bpm, p = 0,028]), PAS no pico do esforço (235 mmHg [216,5-249 mmHg] versus 198 mmHg [191-220,5 mmHg], p = 0,001), FC no pico do esforço (124,5 bpm [115-142 bpm] versus 115 bpm [103,7-124 bpm], p = 0,043) e FCR no 1º minuto (6,5 bpm [4,75-12,75 bpm] versus 14,5 bpm [6,7-22 bpm], p = 0,025) e no 2º minuto (15,5 bpm [13-21,75 bpm] versus 23,5 bpm [16-31,7 bpm], p = 0,005), porém não apresentou mudança no VO2 de pico e nos parâmetros da cintilografia com 123I-MIBG. Conclusão: Apesar de um melhor controle da PAS e na FC em repouso e durante o esforço e uma melhora na FCR, o nebivolol não ocasionou efeito positivo sobre o VO2 de pico e nos parâmetros da cintilografia com 123I-MIBG. A ausência de efeito sobre a atividade adrenérgica pode ser a causa da falta de efeito sobre a capacidade funcional.

Development and in vitro permeation studies of proniosomal based transdermal delivery system of Atenolol

Proniosomes refer to a flexible vesicular carrier with the potential for drug administration through the transdermal route. A proniosome gel type transdermal delivery system of Atenolol was prepared and extensively studied both in vitro drug release and ex vivo permeation studies. The prepared formulations were evaluated for vesicle size, entrapment efficiency, in vitro drug loading, and drug release studies. The release of drug had shown considerable improvement in controlled manner from the prepared gel formulation. It was observed that Span 40 and 60 [A 8] based formulations shows vesicles of minimum size and higher entrapment efficiency compared to the other formulations. Proniosomal transdermal therapeutic system [A 8] was found to be the optimized formulation as it posses good drug release and shows permeation in a steady-state manner over a desired period of time. Also the drug diffusion across snake sheded skin, guinea pig abdomen skin, albino rat, porcine ear correlates better with in vitro drug release studies. The formulation was found to be stable when stored at room temperature and at refrigeration temperature [4 +/- 2degreeC] for 90 days.

Alteration of Left Ventricular Function with Dobutamine Challenge in Patients with Myocardial Bridge

BACKGROUND/AIMS: The aim of this study was to identify changes in left ventricular (LV) performance in patients with a myocardial bridge (MB) in the left anterior descending coronary artery during resting and in an inotropic state. METHODS: Myocardial strain measurement by speckle-tracking echocardiography and conventional LV wall-motion scoring was performed in 18 patients with MB (mean age, 48.1 +/- 1.7 years, eight female) during resting and intravenous dobutamine challenge (10 and 20 microg/kg/min). RESULTS: Conventional LV wall-motion scoring was normal in all patients during resting and in an inotropic state. Peak regional circumferential strain increased dose dependently upon dobutamine challenge. Longitudinal strains of the anterior and anteroseptal segments were, however, reduced at 20 microg/kg/min and showed a dyssynchronous pattern at 20 microg/kg/min. Although there were no significant differences in radial strain and displacement of all segments at rest compared with under 10 microg/kg/min challenge, radial strain and displacement of anterior segments at 20 microg/kg/min were significantly reduced compared with posterior segments at the papillary muscle level (44.8 +/- 14.9% vs. 78.4 +/- 20.1% and 5.3 +/- 2.3 mm vs. 8.5 +/- 1.8 mm, respectively; all p < 0.001), and showed plateau (40%) or biphasic (62%) patterns. CONCLUSIONS: Reduced LV strain of patients with MB after inotropic stimulation was identified. Speckle-tracking strain echocardiography identified a LV myocardial dyssynchrony that was not demonstrated by conventional echocardiography in patients with MB.

Dobutamine stress echocardiography for evaluating cirrhotic cardiomyopathy in liver cirrhosis / 대한간학회지

BACKGROUND/AIMS: The blunted ventricular systolic and diastolic contractile responses to physical and pharmacological stress in cirrhosis are termed cirrhotic cardiomyopathy (CCM). CCM has been known to involve multiple defects in the beta-adrenergic signaling pathway. The aim of this study was to determine whether cirrhotic patients have blunted cardiac responses to catecholamine stimulation through dobutamine stress echocardiography (DSE). METHODS: Seventy-one cirrhotic patients with normal left ventricular (LV) chamber size and ejection fraction were enrolled. The LV systolic and diastolic functions were evaluated by two-dimensional and Doppler echocardiography at rest and during peak dobutamine infusion (40 microg/kg/min). An abnormal response was defined as a decrease of less than 10% in LV end-diastolic volume, a decrease of less than 20% in end-systolic volume, and an increase of less than 10% in LV ejection fraction (EF) at peak dobutamine infusion, based on previously used criteria. The early/late diastolic flow (E/A) ratio and diastolic parameters were also measured. RESULTS: A blunted LV response to dobutamine was observed in 18 of 71 cirrhotic patients (25.4%). The baseline EF was significantly higher in 18 patients with a blunted DSE response than that of those with a normal DSE response (P<0.05). The baseline and peak E/A ratios, which are common diastolic dysfunction markers, were higher in the cirrhosis group than in the control group (P<0.001). No adverse events associated with DSE were observed. CONCLUSIONS: Blunted cardiac responses to dobutamine stimulation, which are implicated in defects in the beta-adrenergic signaling pathway, might contribute to the pathogenesis of CCM in patients with cirrhosis.