Bronchodilatation in vivo by carbon monoxide, a cyclic GMP related messenger.
1. Recent studies suggest that gaseous carbon monoxide (CO) is involved in neurotransmission and that this molecule also is an important vasodilator in vivo. In the present study we evaluated the effect of inhaled CO on guinea-pig airway smooth muscle tone. The mechanisms involved were characterized by use of a cyclic GMP antagonist, Rp-8Br-cyclic GMPS, and a nitric oxide synthase inhibitor, L-NAME. 2. Anaesthetized, ventilated guinea-pigs were given a bolus injection of histamine (0.12 mg kg(-1), i.v.), followed by a continuous infusion of histamine (0.30 microg kg(-1) min(-1)) to increase total pulmonary resistance (RL). Subsequent exposure to 7, 15 or 30 breaths of CO (100%), resulted in a dose-dependent inhibition of the bronchoconstriction. In the highest dose tested (30 breaths), CO inhibited 80% of the histamine-induced increase in RL. 3. In separate experiments, animals receiving histamine infusions followed by 30 breaths of CO, were pretreated with Rp-8Br-cyclic GMPS (0.05 mg kg(-1)). This pretreatment abolished >60% of the CO-induced reduction in RL, but it had no effect on the bronchodilator response induced by salbutamol. In another set of experiments animals were pretreated with L-NAME (1.60 mg kg(-1)). In contrast to the Rp-8Br-cyclic GMPS pretreatment, the pretreatment with L-NAME did not affect the CO-induced reduction in RL. 4. The present findings indicate that CO causes bronchodilatation in vivo via cyclic GMP.
Cardell
L O
LO
Cardiovascular Research Institute, University of California San Francisco, 94143-0130, USA.
Ueki
I F
IF
Stjärne
P
P
Agusti
C
C
Takeyama
K
K
Lindén
A
A
Nadel
J A
JA
D000818:Animals; D001993:Bronchodilator Agents / Q000494:pharmacology*; D002248:Carbon Monoxide / Q000097:blood / Q000494:pharmacology*; D006152:Cyclic GMP / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D010100:Oxygen / Q000097:blood; D015290:Second Messenger Systems
D001993:Bronchodilator Agents; D004791:Enzyme Inhibitors; D002248:Carbon Monoxide; D006632:Histamine; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP; D010100:Oxygen; D019331:NG-Nitroarginine Methyl Ester