Effect of K+ channel blocking drugs and nitric oxide synthase inhibition on the response to hypoxia in rat pulmonary artery rings.
1. The aims of this study were to investigate the effects of potassium (K+) channel blockers and the nitric oxide (NO) synthase inhibitor, L-nitroarginine (L-NOARG), on the response produced by acute hypoxia in rat intrapulmonary artery rings in vitro. 2. In rat phenylephrine-precontracted pulmonary artery rings, hypoxia (pO2 = 7 mmHg) induced a response which consisted of a rapidly developing initial contraction (phase 1), a transient relaxation (phase 2) and a slowly developing sustained contraction (phase 3) over 30 min. The NOS inhibitor, L-NOARG (300 microM), attenuated phase 1 and 3, and amplified phase 2 of the response to hypoxia. The voltage-gated K+ channel blocker 4-aminopyridine (4-AP) (10 mM) also abolished phase 3 and magnified phase 2 of the response to hypoxia. 3. The hypoxic response was not modified by the calcium-activated K+ channel (KCa) blockers, tetraethylammonium (TEA) (20 mM) or charybdotoxin (50 or 200 nM), nor by the ATP-dependent K+ channel (KATP), blocker, glibenclamide (10 microM). 4. L-NOARG (300 microM) and 4-AP (10 mM) also abolished carbachol-induced endothelium-dependent NO-mediated relaxation. Relaxation produced by the NO releasing agent 3-morpholino sydnonimine (SIN-1) was reduced by 4-AP (10 mM) and TEA (20 mM). 5. The data suggest that NO production is reduced during severe hypoxia in rat intrapulmonary artery rings and that this underlies the sustained phase of the hypoxic contraction. The data also suggests that 4-AP-sensitive K+ channels play an important role in the release and or action of NO, and therefore, in the response to hypoxia.
Karamsetty
M R
MR
Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, UK.
Wadsworth
R M
RM
Kane
K A
KA
D000818:Animals; D015687:Cell Hypoxia; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D000860:Hypoxia; D066298:In Vitro Techniques; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D019335:Nitroarginine / Q000494:pharmacology*; D010100:Oxygen / Q000378:metabolism*; D026902:Potassium Channel Blockers; D011651:Pulmonary Artery; D051381:Rats; D017207:Rats, Sprague-Dawley; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
D004791:Enzyme Inhibitors; D026902:Potassium Channel Blockers; D019335:Nitroarginine; D009569:Nitric Oxide; C002385:linsidomine; D008981:Molsidomine; D019001:Nitric Oxide Synthase; D010100:Oxygen