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Articles in PresS, published online ahead of print August 22, 2002
Am J Physiol Heart Circ Physiol, 10.1152/ajpheart.00415.2002
Submitted on May 28, 2002
Accepted on August 19, 2002
1 Departments of Anesthesiology and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
2 Gene Vec, Inc., Gaithersburg, MD, USA
3 Department of Medicine, Clinical Sciences Institute, University College Hospital, Galway, Ireland
* To whom correspondence should be addressed. E-mail: katusic.zvonimir{at}mayo.edu.
The present study was designed to determine the effect of recombinant inducible nitric oxide synthase (iNOS) gene expression on vasomotor function in cerebral arteries. Isolated canine basilar arteries were exposed ex vivo (30 min at 37°C) to an adenoviral vector (107, 108, 109 PFU/ml) encoding either the iNOS gene or the ß-galactosidase reporter gene. Twenty-four hours after transduction, western blot analysis demonstrated expression of iNOS protein only in iNOS (109 PFU/ml) transduced arteries. Immunohistochemical analysis localized iNOS expression predominantly in adventitia. Vascular reactivity of isolated basilar arteries was studied by isometric force recording. Concentration-response curves to uridine 5-triphosphate (UTP) (10-9 to 10-3 M) and DEA-NONOate (10-10 to 10-5 M) were significantly shifted to the right in iNOS gene (109 PFU/ml) transduced rings compared with control and ß-galactosidase transduced rings (P < 0.05, n = 5 - 6). Endothelium-dependent relaxation to bradykinin was significantly attenuated in iNOS transduced rings (P < 0.001, n = 8). The basal level of guanosine 3',5'-cyclic monophosphate (cGMP) and superoxide anion (O2.-) production were elevated in iNOS transduced rings (P < 0.05, n = 7 for cGMP, P < 0.01, n = 6 - 9 for O2.- production). Our results suggest that expression of recombinant iNOS in cerebral arteries reduce vasomotor reactivity to both vasoconstrictor and vasodilator agonists. Attenuation of contractions is most likely due to functional antagonism between UTP and cGMP. Reduction of endothelium-dependent relaxation to bradykinin appears to be mediated in part by reduced reactivity of smooth muscle cells to nitric oxide.
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