Search

The period around birth is a risky time for stroke in infants, which is associated with two major acute and subacute processes: anatomical damage and seizures. It is unclear as to what extent each of these processes independently contributes to poor outcome. Furthermore, it is unclear whether there is an interaction between the two processes — does seizure activity cause additional brain damage beyond that produced by ischemia and/or does brain damage foster seizures? The model of focal cerebral ischemia induced by the intrahippocampal infusion of endothelin-1 (ET-1) in 12-day-old rat was used to examine the role of the endothelin receptors in the development of focal ischemia, symptomatic acute seizures and neurodegeneration. ET-1 (40 pmol/μl) was infused either alone or co-administered with selective antagonists of ETA (BQ123; 70 nmol/μl) or ETB receptors (BQ788; 70 nmol/1 μl). Effects of activation of ETB receptors were studied using selective agonist 4-Ala-ET-1 (40 pmol/1 μl). Regional cerebral blood flow (rCBF) and tissue oxygenation (pO2) were measured in anesthetized animals with a Doppler-flowmeter and a pO2-sensor, respectively. Seizure development was assessed with video-EEG in freely moving rats. Controls received the corresponding volume of the appropriate vehicle (10 mM PBS or 0.01% DMSO–PBS solution; pH 7.4). The extent of hippocampal lesion was determined using FluoroJade B staining performed 24 h after ET-1 infusion. Infusion of ET-1 or ET-1+ETB receptor antagonist reduced rCBF to ~ 25% and pO2 to ~ 10% for about 1.5 h, whereas selective ETB agonist, ET-1+ETA antagonist and the PBS vehicle had only negligible effect on the rCBF and pO2 levels. Reduction of rCBF was associated with the development of lesion in the injected hippocampus. In all groups, except sham operated and PBS controls, epileptiform activity was observed after activation of the ETA or the ETB receptors. The data revealed a positive correlation between the severity of morphological damage and all the measured seizure parameters (seizure frequency, average and total seizure duration) in the ET-1 group. In addition, the severity of morphological damage positively correlated with the average seizure duration in animals after infusion of ET-1+ETA receptor antagonist or after infusion of ET-1+ETB receptor antagonist. Our results indicate that the activation of ETA receptors is crucial for ischemia development, however either ETA or ETB receptors mediate the development of seizures following the application of ET-1 in immature rats. The dissociation between the ischemic-producing and seizure-producing processes suggests that damage is not necessary to induce seizures, although it may exacerbate them.

When endothelin-1(ET-1) was discovered it was hailed as the prototypical endothelium-derived contracting factor (EDCF). However, over the years little evidence emerged convincingly demonstrating that the peptide actually contributes to moment-to-moment changes in vascular tone elicited by endothelial cells. This has been attributed to the profound inhibitory effect of nitric oxide (NO) on both the production (by the endothelium) and the action (on vascular smooth muscle) of ET-1. Hence, the peptide is likely to initiate acute changes in vascular diameter only under extreme conditions of endothelial dysfunction when the NO bioavailability is considerably reduced if not absent. The present essay discusses whether or not this concept should be revised, in particular in view of the potent inhibitory effect exerted by calcitonin gene related peptide (CGRP) released from sensorimotor nerves on vasoconstrictor responses to ET-1.

Chronic kidney disease (CKD) is a life-threatening disease arising as a frequent consequence of diabetes and hypertension. Since it is silent for a long time, it often progresses to end-stage renal disease (ESRD). Managing chronic kidney disease, the prevalence of which is sharply increasing in the last decades due to the ageing of the world population, is thus major health problem. Apart from blockers of renin-angiotensin system, which are used as the "golden standard" in the treatment of CKD due to their antihypertensive and renoprotective effects, other strategies are also applied for the management of this disease. A relatively new class of therapeutics - blockers of endothelin system - seems to be very promising in this field.