Endothelin-1-induced venous contraction is maintained in DOCA-salt hypertension; studies with receptor agonists.
1. Deoxycorticosterone acetate (DOCA) salt hypertension is associated with an endothelin-1 (ET-1)-dependent increase in arterial resistance and mean circulatory filling pressure. Contraction of endothelium-intact arteries and veins from sham and DOCA-salt hypertensive rats to agonists of the ET(A) (ET-1((1-31))) and ET(B) receptor (sarafotoxin 6c; S6c) was investigated in tissue baths as was expression of mRNA for ET-1 and mRNA and protein for the ET(A) and ET(B) receptor. 2. ET-1((1-31)) contracted aorta and vena cava from sham rats with a 30 fold lower potency than ET-1. Contraction was not altered by the ET(B) receptor antagonist BQ788 (100 nM) but was abolished by the ET(A) receptor antagonist ABT-627 (30 nM). 3. In DOCA-salt thoracic aorta, maximum contraction to ET-1 and ET-1((1-31)) was reduced (36.6 +/- 6.3 and 13.3 +/- 4.4% of sham response, respectively); aorta did not contract to S6c. 4. In vena cava from DOCA-salt rats, contraction to ET-1 and ET-1((1-31)) was not reduced compared to sham contraction; vena cava from sham and DOCA-salt rats contracted to S6c with a similar potency. 5. Real time RT-PCR revealed that prepro ET-1 mRNA was increased 6.6 +/- 3.3 fold and 8.7 +/- 3.9 fold greater in DOCA-salt aorta and vena cava, respectively, compared to sham. Vena cava expressed a higher content of ET(A) and ET(B) receptor mRNA than aorta (P < 0.05), but no differences were observed between sham and DOCA-salt tissues. ET(A) and ET(B) receptor protein was identified in all tissues. Immunoreactive ET(A) receptor, observed as a 65, 30 and 28 kDa bands, was expressed 400% greater in DOCA-salt aorta compared to sham, but was not altered in vena cava. Immunoreactive ET(B) receptor, observed as 120, 45 and 30 kDa bands, tended to be higher in vena cava compared to aorta, but was not different in sham and DOCA-salt vena cava. 6. These results suggest that ET(A) receptor function is impaired in aorta but not vena cava of DOCA-salt rats. The ET(B) receptor was present in the aorta but, unlike in veins, does not mediate contraction directly. A sustained response to ET-1 in the venous circulation may contribute to the elevated blood pressure in the DOCA-salt model.
Watts
Stephanie W
SW
Department of Pharmacology and Toxicology, Michigan State University, East Lansing, Michigan 48824-1317, USA. wattss@msu.edu
Fink
Gregory D
GD
Northcott
Carrie A
CA
Galligan
James J
JJ
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D015153:Blotting, Western; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000378:metabolism / Q000494:pharmacology*; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012965:Sodium Chloride; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014666:Vasomotor System / Q000187:drug effects / Q000502:physiology*; D014680:Veins / Q000187:drug effects / Q000502:physiology; D014683:Vena Cava, Superior / Q000187:drug effects / Q000502:physiology
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D012965:Sodium Chloride