Injection of endothelin-1 into the raphe obscurus of rats induces depressor responses predominantly through endothelin ETA receptors

We used in vitro autoradiography to identify the endothelin-1 receptor subtype(s) in the nucleus raphe obscurus of rats. These studies showed dense binding of [I-125]PD151242 (for endothelin ETA receptors), while tissues incubated with [I-125]BQ3020 (for endothelin ETB receptors) had low binding. In addition, we examined the effects of the endothelin receptor antagonists FR 139317 (endothelin ETA receptor-selective antagonist), SE 209670 (endothelin ETA/ETB receptor-non-selective antagonist) and BQ-788 (endothelin ETB receptor-selective antagonist) on the blood pressure responses following administration of endothelin-1 into the nucleus raphe obscurus. The basal mean arterial blood pressure (MABP) of the rats was 110 +/- 7 mmHg (n = 5). This was decreased in a dose-dependent manner by endothelin-1 (0.1, 1 and 10 pmol) microinjected into the nucleus raphe obscurus. This effect occurred within 1-6 s and recovered within 4 +/- 1.2 min at a dose of 10 pmol. The doses of 0.1 pmol and 1 pmol ET-1 had responses, which lasted 1 +/- 0.4 min and 2 +/- 0.2 min, respectively. Small decreases in heart rate accompanied the MAP responses to endothelin-1. For instance, the heart rate decreased by 16 +/- 4 beats min(-1) after 10 Fmol endothelin-1 (control, 366 +/- 6 beats min(-1), n = 5), Decreases in blood pressure induced by endothelin-1 were greatly reduced by pre-administration to the nucleus raphe obscurus of FR139317 (5 nmol/rat) or SB209670 (3 nmol/rat; 97 + 7% and 95 +/- 6%, P < 0.01, n = 5, respectively), but were not affected by BQ-788 (50 nmol/rat; 8 +/- 3%, P > 0.05, n = 5). The antagonists did not influence heart rate when injected to the nucleus raphe obscurus prior to endothelin-1. FR139317 (0.5 nmol) and SB209670 (0.3 nmol) had no effects on endothelin-induced changes in arterial blood pressure. Therefore, the autoradiographic study showed that there are binding sites for ET-1 within the nucleus raphe obscurus of rats, which are predominantly of ETA type. The in vivo study showed that ETA receptors are the pre-dominant mediators of depressor responses induced by endothelin-1 injected into this nucleus.