Endothelin B receptors located on the endothelium provide cardiovascular protection in the hamster

Endothelins (ETs) act through two receptors, namely ET_A and ET_B. In the cardiovascular system, the activation of both receptors leads to vasoconstriction. However, ET_B receptors also mediate endothelium-dependent vasodilatation and clearance of plasma ET-1. With regard to these latter properties, we wanted to assess the contribution of ET_B receptors and the effects of selective and mixed ET receptor blockade on vascular tone in control Syrian Golden hamsters and in Bio 14.6 cardiomyopathic hamsters after bolus injection of ET-1 and IRL-1620, a selective ET_B agonist. In 12-week-old anaesthetized control hamsters, ET-1 (0.5nmol/kg) induced a sustained pressor response which was only partly reduced by the selective ET_A receptor antagonist BQ-123, suggesting a contribution of ET_B receptor activation to the vasoconstrictive effects of ET-1. This was confirmed by injection of the selective ET_B receptor agonist IRL-1620 (1 nmol/kg). However, the pressor response to this agonist was always preceded by a transient vasodilatation, indicating activation of endothelium-located ET_B receptors. When the selective ET_B receptor antagonist BQ-788 was administered, the hypotensive phase following IRL-1620 injection was abolished. Interestingly, BQ-788 or a mixture of BQ-788 and BQ-123 significantly potentiated the pressor responses to ET-1. In 12-week-old Bio 14.6 cardiomyopathic hamsters, ET-1 and IRL-1620 induced haemodynamic responses similar to those observed in control hamsters, although the IRL-1620-induced pressor increase was lower. No difference in cardiac prepro ET-1 mRNA expression was observed between the two strains of hamsters. In conclusion, we suggest that endothelium-located ET_B receptors are involved in the physiological antagonism of ET-dependent protracted pressor effects, and thus may play a protective role in both normal hamsters and those with cardiomyopathy.