Key result
Mixed ET(A/B) receptor antagonism lowered mean circulatory filling pressure and mean arterial blood pressure in DOCA-salt hypertensive rats, whereas ET(B) antagonism alone did not lower MCFP.
Mixed ET(A/B) receptor antagonism effectively lowers mean circulatory filling pressure and mean arterial blood pressure in DOCA-salt hypertensive rats, demonstrating that endogenous ET-1 modulates sympathetic input to veins via ET(B) receptors.
Hypothesis-generating for mixed ET antagonism in salt-sensitive models; leaves open human translation to venous tone.
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.
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Johnson et al. (2001) studied Deoxycorticosterone acetate-salt (DOCA-salt) hypertension. ET(B) selective antagonist (A-1 92621) and mixed ET(A/B) antagonist (A-182086) vs. Sham rats / hexamethonium alone was evaluated on Changes in venomotor tone assessed using repeated measurements of mean circulatory filling pressure (MCFP). Mixed ET(A/B) receptor antagonism lowered mean circulatory filling pressure and mean arterial blood pressure in DOCA-salt hypertensive rats, whereas ET(B) antagonism alone did not lower MCFP.
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