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

Objectives Because the ETB receptor is important in venoconstriction, we ex amined 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-s alt (DOCA-salt) hypertension. Methods Changes in venomotor tone were assessed using repeated measurements of mean circulatory filling pressure (MCFP) in awake, uninephrectomized, D OCA-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 antag onist (12 mg/kg i.v.) alone, or 1 h before ganglion blockade with hexametho nium (30 mg/kg i.v.). Results DOCA-salt rats were hypertensive and exhibited higher MCFP than sha m normotensive rats. The ETA/B receptor antagonist lowered mean arterial bl ood 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 increa sed in both groups. Pre-treatment of DOCA-salt rats, but not sham rats, wit h either antagonist produced greater declines in MCFP following hexamethoni um than after hexamethonium alone. Conclusions The present study confirms previous findings of elevated MCFP i n DOCA-salt hypertensive rats compared to normotensive rats, but is the fir st 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 we ll 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 lower ing MCFP and MABP in DOCA-salt hypertensive rats. J Hypertens 19:431-440 (C ) 2001 Lippincott Williams & Wilkins.