Nitric oxide and sodium nitroprusside-induced relaxation of the human umbilical artery.
In the human umbilical artery (HUA) pre-contracted with the thromboxane mimetic U46619 or with 5-hydroxytryptamine (5-HT), (and pretreated with indomethacin (3 microM) to suppress the synthesis of prostanoids), authentic nitric oxide (NO) evoked concentration-dependent relaxation (pEC(50) 7.05 and 5.99, respectively). In contrast, sodium nitroprusside (SNP) induced relaxation only in U46619 pre-contracted HUA (pEC(50) 6.52). At high (>300 mmHg) vs low (<55 mmHg) oxygen tension the dose-response curves to NO- and SNP-induced relaxations were biphasic and shifted leftward. Preincubation of the arterial rings with the soluble guanylyl cyclase (sGC) inhibitor 1H[1,2,4]oxadiazolo[4, 3-a]quinoxalin-1-one (ODQ; 10 microM) shifted the concentration-response curve to NO, reduced the maximal relaxation response to NO (E(max) 71%) and to SNP (E(max) 10%). Pre-exposure of HUA rings to high extracellular K(+) (50 mM) reduced E(max) relaxation responses to NO (36%) and SNP (1%). Pretreatment of the HUA with the K(+) channel inhibitors, tetraethylammonium (TEA, 1 mM), 4-aminopyridine (4-AP, 0.5 mM), charybdotoxin (0.1 microM) or iberiotoxin (0.1 microM) increased the pEC(30) for NO and SNP and changed the shape of the dose-response curves from biphasic to monophasic. Pre-incubation of HUA rings with TEA (1 mM), 4-AP (0.5 mM) and ODQ (10 microM) significantly reduced the NO-induced maximal relaxation (E(max) 26%) but not the pEC(50) (5.60). These data indicate that SNP-induced relaxation in the HUA is primarily mediated via sGC-cyclic GMP whereas NO-induced relaxation also involves the activation of K(V) and K(Ca) channels and a cyclic GMP/K(+) channel-independent mechanism(s).
Lovren
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F
Department of Pharmacology & Therapeutics and Smooth Muscle Research Group, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada T2N 4N1.
Triggle
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C
D015220:Calcium Channels / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006801:Humans; D066298:In Vitro Techniques; D009543:Nifedipine / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology; D010100:Oxygen / Q000502:physiology; D011188:Potassium / Q000502:physiology; D026902:Potassium Channel Blockers; D015221:Potassium Channels / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D017461:Receptors, Atrial Natriuretic Factor / Q000037:antagonists & inhibitors; D014469:Umbilical Arteries / Q000187:drug effects* / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D015220:Calcium Channels; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D011810:Quinoxalines; D014665:Vasodilator Agents; D009599:Nitroprusside; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D006152:Cyclic GMP; D009543:Nifedipine; D011188:Potassium; D010100:Oxygen