Use of carbon monoxide in minimizing ischemia/reperfusion injury in transplantation.
Carbon monoxide (CO) has been proposed to attenuate the vasoconstrictor response to local hypoxia that contributes to pulmonary hypertension. However, the segmental response to CO, as well as its mechanism of action in the pulmonary circulation, has not been fully defined. To investigate the hemodynamic response to exogenous CO, lungs from male Sprague-Dawley rats were perfused with physiological saline solution. Measurements were made of pulmonary arterial, venous, and capillary pressures. Lungs were constricted with the thromboxane mimetic U-46619. To examine the vasodilatory response to CO, 500 microl of CO-equilibrated physiological saline solution or vehicle were injected 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 microM) or the larger conductance calcium-activated K(+) (BK(Ca)) channel blockers tetraethylammonium chloride (10 mM) and iberiotoxin (100 nM). CO administration decreased vascular resistance to a similar degree in both vascular segments. This vasodilatory response was completely abolished in lungs pretreated with ODQ. Furthermore, CO administration increased whole lung cGMP content, which was prevented by ODQ. Neither tetraethylammonium chloride nor iberiotoxin affected the CO response. We conclude that exogenous CO administration causes vasodilation in the pulmonary vasculature via a soluble guanylyl cyclase-dependent mechanism that does not likely involve activation of K(Ca) channels.