Physiological antagonism of endothelin-1 in human conductance and resistance coronary artery.
The ability of four endogenous vasodilators, nitric oxide (NO; 0.01 - 30 microM), atrial (ANP), brain (BNP) and C-type (CNP) natriuretic peptide (0.1 - 300 nM), to reverse endothelin-1 (ET-1; 10 nM) constrictions in human resistance and conductance coronary arteries (CA) in vitro was investigated. ET-1 (0.1 - 300 nM) constricted resistance CA more potently than conductance CA (P<0.05; EC(50) values 2.98 nM (95% CI: 1.49 - 5.95 nM and 8.58 (4.72 - 15.6 nM) respectively)). The NO-donor diethylamine NONOate fully reversed the ET-1 constriction in conductance CA (E(MAX) 127+/-9.16%), however only partial reversal was observed in resistance CA (E(MAX) 78.8+/-8.13; P<0.05). The soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (100 microM) reduced the maximum response to diethylamine NONOate to 76.9+/-14.4% in conductance CA (P<0.05), but had no effect on resistance CA (E(MAX) 77.2+/-18.4%). There was no difference between responses to ANP in conductance and resistance CA (EC(50) values 4.25 nM (0.84 - 21.4 nM) and 18.4 nM (2.92 - 116 nM), E(MAX) 53.1+/-14.7% and 48.6+/-11.8% respectively). BNP was a more potent vasodilator of conductance than resistance CA. In conductance CA the mean EC(50) value was 2.4 nM (0.74 - 7.75 nM), E(MAX) 54.5+/-14.9%. Concentration-response curves to BNP were incomplete in resistance CA. Concentration-response curves to CNP were incomplete in both conductance and resistance CA. The greater potency of ET-1 in resistance vessels may exacerbate the effects of increased circulating levels of the peptide in disease. Only NO could fully reverse ET-1 mediated constrictions in conductance CA, and none of the dilators tested could completely counteract constrictions in resistance CA.
Wiley
K E
KE
Clinical Pharmacology Unit, University of Cambridge, Level 6, Centre for Clinical Investigation, Box 110, Addenbrooke's Hospital, Cambridge, CB2 2QQ. kew29@hermes.cam.ac.uk
Davenport
A P
AP
D000293:Adolescent; D000328:Adult; D009320:Atrial Natriuretic Factor / Q000502:physiology; D002648:Child; D003331:Coronary Vessels / Q000502:physiology*; D004336:Drug Antagonism; D019332:Endothelin-1 / Q000502:physiology*; D005260:Female; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000502:physiology; D020098:Natriuretic Peptide, C-Type / Q000502:physiology; D009569:Nitric Oxide / Q000502:physiology; D014661:Vasoconstriction / Q000502:physiology*; D014664:Vasodilation / Q000502:physiology*
D019332:Endothelin-1; D020097:Natriuretic Peptide, Brain; D020098:Natriuretic Peptide, C-Type; D009569:Nitric Oxide; D009320:Atrial Natriuretic Factor; D006162:Guanylate Cyclase