The effectiveness of different isomers of octanol as blockers of harmaline-induced tremor

Intracellular recording in the guinea-pig brainstem slice has demonstrated that high molecular weight alcohols block the low threshold calcium channel (LTCC) in the inferior olive (IO). These alcohols thus provide a tool for understanding the function of the pacemaking cellular networks of the olivo-cerebellar system, since the LTCC has been implicated in the oscillatory behavior of these neurons. Aspects of normal and pathological tremor are also believed to be mediated by these circuits, and thus development of effective ways of blocking the LTCC in vivo may eventually lead to novel treatments for essential tremor. The present experiments evaluated the effectiveness of the isomers of octanol in decreasing harmaline-induced tremor in vivo in the rat. Harmaline was used in this study because its tremorgenic action is mediated at the level of IO; octanol was found to be a potent antagonist of harmaline-induced tremor. Significant differences between the isomers further suggested conformational differences. This, taken in conjunction with the lack of effect of octanol in both IO lesioned rats and oxotremorine-induced tremor, implied that the action of the alcohol may be mediated at a specific binding site. These findings thus support the conclusions that the antagonism of harmaline-induced tremor by octanol occurs in the IO, and, in view of the previously reported in vitro data, that octanol may be an effective blocker of the LTCC in vivo.     

Ginseng–Aconite Decoction elicits a positive inotropic effect via the reverse mode Na/Ca exchanger in beating rabbit atria

Ethnopharmacological relevance

Ginseng–Aconite Decoction (GAD), a traditional oriental medicine composed of Panax ginseng C.A. Mey. (Araliaceae) and Aconitum carmichaeli Debx. (Ranunculaceae) has been used as treatment for cardiovascular diseases from Song Dynasty of China. The purpose of the present study was to elucidate the possible mechanisms of GAD-induced positive inotropic effect.

Material and methods

GAD-induced changes in atrial dynamics and cAMP efflux were determined in isolated perfused beating rabbit atria.

Results

GAD significantly increased atrial dynamics such as stroke volume, pulse pressure and augmented cAMP efflux in beating rabbit atria. The inotropic effect was significantly attenuated by pre-treatment with KB-R7943, a reverse mode Na⁺/Ca²⁺ exchanger blocker. The GAD-induced increase in atrial dynamics was also markedly inhibited by staurosporine, a non-selective protein kinase inhibitor, and partly blocked by KT5720, a selective PKA inhibitor. The effect of GAD on atrial dynamics was not altered by pre-treatment with propranolol, a β-adrenergic receptor inhibitor, or diltiazem, an L-type Ca²⁺channel blocker. The phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine (IBMX) failed to modulate the GAD-induced increase in atrial dynamics, but markedly attenuated cAMP efflux in the beating atria.

Conclusion

These results suggest that the GAD-induced positive inotropic effect in beating rabbit atria may be attributable to stimulation of the reverse mode Na⁺/Ca²⁺ exchanger, while PKA activity would, at least in part, be participated in the course.     

朝医葛根浮萍汤及其拆方对心脏正性肌力及心房钠尿肽分泌的影响

目的：研究朝医葛根浮萍汤及其拆方（葛根、浮萍、大黄）对家兔心肌正性肌力及心房钠尿肽（atrial natriuretic peptide,ANP）分泌的影响.方法：采用离体搏动心房灌流模型来观察葛根浮萍汤及其所含药物对心房正性肌力及ANP分泌的变化.结果：葛根浮萍汤增强心房每回搏输出量（stroke volume,SV）和心房搏动压（pulse pressure,PP）,并明显抑制ANP分泌量;浮萍和大黄可不同程度地增强SV和PP,并抑制ANP分泌;葛根则不改变心肌正性肌力和ANP分泌;阻断L-型Ca2＋型通道（L-type Ca2＋channel,LTCC）可抑制葛根浮萍汤、浮萍及大黄对心肌正性肌力的增强作用,而预处理-肾上腺素受体（adrenergic receptor,AR）阻断剂则不会影响它们对心肌正性肌力及ANP分泌的变化.结论：葛根浮萍汤及其所含的浮萍、大黄均具有增强心肌正性肌力及抑制ANP分泌的作用,其作用主要可能与调节心肌细胞膜上的LTCC功能有关.     

