Nitrosyl-cobinamide, a new and direct nitric oxide releasing drug effective in vivo.
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.
Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0652, USA.
Kate E
KE
Broderick
Luis
L
Alvarez
Mahesh
M
Balasubramanian
Darrell D
DD
Belke
Ayako
A
Makino
Adriano
A
Chan
Virgil L
VL
Woods
Wolfgang H
WH
Dillmann
Vijay S
VS
Sharma
Renate B
RB
Pilz
Timothy D
TD
Bigby
Gerry R
GR
Boss
D000787:Angina Pectoris / Q000188:drug therapy / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D003038:Cobamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects; D004331:Drosophila melanogaster; D004353:Drug Evaluation, Preclinical; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism; D008317:Malpighian Tubules / Q000378:metabolism; D051379:Mice; D009126:Muscle Relaxation / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009603:Nitroso Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D009924:Organ Culture Techniques; D051381:Rats; D014665:Vasodilator Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D003038:Cobamides; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; D014665:Vasodilator Agents; C017142:cobinamide; D009569:Nitric Oxide