on November 29, 2004
Published online before print November 29, 2004, doi: 10.1161/01.STR.0000150489.47080.67
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Submitted on September 23, 2004
From the Departments of Anesthesiology and Molecular Pharmacology and Experimental Therapeutics (J.S., A.V.R.S., L.A.S., M.A., Z.S.K.), Mayo Clinic, Rochester, Minn; and Department of Pharmacology and Molecular Cardiobiology Program (W.C.S.), Yale University School of Medicine, New Haven, Conn. * To whom correspondence should be addressed. E-mail: katusic.zvonimir{at}mayo.edu.
Background and Purpose--Mutation of serine 1179 to aspartate on the endothelial NO synthase (eNOS) increases NO production in the absence of stimulation by agonists. The present study was designed to determine the effect of recombinant S1179DeNOS gene expression on the vasomotor function of human pial arteries. Methods--Pial arteries were isolated from 28 patients undergoing temporal lobectomy for intractable seizures. Adenoviral vectors (1010 pfu/mL) encoding Results--Contractions to cumulative additions of U46619 were not affected by expression of LacZ or S1179DeNOS. Endothelium-dependent relaxations to bradykinin or endothelium-independent relaxations to Diethylaminodiazen-1-ium-1,2-dioate were significantly reduced in arteries expressing S1179DeNOS. A superoxide dismutase mimetic, manganese (III) tetrakis (4-benzoic acid) porphyrin chloride, failed to improve the reduced relaxations to bradykinin. The levels of cGMP were significantly elevated in arteries expressing S1179DeNOS. Conclusions--Our results support the concept that high local production of NO in pial arterial wall causes adaptive reduction of vasodilator reactivity to NO.
Revised on October 15, 2004
Accepted on October 20, 2004
Expression and Function of Recombinant S1179D Endothelial NO Synthase in Human Pial Arteries
Joseph Sorenson BS;
-galactosidase (AdCMVLacZ) or S1179DeNOS (AdCMVS1179DeNOS) were used for ex vivo gene transfer, and vasomotor function was evaluated in control and transduced arteries.
Key words: free radicals • gene therapy • nitric oxide
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