Erythropoietin Produces a Dual Effect on Carotid Body Chemoreception in Male Rats

Erythropoietin (EPO) regulates respiration under conditions of normoxia and hypoxia through interaction with the respiratory centers of the brainstem. Here we investigate the dose-dependent impact of EPO in the CB response to hypoxia and hypercapnia. We show, in isolated “en bloc” carotid body (CB) preparations containing the carotid sinus nerve (CSN) from adult male Sprague Dawley rats, that EPO acts as a stimulator of CSN activity in response to hypoxia at concentrations below 0.5 IU/ml. Under hypercapnic conditions, EPO did not influence the CSN response. EPO concentrations above 0.5 IU/ml decreased the response of the CSN to both hypoxia and hypercapnia, reaching complete inhibition at 2 IU/ml. The inhibitory action of high-dose EPO on the CSN activity might result from an increase in nitric oxide (NO) production. Accordingly, CB preparations were incubated with 2 IU/ml EPO and the unspecific NO synthase inhibitor (L-NAME), or the neuronal-specific NO synthase inhibitor (7NI). Both NO inhibitors fully restored the CSN activity in response to hypoxia and hypercapnia in presence of EPO. Our results show that EPO activates the CB response to hypoxia when its concentration does not exceed the threshold at which NO inhibitors masks EPO’s action.

Peculiarities of influence of NO-synthase inhibitors on behavioral parameters of rats

Aim. A comparative study of the influence of nitric oxide synthase (NO-synthase) inhibitors on the parameters of anxiety, motor activity and pain sensitivity of rats. Materials and Methods. The work was conducted on male rats of Wistar line. The anxiety level and locomotor activity of rats were studied in the elevated plus maze (EPM) test. Pain sensitivity of the animals was tested on the hotplate apparatus. In the work, selective inhibitor of inducible isoform of NO-synthase aminoguanidine at a dose of 50 mg/kg, and non-selective inhibitor of this enzyme N-nitro-L-arginine at a dose of 50 mg/kg, were used. Rats of the control group were introduced the equivalent quantity of normal saline. NO-synthase inducible inhibitor aminoguadinine did not produce any influence on the anxiety level, but led to reduction of the horizontal motor activity of rats. Introduction of non-selective NO-synthase inhibitor N-nitro-L-arginine was accompanied by reduction of the anxiety and of the locomotor activity of animals in the EPM test. Both investigated NO-synthase inhibitors induced alteration of pain sensitivity of rats in the form of hypoalgesia. Here, the most pronounced nociceptive effect was observed with introduction of non-selective NO-synthase inhibitor. Conclusion. In the work the evidence of participation of inducible isoform of NO-synthase in realization of the motor activity and pain sensitivity processes in rats is shown. In result of the conducted experiments it was found that introduction of non-selective NO-synthase inhibitor N-nitro-L-arginine was accompanied by evident alterations of anxious behavior, locomotor activity and nociceptive sensitivity of rats. The results obtained confirm the important role of the system of regulation of nitric oxide synthesis in neurochemical mechanisms of behavioral reactions in rats.

An experimental model of gestosis in rats

Одной из ведущих проблем акушерства остается гестоз. В связи с инвазивностью и этическими проблемами использования большинства методов изучения тканей фетоплацентарного комплекса, поиск адекватных экспериментальных моделей гестоза является актуальной задачей современной фармакологии и экспериментальной терапии. Цель исследования - экспериментальное обоснование использования модели гестоза у крыс, вызванного введением ингибитора NО-синтазы Nω-нитро-L-аргинином, в доклиническом изучении потенциальных веществ для лечения и профилактики гестоза и плацентарной дисфункции. Методика. Экспериментальный гестоз вызывали введением ингибитора NО-синтазы Nω-нитро-L-аргинина в дозе 50 мг/кг с 13-го по 19-й день гестации у крыс. Результаты. Установлено, что Nω-нитро-L-аргинин вызывает гипертензию, протеинурию, повышение уровня эндотелина в сыворотке крови, нарушения гистоструктуры плаценты, матки, печени, почек, что приводит к развитию плацентарной дисфункции, почечной и печеночной неполноценности. Полиорганные изменения нарушают внутриутробное развитие плодов крыс, что проявляется задержкой их роста и развития: снижение массы тела и кранио-каудального размера. Заключение. Полученные данные соответствуют клинической и морфологической картине гестоза беременных, что позволяет использовать данную экспериментальную модель патологии при доклинических испытаниях лекарственных препаратов, предназначаемых для лечения и профилактики данного заболевания. Gestosis remains one of the main problems in obstetrics. Due to the invasiveness and unethicality of most methods for studying tissues of the fetoplacental complex, searching for adequate experimental models of gestosis is a relevant challenge of modern pharmacology. The aim of the study was to experimentally substantiate the use of Nω-nitro-L-arginine, the NO synthase inhibitor, to model gestosis in rats for pre-clinical study of candidate substances for the treatment and prevention of gestosis and placental dysfunction. Methods. Experimental gestosis was induced in rats with the NO-synthase inhibitor, Nω-nitro-L-arginine (50 mg/kg s.c., from day 13 to day 19 of gestation). Results. Nω-nitro-L-arginine induced hypertension; proteinuria; an increase in serum endothelin level; damage to the placenta, uterus, liver, and kidney, which led to placental dysfunction; and renal and hepatic impairment. The multisystemic changes impaired the fetal development, which was evident as a delay in fetus growth and maturation, weight loss, and decreased cranio-caudal size. Conclusion. The obtained results comply with the clinical and morphological picture of gestosis, which justifies using this experimental model in pre-clinical studies of the substances intended for treatment and prevention of this disease.