Jp. Gratton et al., ETB receptor blockade potentiates the pressor response to big endothelin-1but not big endothelin-2 in the anesthetized rabbit, HYPERTENSIO, 35(3), 2000, pp. 726-731
Citations number
17
Categorie Soggetti
Cardiovascular & Respiratory Systems","Cardiovascular & Hematology Research
The precursor of endothelin-1, big endothelin-1, is considered to be a more
reliable marker of systemic production of vasoactive peptide. However, it
is largely unclear whether ETB receptor-dependent clearance and endothelium
-derived relaxing factors affect the precursor in a similar manner to matur
e ET-1. These ETB-dependent modulations of big ET-1 and big ET-2 presser pr
operties were therefore studied in the anesthetized rabbit. When injected i
nto the left cardiac ventricle, ET-1 and ET-2 (0.01 to 1 nmol/kg) each indu
ced biphasic responses (a depressor followed by a presser response), wherea
s big ET-1 and big ET-2 (0.1 to 3 nmol/kg) caused only protracted presser r
esponses. The highest dose of big ET-1 caused significantly greater respons
es than ET-1, ET-2, or big ET-2. A selective ETA receptor antagonist, BQ-12
3 (1 mg/kg), markedly reduced presser responses to all 4 peptides, whereas
blockade of ETB receptors with BQ-788 (0.25 mg/kg) sharply potentiated the
responses to ET-1, ET-2, and big ET-1, but not to big ET-2. Indomethacin (1
0 mg/kg) sharply potentiated the presser response to ET-1 (1 nmol/kg), but
not big ET-1, at all time points. In control animals, ET-1, but not big ET-
1, also triggered an indomethacin-sensitive increase in circulating prostac
yclin. Finally, systemically administered big ET-1, but not big ET-2, induc
ed a phosphoramidon-sensitive increase in plasma IR-ET. Our results suggest
a significant limiting role of ETB receptors on presser responses to big E
T-1. In contrast, the same receptor entities do not modulate the hemodynami
c properties of the ET-2 precursor, given that, unlike big ET-1, it is poor
ly converted in the pulmonary or systemic circulation in anesthetized rabbi
ts.