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Am J Physiol Heart Circ Physiol 278: H1799-H1806, 2000;
0363-6135/00 $5.00
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Vol. 278, Issue 6, H1799-H1806, June 2000

Impaired nitric oxide-mediated vasodilation in transgenic sickle mouse

Dhananjaya K. Kaul, Xiao-Du Liu, Mary E. Fabry, and Ronald L. Nagel

Department of Medicine, Division of Hematology, Albert Einstein College of Medicine, Bronx, New York 10461

Transgenic sickle mice expressing human beta S- and beta S-Antilles-globins show intravascular sickling, red blood cell adhesion, and attenuated arteriolar constriction in response to oxygen. We hypothesize that these abnormalities and the likely endothelial damage, also reported in sickle cell anemia, alter nitric oxide (NO)-mediated microvascular responses and hemodynamics in this mouse model. Transgenic mice showed a lower mean arterial pressure (MAP) compared with control groups (90 ± 7 vs. 113 ± 8 mmHg, P < 0.00001), accompanied by increased endothelial nitric oxide synthase (eNOS) expression. NG-nitro-L-arginine methyl ester (L-NAME), a nonselective inhibitor of NOS, caused an ~30% increase in MAP and ~40% decrease in the diameters of cremaster muscle arterioles (branching orders: A2 and A3) in both control and transgenic mice, confirming NOS activity; these changes were reversible after L-arginine administration. Aminoguanidine, an inhibitor of inducible NOS, had no effect. Transgenic mice showed a decreased (P < 0.02-0.01) arteriolar dilation in response to NO-mediated vasodilators, i.e., ACh and sodium nitroprusside (SNP). Indomethacin did not alter the responses to ACh and SNP. Forskolin, a cAMP-activating agent, caused a comparable dilation of A2 and A3 vessels (~44 and 70%) in both groups of mice. Thus in transgenic mice, an increased eNOS/NO activity results in lower blood pressure and diminished arteriolar responses to NO-mediated vasodilators. Although the increased NOS/NO activity may compensate for flow abnormalities, it may also cause pathophysiological alterations in vascular tone.

mean arterial pressure; microcirculation; sickle cell anemia; vascular tone


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