Endothelin alters the reactivity of vasa vasorum: mechanisms and implications for conduit vessel physiology and pathophysiology.
1 The walls of certain large blood vessels are nourished by the vasa vasorum, a network of microvessels that penetrate the adventitia and media of the vessel wall. The purpose of this study was to characterize endothelin-1 (ET-1)-mediated contraction of vasa and to investigate whether threshold concentrations of ET-1 alters the sensitivity to constrictors. Arterial vasa were dissected from the walls of porcine thoracic aorta and mounted in a tension myograph. 2 ET-1 and ETB-selective agonist, sarafotoxin 6c (S6c), produced concentration-dependent contraction. ETA receptor antagonist, BQ123 (10 microM), caused a biphasic rightward shift of ET-1 response curves. ETB receptor antagonist, BQ788 (1 microM), produced a rightward shift of response curves to ET-1 and S6c of 5- and 80 fold respectively. 3 ET-1 responses were abolished in Ca2+-free PSS but unaffected by selective depletion of intracellular Ca2+ stores. Nifedipine (10 microM), an L-type Ca2+ channel blocker, attenuated ET-1 responses by 44%. Inhibition of receptor-operated Ca2+ channels or non-selective cation entry using SKF 96365 (30 microM) and Ni2+ (1 mM) respectively, attenuated ET-1 contractions by 60%. 4 ET-1 (1-3 nM) enhanced responses to noradrenaline (NA) (4 fold) but not to thromboxane A2-mimetic, whilst K+ (10-20 mM) sensitized vasa to both types of constrictor. 5 Therefore, ET-1-induced contraction of isolated vasa is mediated by ETA and ETB receptors and involves Ca2+ influx through L-type and non-L-type Ca2+ channels. Furthermore elevation of basal tone of vasa vasorum alters the profile of contractile reactivity. These results suggest that ET-1 may be an important regulator of vasa vasorum reactivity.
Scotland
R
R
Centre for Clinical Pharmacology, University College London, Rayne Institute, 5 University St, London, WC1E 6JJ. r.scotland@ucl.ac.uk
Vallance
P
P
Ahluwalia
A
A
D000818:Animals; D002118:Calcium / Q000494:pharmacology; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D019332:Endothelin-1 / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D009532:Nickel / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D013552:Swine; D014651:Vasa Vasorum / Q000187:drug effects* / Q000502:physiology / Q000503:physiopathology; D014661:Vasoconstriction / Q000187:drug effects
D019332:Endothelin-1; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007211:Indoles; D009842:Oligopeptides; D010880:Piperidines; D011450:Prostaglandin Endoperoxides, Synthetic; C086539:BQ 788; C028429:U 44069; D009532:Nickel; D000252:Calcium-Transporting ATPases; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; D011188:Potassium; D002118:Calcium; D009638:Norepinephrine; C000543:cyclopiazonic acid