Impaired nitric oxide-mediated vasodilation in transgenic sickle mouse

Transgenic sickle mice expressing human beta(S)- and beta(S-Antilles)-globi ns show intravascular sickling, red blood cell adhesion, and attenuated art eriolar constriction in response to oxygen. We hypothesize that these abnor malities and the likely endothelial damage, also reported in sickle cell an emia, alter nitric oxide (NO)-mediated microvascular responses and hemodyna mics in this mouse model. Transgenic mice showed a lower mean arterial pres sure (MAP) compared with control groups (90 +/- 7 vs. 113 +/- 8 mmHg, P < 0 .00001), accompanied by increased endothelial nitric oxide synthase (eNOS) expression. N-G-nitro-L-arginine methyl ester (L-NAME), a nonselective inhi bitor of NOS, caused an similar to 30% increase in MAP and similar to 40% d ecrease in the diameters of cremaster muscle arterioles (branching orders: A2 and A3) in both control and transgenic mice, confirming NOS activity; th ese changes were reversible after L-arginine administration. Aminoguanidine , an inhibitor of inducible NOS, had no effect. Transgenic mice showed a de creased (P, 0.02-0.01) arteriolar dilation in response to NO-mediated vasod ilators, i.e., ACh and sodium nitroprusside (SNP). Indomethacin did not alt er the responses to ACh and SNP. Forskolin, a cAMP-activating agent, caused a comparable dilation of A2 and A3 vessels (similar to 44 and 70%) in both groups of mice. Thus in transgenic mice, an increased eNOS/NO activity res ults in lower blood pressure and diminished arteriolar responses to NO-medi ated vasodilators. Although the increased NOS/NO activity may compensate fo r flow abnormalities, it may also cause pathophysiological alterations in v ascular tone.