Orexins are hypothalamic peptides that play an important role in maintaining wakefulness in mammals. Permanent deficit in orexinergic function is a pathophysiological hallmark of rodent, canine and human narcolepsy. Here we report that in rats, dogs and humans, somnolence is induced by pharmacological blockade of both orexin OX(1) and OX(2) receptors. When administered orally during the active period of the circadian cycle, a dual antagonist increased, in rats, electrophysiological indices of both non-REM and, particularly, REM sleep, in contrast to GABA(A) receptor modulators; in dogs, it caused somnolence and increased surrogate markers of REM sleep; and in humans, it caused subjective and objective electrophysiological signs of sleep. No signs of cataplexy were observed, in contrast to the rodent, dog or human narcolepsy syndromes. These results open new perspectives for investigating the role of endogenous orexins in sleep-wake regulation.
Endothelin has been described as the most potent vasoconstrictor known. Recent research shows that it is also a growth factor, a promoter of fibrosis and inflammation, and a key initiator of endothelial dysfunction. Endothelin becomes, therefore, a candidate in the pathogenesis of many chronic cardiovascular and fibrotic diseases, and inhibition of endothelin function is a potential therapeutic approach for those diseases. Endothelin receptor antagonists are now established therapy in the treatment of pulmonary arterial hypertension, and present promising perspectives in diabetic nephropathy, peripheral arterial disease, hypertension, heart failure, and pulmonary diseases. Endothelin binds to two endothelin receptors, ET A and ET B , and their respective roles are actively debated. A major challenge lies in the understanding of what is the preferred profile for new drugs: selective ET A antagonism or dual ET A and ET B receptor antagonism. A number of cardiovascular diseases are characterized by an up-regulation of smooth muscle cell ET B receptors mediating vasoconstriction and proliferation, and a down-regulation of endothelial ET B receptors, as compared to the physiological state, creating a situation where both ET A and ET B receptors contribute to vasoconstriction and remodeling. When these two receptor subtypes co-exist, a cross-talk between them, probably a result of receptor heterodimerization, suggests that dual ET A /ET B receptor antagonism may be necessary to obtain maximal efficacy. Drug Dev. Res. 67:825-834, 2006.
Brisbare-Roch et al. reply:We agree with Tafti that animal and human orexin deficiency syndromes suggest a theoretical risk of cataplexy following administration of an orexin receptor antagonist. Our study involved healthy rodent, canine and human subjects, in whom a dual OX 1 /OX 2 receptor antagonist that crosses the blood-brain barrier elicited somnolence and sleep, but not cataplexy, when administered as a single oral dose during the active period of the circadian cycle 1 . The absence of cataplexy in all three species was in contrast to the narcolepsy-cataplexy syndromes commonly observed in rodents, canines and humans. Thus it appears that the impact of acute and transient pharmacological antagonism of OX 1 and OX 2 receptors differs from that of a chronic and life-long deactivation induced by genetic or acquired orexin peptide or orexin receptor deficits. Our observations confirm those from other studies, and suggest that somnolence and cataplexy might be separable phenomena and that orexin deficit per se is not sufficient to cause cataplexy. Some narcoleptic patients do not develop cataplexy despite low CSF orexins 2,3 , and loss of hypothalamic factors besides orexins, such as neuronal activity-regulated pentraxin (Narp), dynorphin and glutamate, possibly contributes to the narcolepsy syndrome 4-6 . Many additional variables may have contributed to the occurrence of somnolence without cataplexy that we observed: the dosage, the degree of receptor antagonism, the relative inhibition at OX 1 and OX 2 receptors, and the duration of orexin receptor blockade.Concerning our experimental approaches, we are of the opinion that the methods described in our article, in particular for assessing the presence of cataplexy, fully allow the conclusions drawn. We also do not consider it critically important to demonstrate that our drug blocks the effects of exogenously administered orexins. Such experiments serve only to recapitulate agonist-antagonist interactions already demonstrated in vitro. Our goal, rather, was to assess the impact of our compound on endogenous orexins and the maintenance of wakefulness.Tafti states that ACT-078573 treatment of rats primarily decreased their locomotor activity during wakefulness, rather than inducing
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