Studies have shown that endothelial cells damaged by SAH
Studies have shown that endothelial cells damaged by SAH can release a large amount of ET-1, thus its plasma level is elevated and is positively correlated with the symptoms of SAH (Lei et al., 2015, Masaoka et al., 1989). Our data obtained from SAH-along rabbits were consistent with these findings. In contrast, a significant increase in plasma ET-1 level on day 1 and day 4 was also observed in SAH rabbits that were intracisternally administrated with BQ-123. Although the plasma ET-1 levels were significantly elevated, the microcirculatory perfusion appeared to be intact as indicated by increased CBF and shortened MTT. This finding indicates that blockage of ET-1 receptors with BQ-123 could not prevent the production of ET-1 but its biological action via ET-1 receptors was mitigated, as a result, elevated ET-1 in the circulation was no longer be able to cause vasoconstriction. Studies by Faraco et al. (2013) showed that circulating ET1 does not alter resting CBF. Only when the blood–brain barrier is impaired, the cerebrovascular function could be affected by elevated ET-1 levels. In our study, there was a gradual increase in ET-1 content in the first 4 days in SAH rabbit treated with BQ-123, but such an elevation of ET-1 appeared to be a short-lived and a significant decline to the baseline level was usually achieved around the seventh day post-SAH. Clearly, a pharmacokinetic profile of BQ-123 in animal mode of SAH needs to be investigated further.
From day 4 to day 10 after SAH, patients have an increased risk of developing delayed cerebral ischemia (DCI), which may be manifested as headache, confusion, focal neurological deficit, and worsening levels of consciousness (Hijdra et al., 1986, Roos et al., 2000). In our study, CTP parameters (MTT CBF) reflected microcirculatory hypoperfusion on days 4 and 7 after SAH, and neurological symptoms showed significant deterioration, consistent with the onset of DCI in humans (Hijdra et al., 1986, Roos et al., 2000). Although hydroxylase perfusion was significantly improved after BQ-123 intervention as determined by the performance of CTP parameters, improvement of neurological symptoms appeared to be limited. This suggests that endothelin receptor antagonists can improve brain microcirculation after SAH, but has a limited effect on DCI. In their studies, Kramer and Fletcher, 2009, Laban et al., 2015 independently showed that endothelin antagonists can reduce cerebral vasospasm. Hence, it may not improve the prognosis. On the other hand. This suggests that DCI is associated with poor prognosis, but the occurrence of DCI cannot be completely attributed to microcirculatory disorders caused by vasospasm. Recently, several experiments to clarify the pathogenesis of DCI have shown that the deterioration of neurological symptoms and poor prognosis after SAH are closely related to the mechanisms of cortical spreading depression, thromboembolism and impaired brain autoregulation (Ohkuma et al., 2000, Dreier et al., 2006, Vergouwen et al., 2012); in addition to microcirculatory dysfunction. It has also been suggested in a study that the side effects of endothelin antagonists such as the hypotension and pulmonary complications could potentially counterbalance the beneficial effects of reducing vasospasm (Macdonald, 2012). Some methods of reducing the side effects of ET antagonists may be the key to the future of these drugs.
Materials and methods
Introduction G protein-coupled receptors (GPCRs) comprise a diverse family of seven transmembrane domain-containing receptors represented by over 800 genes in humans. GPCRs respond to a range of stimuli, including peptides, hormones, growth factors, lipids, odorants, and light . Upon ligand binding, GPCRs activate heterotrimeric G proteins, consisting of an α, β, and γ subunits, which subsequently activate downstream effectors and signalling cascades. Cardiovascular tissues (heart, aorta and smooth muscle) express more than 150 GPCRs , but in many cases their signalling and physiological roles remain incompletely understood.