Nitrosyl-cobinamide, a new and direct nitric oxide-releasing drug effective in vivo

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

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1432-1440
Number of pages9
JournalExperimental Biology and Medicine
Volume232
Issue number11
DOIs
StatePublished - Dec 1 2007
Externally publishedYes

Keywords

  • Hypertension
  • Nitric oxide
  • Nitrosyl-cobinamide

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'Nitrosyl-cobinamide, a new and direct nitric oxide-releasing drug effective in vivo'. Together they form a unique fingerprint.

  • Cite this

    Broderick, K. E., Alvarez, L., Balasubramanian, M., Belke, D. D., Makino, A., Chan, A., Woods, V. L., Dillmann, W. H., Sharma, V. S., Pilz, R. B., Bigby, T. D., & Boss, G. R. (2007). Nitrosyl-cobinamide, a new and direct nitric oxide-releasing drug effective in vivo. Experimental Biology and Medicine, 232(11), 1432-1440. https://doi.org/10.3181/0703-RM-70