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1 Nephrology and 2 Gastroenterology Research Units and 3 Department of Anesthesiology, Mayo Clinic/Foundation, Rochester 55905; and 4 Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455
We investigated a transgenic
mouse model of sickle cell disease, homozygous for deletion of mouse
-globin and containing transgenes for human S
and S-antilles globins linked to the transgene for
human 
-globin. In these mice, basal cGMP production in aortic rings
is increased, whereas relaxation to an endothelium-dependent
vasodilator, A-23187, is impaired. In contrast, aortic expression of
endothelial nitric oxide synthase (NOS) is unaltered in sickle mice,
whereas expression of inducible NOS is not detected in either group;
plasma nitrate/nitrite concentrations and NOS activity are similar in
both groups. Increased cGMP may reflect the stimulatory effect of
peroxides (an activator of guanylate cyclase), because lipid
peroxidation is increased in aortae and in plasma in sickle mice.
Despite increased vascular cGMP levels in sickle mice, conscious
systolic blood pressure is comparable to that of aged-matched controls;
sickle mice, however, evince a greater rise in systolic blood pressure
in response to nitro-L-arginine methyl ester, an inhibitor
of NOS. Systemic concentrations of the vasoconstrictive oxidative
product 8-isoprostane are increased in sickle mice. We conclude that
vascular responses are altered in this transgenic sickle mouse and are
accompanied by increased lipid peroxidation and production of cGMP; we
suggest that oxidant-inducible vasoconstrictor systems such as
isoprostanes may oppose nitric oxide-dependent and nitric
oxide-independent mechanisms of vasodilatation in this transgenic
sickle mouse. Destabilization of the vasoactive balance in the sickle
vasculature by clinically relevant states may predispose to
vasoocclusive disease.
cellular redox; vasculature; peroxide; cyclic guanosine 5'-monophosphate
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