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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.

The interest of researchers for ligands of the endothelin receptors ET A and ET B is due to their extensive therapeutic potential. In particular, receptor antagonists are useful in a number of diseases such as pulmonary hypertension, acute myocardial infarction, congestive heart failure, renal failure, and atherosclerosis. In the context of our research program aimed to the development of new endothelin receptor ligands, in this paper we describe the synthesis and structure- activity relationships of a new series of 1,3,5-substituted pyrrole-2-carboxylic acid derivatives 27-40 possessing the structural features for ET receptors binding. New synthesized compounds were tested on ET A and ET B receptors stably expressed in CHO cells and some of them showed interesting affinity and selectivity towards ET A receptors.