[Nitric oxide and hemoglobin].
Nitric oxide (NO) is produced by nitric oxide synthases (cNOS and iNOS) in endothelial cells upon stimulation by various agents like Ca(2+)-calmodulin, cytokines and TNF. It acts as a paracrine on adjacent cells to activate soluble guanylyl cyclase in the production of cGMP, a second messenger in signal transduction cascades, leading to various cellular responses. The circulating blood contains certain steady-state concentrations of NO in the plasma in order to maintain normal vascular tone and other appropriate conditions for the systemic and pulmonary circulation. This homeostasis of NO in the rapidly moving blood must be maintained by a delicate balance between its production by NOSs and its instant scavenging by hemoglobin (Hb) in the erythrocytes. Under physiological conditions ([NO] <<< [Hb]), NO is sequestered by deoxy Hb to form alpha-nitrosyl Hb, alpha (Fe-NO)2 beta (Fe)2, where NO is tightly (KD = 10(-12) M) bound to the alpha-subunits. Upon binding NO to the alpha-subunbits, Hb shifts its conformation to a T-(low-affinity extreme) state and its beta-subunits become an efficient O2 carrier. The same molecular mechanism of NO-induced conformation change operates in both Hb and soluble guanylyl cyclase. This is caused by the NO-induced trans-axial cleavage of the heme Fe-proximal His bonds in these hemoproteins. This bond cleavage mechanism allows Hb to survive as an effective O2 carrier even after sequestration of NO. The NO sequestered in Hb is eventually oxidized aerobically to NO3- in the reaction of Fe-NO + O2-->Fe(+) + NO3. Met Hb (Fe+) so formed is cycled back to deoxy Hb (Fe) by intra-erythrocyte Hb reductase to complete the NO scavenging. Thus, the NO in the blood acts on soluble guanylyl cyclase in vascular smooth muscles to dilate the blood vessels to increase blood delivery, whereas excess NO in the blood, which is sequestered by Hb, could help Hb to deliver O2 more efficiently in peripheral tissues.
Yonetani
T
T
Department of Biochemistry & Biophysics, University of Pennsylvania Medical Center, Philadelphia 19104-6089, USA.
D000818:Animals; D006454:Hemoglobins / Q000502:physiology*; D009569:Nitric Oxide / Q000502:physiology*
D006454:Hemoglobins; C008657:nitrosyl hemoglobin; D009569:Nitric Oxide