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ORIGINAL RESEARCH ARTICLE

Nitrosyl-Cobinamide, a New and Direct Nitric Oxide–Releasing Drug Effective In Vivo

Kate E. Broderick^*,1, Luis Alvarez^*,1, Mahesh Balasubramanian^*, Darrell D. Belke^*, Ayako Makino^*, Adriano Chan^*, Virgil L. Woods, Jr.^*, Wolfgang H. Dillmann^*, Vijay S. Sharma^*, Renate B. Pilz^*, Timothy D. Bigby and Gerry R. Boss^*,2

^* Department of Medicine, University of California, San Diego, La Jolla, California 92093; and VA San Diego Health Care System, La Jolla, California 92161

To whom requests for reprints should be addressed at ² Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0652. E-mail: gboss{at}ucsd.edu

A limited number of nitric oxide (NO)-generating drugs are available for clinical use for acute and chronic conditions. Most of these agents are organic nitrates, which do not directly release NO; tolerance to the drugs develops, in part, as a consequence of their conversion to NO. We synthesized nitrosyl-cobinamide (NO-Cbi) from cobinamide, a structural analog of cobalamin (vitamin B₁₂). NO-Cbi is a direct NO-releasing agent that we found was stable in water, but under physiologic conditions, it released NO with a half-life of 30 mins to 1 h. We show in five different biological systems that NO-Cbi is an effective NO-releasing drug. First, in cultured rat vascular smooth muscle cells, NO-Cbi induced phosphorylation of vasodilator-stimulated phosphoprotein, a downstream target of cGMP and cGMP-dependent protein kinase. Second, in isolated Drosophila melanogaster Malpighian tubules, NO-Cbi–stimulated fluid secretion was similar to that stimulated by Deta-NONOate and a cGMP analog. Third, in isolated mouse hearts, NO-Cbi increased coronary flow much more potently than nitroglycerin. Fourth, in contracted mouse aortic rings, NO-Cbi induced relaxation, albeit to a lesser extent than sodium nitroprusside. Fifth, in intact mice, a single NO-Cbi injection rapidly reduced blood pressure, and blood pressure returned to normal after 45 mins; repeated NO-Cbi injections induced the expected fall in blood pressure. These studies indicate that NO-Cbi is a useful NO donor that can be used experimentally in the laboratory; moreover, it could be developed into a vasodilating drug for treating hypertension and potentially other diseases such as angina and congestive heart failure.

Key Words: nitric oxide • hypertension • nitrosyl-cobinamide