title: Carbon monoxide inhibits hypoxic pulmonary vasoconstriction in rats by a cGMP-independent mechanism.
abstract: Hypoxia activates erythropoietin-producing cells, chemoreceptor cells of the carotid body and pulmonary artery smooth muscle cells (PSMC) with a comparable arterial PO2 threshold of some 70 mmHg. The inhibition by CO of the hypoxic responses in the two former cell types has led to the proposal that a haemoprotein is involved in the detection of the PO2 levels. Here, we report the effect of CO on the hypoxic pulmonary vasoconstriction (HPV). Pulmonary arterial pressure (PAP) was measured in an in situ, blood-perfused lung preparation. PAP in normoxia (20% O2, 5% CO2) was 15.2+/-1.8 mmHg, and hypoxia (2% O2, 5% CO2) produced a DeltaPAP of 6.3+/-0.4 mmHg. Addition of 8% or 15% CO to the hypoxic gas mixture reduced the DeltaPAP by 88.3+/-2.7% and 78.2+/-6.1% respectively. The same levels of CO did not affect normoxic PAP nor reduced the DeltaPAP produced by angiotensin II. The effect of CO was studied after inhibition of the NO-cyclic guanosine monophosphate (cGMP) cascade with N-methyl-l-arginine (5.10(-5) M) or methylene blue (1.4.10(-4) M). It was found that both inhibitors more than doubled the hypoxic DeltaPAP without altering the effectiveness of CO to inhibit the HPV. In in vitro experiments we verified the inhibition of guanylate cyclase by measuring the levels of cGMP in segments of the pulmonary artery. Cyclic GMP levels were 1.4+/-0.2 (normoxia), 2.5+/-0.3 (hypoxia) and 3.3+/-0.5 pmole/mg tissue (hypoxia plus 8% CO); sodium nitroprusside increased normoxic cGMP levels about fourfold. Methylene blue reduced cGMP levels to less than 10% in all cases, and abolished the differences among normoxic, hypoxic and hypoxic plus CO groups. It is concluded that CO inhibits HPV by a NO-cGMP independent mechanism and it is proposed that a haemoprotein could be involved in O2-sensing in PSMC.
authors.affiliation: Intensive Care Unit, University Hospital of Valladolid, 47005 Valladolid, Spain.
authors.forename: L
authors.initials: L
authors.lastname: Tamayo
authors.forename: J R
authors.initials: JR
authors.lastname: López-López
authors.forename: J
authors.initials: J
authors.lastname: Castañeda
authors.forename: C
authors.initials: C
authors.lastname: González
mesh_terms: D000818:Animals; D002248:Carbon Monoxide / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D000860:Hypoxia / Q000503:physiopathology*; D066298:In Vitro Techniques; D008751:Methylene Blue / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D011651:Pulmonary Artery / Q000378:metabolism; D011652:Pulmonary Circulation / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology*
chemical_list: D004791:Enzyme Inhibitors; D019335:Nitroarginine; D002248:Carbon Monoxide; D019001:Nitric Oxide Synthase; D006162:Guanylate Cyclase; D006152:Cyclic GMP; D008751:Methylene Blue