Journal of hypertension · 2001
Effect of an ET(B)-selective and a mixed ET(A/B) endothelin receptor antagonist on venomotor tone in deoxycorticosterone-salt hypertension.
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Johnson R J, Galligan J J, Fink G D
Аннотация
OBJECTIVES: Because the ET(B) receptor is important in venoconstriction, we examined the effects of a selective ET(B) receptor antagonist (A-1 92621) and a mixed ET(A/B) receptor antagonist (A-182086) on endogenous endothelin-1 (ET-1) contributions to elevated venomotor tone in deoxycorticosterone acetate-salt (DOCA-salt) hypertension.
METHODS: Changes in venomotor tone were assessed using repeated measurements of mean circulatory filling pressure (MCFP) in awake, uninephrectomized, DOCA-salt-treated rats and uninephrectomized sham rats following intravenous (i.v.) injections of the ET(B) antagonist (12 mg/kg i.v.) or the ET(A/B) antagonist (12 mg/kg i.v.) alone, or 1 h before ganglion blockade with hexamethonium (30 mg/kg i.v.).
RESULTS: DOCA-salt rats were hypertensive and exhibited higher MCFP than sham normotensive rats. The ET(A/B) receptor antagonist lowered mean arterial blood pressure (MABP) in DOCA-salt and sham rats, but MCFP fell in DOCA-salt rats only. The ET(B) antagonist produced no changes in MCFP while MABP increased in both groups. Pre-treatment of DOCA-salt rats, but not sham rats, with either antagonist produced greater declines in MCFP following hexamethonium than after hexamethonium alone.
CONCLUSIONS: The present study confirms previous findings of elevated MCFP in DOCA-salt hypertensive rats compared to normotensive rats, but is the first to show that venomotor tone is affected by the actions of endogenous ET-1 acting at ET(B) receptors to modulate sympathetic input to the veins, as well as direct actions of ET-1 on vascular smooth muscle (VSM) ET(A) receptors. We also showed that mixed ET(A/B) receptor antagonism was effective in lowering MCFP and MABP in DOCA-salt hypertensive rats.
METHODS: Changes in venomotor tone were assessed using repeated measurements of mean circulatory filling pressure (MCFP) in awake, uninephrectomized, DOCA-salt-treated rats and uninephrectomized sham rats following intravenous (i.v.) injections of the ET(B) antagonist (12 mg/kg i.v.) or the ET(A/B) antagonist (12 mg/kg i.v.) alone, or 1 h before ganglion blockade with hexamethonium (30 mg/kg i.v.).
RESULTS: DOCA-salt rats were hypertensive and exhibited higher MCFP than sham normotensive rats. The ET(A/B) receptor antagonist lowered mean arterial blood pressure (MABP) in DOCA-salt and sham rats, but MCFP fell in DOCA-salt rats only. The ET(B) antagonist produced no changes in MCFP while MABP increased in both groups. Pre-treatment of DOCA-salt rats, but not sham rats, with either antagonist produced greater declines in MCFP following hexamethonium than after hexamethonium alone.
CONCLUSIONS: The present study confirms previous findings of elevated MCFP in DOCA-salt hypertensive rats compared to normotensive rats, but is the first to show that venomotor tone is affected by the actions of endogenous ET-1 acting at ET(B) receptors to modulate sympathetic input to the veins, as well as direct actions of ET-1 on vascular smooth muscle (VSM) ET(A) receptors. We also showed that mixed ET(A/B) receptor antagonism was effective in lowering MCFP and MABP in DOCA-salt hypertensive rats.