Effect of an ETB-selective and a mixed ETA/B endothelin receptor antagonist on venomotor tone in deoxycorticosterone–salt hypertension


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Abstract

ObjectivesBecause the ETB receptor is important in venoconstriction, we examined the effects of a selective ETB receptor antagonist (A-192621) and a mixed ETA/B receptor antagonist (A-182086) on endogenous endothelin-1 (ET-1) contributions to elevated venomotor tone in deoxycorticosterone acetate–salt (DOCA-salt) hypertension.MethodsChanges 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 ETB antagonist (12 mg/kg i.v.) or the ETA/B antagonist (12 mg/kg i.v.) alone, or 1 h before ganglion blockade with hexamethonium (30 mg/kg i.v.).ResultsDOCA-salt rats were hypertensive and exhibited higher MCFP than sham normotensive rats. The ETA/B receptor antagonist lowered mean arterial blood pressure (MABP) in DOCA-salt and sham rats, but MCFP fell in DOCA-salt rats only. The ETB 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.ConclusionsThe 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 ETB receptors to modulate sympathetic input to the veins, as well as direct actions of ET-1 on vascular smooth muscle (VSM) ETA receptors. We also showed that mixed ETA/B receptor antagonism was effective in lowering MCFP and MABP in DOCA-salt hypertensive rats.

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