2019 HRS expert consensus statement on evaluation,risk stratification,and management of arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy (ACM) is an arrhythmogenic disorder of the myocardium not secondary to ischemic, hypertensive, or valvular heart disease. ACM incorporates a broad spectrum of genetic, systemic, infectious, and inflammatory disorders. This designation includes, but is not limited to, arrhythmogenic right/left ventricular cardiomyopathy, cardiac amyloidosis, sarcoidosis, Chagas disease, and left ventricular noncompaction. The ACM phenotype overlaps with other cardiomyopathies, particularly dilated cardiomyopathy with arrhythmia presentation that may be associated with ventricular dilatation and/or impaired systolic function. This expert consensus statement provides the clinician with guidance on evaluation and management of ACM and includes clinically relevant information on genetics and disease mechanisms. PICO questions were utilized to evaluate contemporary evidence and provide clinical guidance related to exercise in arrhythmogenic right ventricular cardiomyopathy. Recommendations were developed and approved by an expert writing group, after a systematic literature search with evidence tables, and discussion of their own clinical experience, to present the current knowledge in the field. Each recommendation is presented using the Class of Recommendation and Level of Evidence system formulated by the American College of Cardiology and the American Heart Association and is accompanied by references and explanatory text to provide essential context. The ongoing recognition of the genetic basis of ACM provides the opportunity to examine the diverse triggers and potential common pathway for the development of disease and arrhythmia.     

K2O对Li2O-SiO2系微晶玻璃低温共烧陶瓷的影响

采用烧结法制备了Li2O SiO2系微晶玻璃低温共烧陶瓷。通过热膨胀系数、DTA、XRD、影像式烧结点试验仪、SEM、体积电阻率等方法,研究了K2O含量对玻璃热力学性质、析晶行为、烧结性能、形貌和电学性能的影响。结果表明：用K2O取代Li2O,可降低玻璃转变温度,减弱析晶倾向,提高热膨胀系数和析晶活化能;K2O有助于玻璃粉体烧结致密,可以控制微晶玻璃晶相组成和含量。电学性能研究结果表明,K2O可显著提高微晶玻璃的电学性能。     

Voltage-gated calcium channels in the etiopathogenesis and treatment of absence epilepsy

Voltage-gated calcium channels are key elements in regulating neuronal excitability and are thus of central importance in the pathogenesis of various forms of epilepsies. Among these, absence epilepsies represent about 10% of epileptic seizures in humans. They are electroencephalographically characterized by bilateral synchronous spike-wave discharge activity associated with loss or severe impairment of consciousness. Extensive studies during the last decades revealed that pathophysiologically increased oscillatory activity, i.e., hyperoscillation within the reticulothalamocortical circuitry, is the electrophysiological correlate of absence epilepsy, with extrathalamocortical structures, e.g., brainstem and cerebellum, projecting to the thalamocortical circuitry, thereby modulating its activity. Voltage-gated calcium channels are one of the central players regulating the transition from tonic to rebound burst-firing modes in both thalamic relay and reticular thalamic nucleus neurons, the burst-firing mode being the substrate of the thalamocortical oscillation. Thus, pharmacological interference with these channels enables effective control of spike-wave discharge activity in patients suffering from absence seizures. In this review, we summarize the medical history of absence epilepsies, their classification and terminology, the diagnostic armamentarium available today and the etiopathogenesis of absences. Finally, various antiepileptic drugs that have been proven to or are supposed to exert anti-absence effects are discussed with respect to their pharmacodynamics and pharmacokinetics.     

石菖蒲远志散对家兔心房正性肌力作用的机制研究

目的：观察朝医石菖蒲远志散对家兔心房正性肌力的作用机制。方法：采用家兔离体搏动心房灌流模型,处理不同剂量的石菖蒲远志散（0．1,0．3,1g·L^－1）,观察对家兔心房正性肌力的变化,并选择最佳剂量探讨其作用机制。实验指标中环磷酸腺苷（3,5-cyclicadenosine monophosphat,cAMP）含量的测定采用放射性免疫法。结果：不同剂量的石菖蒲远志散可使离体家兔心房每搏输出量（strokevolume）、心房搏动压（pulsepressure）及灌流液中cAMP流出量比给药前呈现浓度依赖性递增趋势。阻断β-肾上腺素受体（adren-ergicreceptor,AR）或LTCC（L-typeCa^2＋channel,LTCC）均可抑制石菖蒲远志散对心房正性肌力的增强作用。结论：石菖蒲远志散主要通过影响B-AR-cAMP-LTCC信号传导途径增强心房正性肌力。