CARBON-MONOXIDE INHIBITS HYPOXIC PULMONARY VASOCONSTRICTION IN RATS BY A CGMP-INDEPENDENT MECHANISM

Hypoxia activates erythropoietin-producing cells, chemoreceptor cells of the carotid body and pulmonary artery smooth muscle cells (PSMC) wi th 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 t o 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 measure d in an in situ, blood-perfused lung preparation. PAP in normoxia (20% O-2, 5% CO2) was 15.2+/-1.8 mmHg, and hypoxia (2% O-2, 5% CO2) produc ed a Delta PAP of 6.3+/-0.4 mmHg. Addition of 8% or 15% CO to the hypo xic gas mixture reduced the Delta PAP by 88.3+/-2.7% and 78.2+/-6.1% r espectively. The same levels of CO did not affect normoxic PAP nor red uced the Delta PAP produced by angiotensin II. The effect of CO was st udied 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 hyp oxic Delta PAP 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 a rtery. 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 nitroprus side increased normoxic cGMP levels about fourfold. Methylene blue red uced cGMP levels to less than 10% in all cases, and abolished the diff erences among normoxic, hypoxic and hypoxic plus CO groups. It is conc luded that CO inhibits HPV by a NO-cGMP independent mechanism and it i s proposed that a haemoprotein could be involved in O-2-sensing in PSM C.