Homogeneous segmental profile of carbon monoxide-mediated pulmonary vasodilation in rats

Carbon monoxide (CO) has been proposed to attenuate the vasoconstrictor res ponse to local hypoxia that contributes to pulmonary hypertension. However, the segmental response to CO, as well as its mechanism of action in the pu lmonary circulation, has not been fully defined. To investigate the hemodyn amic response to exogenous CO, lungs from male Sprague-Dawley rats were per fused with physiological saline solution. Measurements were made of pulmona ry arterial, venous, and capillary pressures. Lungs were constricted with t he thromboxane mimetic U-46619. To examine the vasodilatory response to CO, 500 mul of CO-equilibrated physiological saline solution or vehicle were i njected into the arterial line. Additionally, CO and vehicle responses were examined in the presence of the soluble guanylyl cyclase inhibitor 1H-[1,2 ,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 10 muM) or the larger conductanc e calcium-activated K+ (BKCa) channel blockers tetraethylammonium chloride (10 mM) and iberiotoxin (100 nM). CO administration decreased vascular resi stance to a similar degree in both vascular segments. This vasodilatory res ponse was completely abolished in lungs pretreated with ODQ. Furthermore, C O administration increased whole lung cGMP content, which was prevented by ODQ. Neither tetraethylammonium chloride nor iberiotoxin affected the CO re sponse. We conclude that exogenous CO administration causes vasodilation in the pulmonary vasculature via a soluble guanylyl cyclase-dependent mechani sm that does not likely involve activation of K-Ca channels.