Effect of an ET(B)-selective and a mixed ET(A/B) endothelin receptor antagonist on venomotor tone in deoxycorticosterone-salt hypertension.
OBJECTIVE
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.
Johnson
R J
RJ
Department of Pharmacology and Toxicology, Michigan State University, East Lansing 48824, USA. johns741@pilot.msu.edu
Galligan
J J
JJ
Fink
G D
GD
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003900:Desoxycorticosterone / Q000633:toxicity; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects; D018738:Hexamethonium / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000503:physiopathology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D012965:Sodium Chloride / Q000008:administration & dosage; D014666:Vasomotor System / Q000187:drug effects* / Q000503:physiopathology*
C120508:A 192621; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D018738:Hexamethonium; D003900:Desoxycorticosterone; D012965:Sodium Chloride