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(12) United States Patent (10) Patent N0.: US 6,310,270 B1 Huang Et Al

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(12) United States Patent (10) Patent N0.: US 6,310,270 B1 Huang Et Al US006310270B1 (12) United States Patent (10) Patent N0.: US 6,310,270 B1 Huang et al. (45) Date of Patent: Oct. 30, 2001 (54) ENDOTHELIAL NOS KNOCKOUT MICE Benrath, J. et al., “Substance P and nitric oxide mediate AND METHODS OF USE Wound healing of ultraviolet photodamaged rat skin: evi dence for an effect of nitric oxide on keratinocyte prolifera (75) Inventors: Paul L. Huang, Boston; Mark C. tion,” Nerosci. Letts. 200.'17—20 (Nov. 1995). Fishman, Newton Center; Michael A. Boeckxstaens, G.E. et al., “Evidence for nitric oxide as Moskowitz, Belmont, all of MA (US) mediator of non—adrenergic, non—cholinergic relaxations induced by ATP and GABA in the canine gut,” Br J. (73) Assignee: The General Hospital Corporation, Pharmacol. 102:434—438 (1991). Boston, MA (US) Bohme, G.A. et al., “Possible involvement of nitric oxide in ( * ) Notice: Subject to any disclaimer, the term of this long—term potentiation,” Eur J. Pharmacol. 199:379—381 patent is extended or adjusted under 35 (1991). U.S.C. 154(b) by 0 days. Booth, R.F.G. et al., “Rapid development of atherosclerotic lesions in the rabbit carotid artery induced by perivascular (21) Appl. No.: 08/818,082 manipulation,” Atherosclerosis 76.'257—268 (1989). Bredt, D.S. et al., “Localization of nitric oxide synthase (22) Filed: Mar. 14, 1997 indicating a neural role for nitric oxide,” Nature Related US. Application Data 347:768—770. (60) Provisional application No. 60/027,362, ?led on Sep. 18, Bredt, D.S. and Snyder, S.H., “Isolation of nitric oxide 1996, and provisional application No. 60/013,525, ?led on synthetase, a calmodulin—requiring enzyme,” Proc. Natl. Mar. 15, 1996. Acad. Sci. USA 87:682—685 (1990). Bredt, D.S. and Snyder, S.H., “Nitric Oxide, a Novel Neu (51) Int. Cl? ...................... .. A01K 67/00; A01K 67/033; ronal Messenger,” Neuron 8.'3—11 (1992). 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Archer, S., “Measurement of nitric oxide in biological (57) ABSTRACT models,” FASEB J. 7:349—360 (1993). Babbedge, R.C. et al., “Inhibition of rat cerebellar nitric This invention relates to transgenic non-human animals oxide synthase by 7—nitro indaZole and related substituted comprising a disrupted endothelial nitric oxide synthase indaZoles,” Br J. Pharmacol. 110:225—228 (1993). gene. These animals exhibit abnormal Wound-healing prop Bath, P.M.W., “The effect of nitric oxide—donating vasodi erties and hypertension. This invention also relates to meth lators on monocyte chemotaxis and intracellular cGMP ods of using the transgenic animals to screen for compounds concentrations in vitro,” Eur. J. Clin. Pharmacol. 45.'53—58 having a potential therapeutic utility for vascular endothelial (1993). disorders, such as hypertension, cerebral ischemia or stroke, Beckman, J.S. et al., “Oxidative Chemistry of Peroxyni atherosclerosis and Wound-healing activities. Moreover, this trite,” Meth. Enzymol. 233.'229—240 (1994). invention also relates to methods of treating a patient Beckman, J.S. et al., “Extensive Nitration of Protein suffering from hypertension and Wound-healing abnormali Tyrosines in Human Atherosclerosis Detected by Immuno ties With the compounds identi?ed using the transgenic histochemistry,” Biol. Chem. Hoppe—Seyler 375:81—88 animals, and methods of making the transgenic animals. A (1994). method of treating a Wound using nitroglycerin is also Benditt, ER and Benditt, J .M., “Evidence for a Monoclonal provided. Origin of Human Atherosclerotic Plaques,” Proc. Natl. Acad. Sci. USA 70(®:1753—1756 (1973). 29 Claims, 24 Drawing Sheets US 6,310,270 B1 Page 2 OTHER PUBLICATIONS Hamberg, L.M. et al., “Time Effects of L—Arginine on Cerebral Hemodynamics and Ischemic Volume During Curran, R.D. et al., “Hepatocytes Produce Nitrogen Oxides Acute Focal Ischemia Demonstrated by Dynamic MRI,” from L—Arginine in Response to In?ammatory Products of Proc. Soc. Mag. Res. 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